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Abstracts of the XXV World Congress of Psychiatric Genetics (WCPG): Poster Abstracts Saturday, October 14, 2017 Poster Session I 11:30 a.m. - 1:30 p.m. SA1. REPLICATION OF RS300774, A GENETIC BIOMAR- KER NEAR ACP1, ASSOCIATED WITH SUICIDE ATTEMPTS IN PATIENTS WITH SCHIZOPHRENIA AND SCHIZOAFFEC- TIVE DISORDER: RELATION TO BRAIN CHOLESTEROL BIOSYNTHESIS Herbert Meltzer n ,1 , Jiang Li 1 , Akane Yoshikawa 2 1 Northwestern University 2 The University of Tokyo Background: Genome-wide linkage or case-control stu- dies have identied genomic loci/regions associated with Suicidal Behavior (SB) in alcoholism, Bipolar Disorder (BD), and Major Depression (MDD). The most robust of these is for a SNP, rs300774, located at 2p25 anking Acid Phosphatase 1 (ACP1), which approached genome-wide signicance for association with SB, (p = 5.07E-8), based on combining two samples with European ancestry (Willour, V. L. et al., 2012). An independent candidate SNP study of SB as a quantitative trait found the same association (p = 0.0012) in BD + MDD patients with European ancestry (Pawlak et al., 2016). Further analyses showed that this signicant associa- tion was only signicant in males or BD patients but not in females or MDD patients. The aim of this study was to determine if rs300774 and two other replicated SNPs with combined p o 1E-5 from Willours Study, rs7296262, and rs10437629, were associated with SB in Schizophrenia (SCZ) or Schizoaffective Disorder (SAD). Methods: 162 genetically-veried Caucasian patients with SCZ or SAD were prospectively phenotyped for presence (45.7%) or absence (54.3%) of a lifetime suicide attempt. rs300774 was genotyped and two others were imputed from a GWAS dataset. cis or trans -eQTL analyses was based on scanDB (blood) and Braineac (Brain tissues). Co-expression analysis and differential gene expression analysis were conducted on the transcriptomic datasets derived from post-mortem brain tissue, including dorsolateral prefrontal cortex (DLPFC) (n = 269) from Braincloud, hypothalamus (n = 96) from GTEx. Genome-wide signicant co-expression was dened as unadjusted p o 2.5E-9, assuming a total of 20,000 genes in the parallel computing. The differential gene expression for the candidate genes were analyzed by ANCOVA (SPSS) with full factorial model, adjusted for age, gender, Post-Mortem Interval (PMI), and Brain PH available from two independent transcriptomic datasets, DLPFC (BA46) with enriched suicide completers in patients with SCZ or BD [GSE12649] or SCZ only [GSE21138] vs matched control subjects. Results: After controlling for genetic architecture and gender, rs300774 was signicantly associated with SB (p = 0.012), in males (p = 0.046) but not females (p = 0.21). rs7296262 and rs10437629 were not associated with SB in this study. rs300774 could be a cis-eQTL for ACP1, with minor allele carriers having lower expression levels (p = 0.002). rs300774 also functions as a trans-eQTL for several genes related to cholesterol biosynthesis and the wnt-β- catenin pathway (p 0.0001). Co-expression analysis of SB candidate genes in brain suggest ACP1 is important for regulation of a number of brain mechanisms linked to SB, including cholesterol biosynthesis, β-catenin-mediated sig- naling pathway, serotonin, GABA, and the stress response via ARHGAP35 (p190rhogap), a repressor of glucocorticoid receptor (NR3C1) transcription. However, no signicant differential gene expression in candidate genes coexpressed with ACP1 between suicide completers and controls was observed. Discussion: This study provides additional support for rs300774 as a transdiagnostic biomarker for SB and that ACP1 and cholesterol related substances may have an important role in the risk for suicide. Its utility as a biomarker for SB in additional psychiatric disorders and those who may not manifest psychiatric symptoms prior to SB require further study. Study of the potential use of rs300774 genotype as a clinical test for risk of SB would also be of interest. www.elsevier.com/locate/euroneuro 0924-977X European Neuropsychopharmacology (]]]]) ], ]]]]]]

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Page 1: Abstracts of the XXV World Congress of Psychiatric ... · Abstracts of the XXV World Congress of Psychiatric Genetics (WCPG): Poster Abstracts Saturday, October 14, 2017 Poster Session

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

0924-977X

www.elsevier.com/locate/euroneuro

Abstracts of the XXV World Congress of Psychiatric Genetics(WCPG): Poster Abstracts

Saturday, October 14, 2017

Poster Session I11:30 a.m. - 1:30 p.m.

SA1. REPLICATION OF RS300774, A GENETIC BIOMAR-KER NEAR ACP1, ASSOCIATED WITH SUICIDE ATTEMPTSIN PATIENTS WITH SCHIZOPHRENIA AND SCHIZOAFFEC-TIVE DISORDER: RELATION TO BRAIN CHOLESTEROLBIOSYNTHESIS

Herbert Meltzern,1, Jiang Li1, Akane Yoshikawa2

1Northwestern University2The University of Tokyo

Background: Genome-wide linkage or case-control stu-dies have identified genomic loci/regions associated withSuicidal Behavior (SB) in alcoholism, Bipolar Disorder (BD),and Major Depression (MDD). The most robust of these is fora SNP, rs300774, located at 2p25 flanking Acid Phosphatase 1(ACP1), which approached genome-wide significance forassociation with SB, (p = 5.07E-8), based on combiningtwo samples with European ancestry (Willour, V. L. et al.,2012). An independent candidate SNP study of SB as aquantitative trait found the same association (p = 0.0012) inBD + MDD patients with European ancestry (Pawlak et al.,2016). Further analyses showed that this significant associa-tion was only significant in males or BD patients but not infemales or MDD patients. The aim of this study was todetermine if rs300774 and two other replicated SNPs withcombined p o 1E-5 from Willour’s Study, rs7296262, andrs10437629, were associated with SB in Schizophrenia (SCZ)or Schizoaffective Disorder (SAD).Methods: 162 genetically-verified Caucasian patients withSCZ or SAD were prospectively phenotyped for presence(45.7%) or absence (54.3%) of a lifetime suicide attempt.rs300774 was genotyped and two others were imputed froma GWAS dataset. cis or trans -eQTL analyses was based onscanDB (blood) and Braineac (Brain tissues). Co-expression

analysis and differential gene expression analysis wereconducted on the transcriptomic datasets derived frompost-mortem brain tissue, including dorsolateral prefrontalcortex (DLPFC) (n = 269) from Braincloud, hypothalamus (n= 96) from GTEx. Genome-wide significant co-expressionwas defined as unadjusted p o 2.5E-9, assuming a total of20,000 genes in the parallel computing. The differentialgene expression for the candidate genes were analyzed byANCOVA (SPSS) with full factorial model, adjusted for age,gender, Post-Mortem Interval (PMI), and Brain PH availablefrom two independent transcriptomic datasets, DLPFC(BA46) with enriched suicide completers in patients withSCZ or BD [GSE12649] or SCZ only [GSE21138] vs matchedcontrol subjects.Results: After controlling for genetic architecture andgender, rs300774 was significantly associated with SB (p =0.012), in males (p = 0.046) but not females (p = 0.21).rs7296262 and rs10437629 were not associated with SB inthis study. rs300774 could be a cis-eQTL for ACP1, withminor allele carriers having lower expression levels (p =0.002). rs300774 also functions as a trans-eQTL for severalgenes related to cholesterol biosynthesis and the wnt-β-catenin pathway (p ≤ 0.0001). Co-expression analysis of SBcandidate genes in brain suggest ACP1 is important forregulation of a number of brain mechanisms linked to SB,including cholesterol biosynthesis, β-catenin-mediated sig-naling pathway, serotonin, GABA, and the stress responsevia ARHGAP35 (p190rhogap), a repressor of glucocorticoidreceptor (NR3C1) transcription. However, no significantdifferential gene expression in candidate genes coexpressedwith ACP1 between suicide completers and controls wasobserved.Discussion: This study provides additional support forrs300774 as a transdiagnostic biomarker for SB and thatACP1 and cholesterol related substances may have animportant role in the risk for suicide. Its utility as abiomarker for SB in additional psychiatric disorders andthose who may not manifest psychiatric symptoms prior toSB require further study. Study of the potential use ofrs300774 genotype as a clinical test for risk of SB would alsobe of interest.

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M. Barbu et al.2

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.073

SA2. GENE-SET ANALYSIS OF SEROTONERGIC SYNAPSEGENES IN ADULTHOOD ADHD

Alana Castro Panzenhagen2, Renata Basso Cupertino2,Bruna Santos2, Djenifer B. Kappel2, Jaqueline B. Schuch2,Diana Müller2, Cibele Edom Bandeira2, Diego Rovaris2,Stefania Pigatto Teche3, Carlos A.I. Salgado3, Nina RothMota4, Eugenio H. Grevet3, Claiton H.D. Bau2,Verônica Contini

n

1Postgraduate Program in Biotechnology, UNIVATES2Universidade Federal do Rio Grande do Sul3ADHD Outpatient Program, Adult Division, Hospital deClínicas de Porto Alegre4Radboud University Nijmegen Medical Centre

Background: Attention-Deficit Hyperactivity Disorder(ADHD) is highly heritable and has been associated withseveral genes in different reports. The serotonergic genesare among the most consistently associated with ADHD andrelated phenotypes, according to meta-analyses. Therefore,the aim of this study was to investigate associationsbetween serotonergic pathway genes and ADHD suscept-ibility and treatment, through gene-set approach. Thegene-set analysis increases statistical power, when com-pared to genome-wide association studies, making it abetter approach for samples limited in size. Therefore,the aim of this study was to investigate associationsbetween serotonergic pathway genes and ADHD suscept-ibility and treatment, through gene-set approach.Methods: The sample comprised 407 subjects with ADHDand 463 controls (negatively screened for ADHD). Individualswere diagnosed according to the DSM-IV criteria at the adultdivision of the ADHD Outpatient Clinic from Hospital deClínicas de Porto Alegre (ProDAH-A HCPA). All subjects wereunrelated Brazilian adults of European descent. For 189patients with ADHD, the treatment response to immediate-release methylphenidate (at least 30 days) was assessed.The outcome measure was the variation in ADHD severityscores according to SNAP-IV. Genome-wide genotypes wereassessed using the Psych Chip array or imputed based on thestandard Ricopili pipeline. The final data retained 5,842,763SNPs across the genome. The gene locations for build 37(hg19) were used for SNP annotation to genes. Gene-basedanalyses were performed in MAGMA, using the multi=allmodel, which has higher sensitivity to different geneticarchitecture variation. Serotonergic gene-set was selectedbased on the Kyoto Encyclopedia of Genes and Genomes(KEGG) serotonergic synapse pathway. The gene-set com-prised 103 genes, including serotonin transporter, receptorsand other related genes.Results: The competitive gene-set analysis for ADHDsusceptibility was not significant (P-value=0.11). Since theserotonergic system is widely associated with mood dis-orders, especially in women, the same analysis was

performed, including gender and mood disorder as covari-ates, revealing a P-value=0.28. Furthermore, the gene-setanalyses concerning treatment response revealed no sig-nificant result. Two analyses were performed, without anycovariates (P-value=0.24), and adjusting by other drugs useand total baseline SNAP score in the analysis (P-value=0.28).Discussion: These findings suggest that the gene-setinvestigated for the serotonergic system does not fulfillthe expectation of explaining more of the ADHD suscept-ibility and treatment response as compared with the wholegenome. However, it should be pointed out that even for thegene-set approach our sample size is limited, and the sameanalysis should be repeated in larger samples.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.074

SA3. REDUCED CORTICAL THICKNESS IN CHILDRENWITH ADHD: ROLE OF NET16 AND MATERNAL SMOKINGDURING PREGNANCY

Nellie Fotopoulosn,1, Gabriel Devenyi1,

Mallar M. Chakravarty2, Sherif Karama3, Natalie Grizenko4,Ridha Joober4

1Douglas Mental Health University Institute2Cerebral Imaging Centre, Douglas Mental Health UniversityInstitute, McGill University3McGill University, Montreal Neurological Institute4Douglas Mental Health University Institute,McGill University

Background: ADHD is the most common childhood-onsetpsychiatric disorder, affecting 5% of children. Costing over7 bn $CAD annually, ADHD has broad negative impacts on theindividual and society. Psychostimulants are effective inmanaging symptoms and implicate the catecholamine sys-tems. ADHD is heterogeneous and arises by complex inter-play of genetic and environmental factors. Despite the highheritability of ADHD (76%), causal genes have yet to bedetermined. A linkage study by our team uncovered amodest over transmittance of NET16 (rs36021) in ADHDchildren. Interestingly, upon stratification according tomaternal smoking during pregnancy (MSDP), this resultbecame highly significant in exposed children. Our findingsindicate that MSDP plays a role in the etiology of ADHD,possibly through interaction with NET16. To shed light onthe pathophysiology of ADHD, we used MRI to explore theimpact of this interaction on cortical structures in childrenwith ADHD.Methods: We began by modelling the effects of (1) MSDP,(2) NET16, and (3) both MSDP and NET16 on the cortex.Subjects (n=143; 6–12 years) were recruited from an on-going clinical trial at the ADHD clinic. Genetic, epigenetic,environmental, cognitive, clinical and structural data werecollected. Subjects were scanned on a 3 T Siemens MRI for18 minutes to obtain T1/T2-weighted images. To address

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3PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

motion biases and minimize procedural failures, childrenrehearsed on a mock scanner and only scans that passedquality control were used in the analysis (n=111). CIVET-1.1.12 and RMINC were used to acquire cortical measure-ments and perform linear modelling. We included age, sex,medication, NET16 genotype group and MSDP as predictors,and cortical measurements as main outcome measures.Results: (1) Our first model found no significant differ-ences in cortical thickness among ADHD children exposedand not exposed to MSDP. (2) Our second model showed amoderate effect of NET16 genotype group on corticalthickness. Children belonging to the homozygous groups(AA, TT) had significant reductions in cortical thickness inthe medial/inferior prefrontal cortex and the left inferiortemporal lobe (t=2.46; 10% FDR) vs. children in theheterozygote group (AT). These regions have been pre-viously associated with ADHD, where the PFC plays a rolein executive functioning and the temporal lobes workalongside the amygdala to enable learning, memory andemotional responses. (3) Importantly, our third modelcombining MSDP and NET16 showed an even larger decreasein cortical thickness in the same regions (t=3.91; 5% FDR).Secondary analyses revealed that ADHD children with homo-zygous genotypes (AA, TT) exposed to MSDP were signifi-cantly more severe in a specific set of externalizingsymptoms.Discussion: We are aiming to provide a biological linkbetween ADHD risk factors (NET16 and MSDP), corticalthickness and behavioural/clinical outcomes. Such findingscan provide insight into the pathophysiology of ADHD, as wellas play a role in the transcendent process of understandingthe human brain. In accordance with the literature and ourprevious findings, our current results hint towards an associa-tion between decreased cortical thickness in the PFC andtemporal lobes and increased ADHD symptom severity.Furthermore, it has been suggested that children exposedto MSDP have a distinct ADHD phenotype and respond well tocertain treatments. Therefore, our findings can help diminishclinical heterogeneity by enabling clinicians to subgroupADHD patients with regards to MSDP exposure.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.075

SA4. CONVERGENT FUNCTIONAL GENOMICS APPROACHTO IDENTIFY GENES INVOLVED IN ATTENTION DEFICIT/HYPERACTIVITY DISORDER

Paula Roviran,1, María Soler Artigas2,

Iris Garcia-Martínez3, Cristina Sánchez-Mora3,Mireia Pagerols3, Eva Calvo-Sánchez3, Niall Mortimer3,Montse Corrales4, Vanesa Richarte4, Bru Cormand5,Miguel Casas4, Josep Antoni Ramos-Quiroga6, Marta Ribasés3

1Psychiatric Genetics Unit, Vall d’Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona, Mental HealthHospital Universitari Vall d’Hebron

2Psychiatric Genetics Unit, Vall d'Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona, CIBERSAM3Psychiatric Genetics Unit, Vall d'Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona4Hospital Universitari Vall d’Hebron5University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER),Instituto de Salud Carlos III, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat6Hospital Universitari Vall d’Hebron, Centro de Investiga-ción Biomédica en Red de Salud Mental (CIBERSAM),Instituto de Salud Carlos III, Psychiatric Genetics Unit,Group of Psychiatry, Mental Health and Addiction, Valld’Hebron Research Institute (VHIR), Universitat Autònomade Barcelona, Universitat Autònoma de Barcelona

Background: The PGC + iPSYCH GWAS meta-analysis hasled to the discovery of DNA variants associated with ADHD,but most of the heritability of this polygenic disorder is stillmissing. One of the main challenges is going from trait-associated variants to plausible causal genes and biologicalmechanisms. We propose an alternative approach to iden-tify genes potentially involved in ADHD, focusing our atten-tion on differentially expressed genes in Peripheral BloodMononuclear Cell (PBMCs) of subjects with ADHD andcontrols to identify sequence variants that could explainthese expression differences and to further test theircontribution to ADHD.Methods: We isolated PBMCs from whole blood of ADHDpatients and controls using the Ficoll density gradientmethod and total RNA was subsequently extracted. Genometranscriptome profiling was performed using the AffymetrixHuman Gene 1.1 ST Array and genotyping was assessed withIllumina Human Omni1-Quad and Human Omni 2.5-QuadBeadchip platforms. Imputation was run with the Ricopilipipeline (https://sites.google.com/a/broadinstitute.org/ricopili/) using the European population of the 1000 Gen-omes project as the reference panel. For differentialexpression P-values, Benjamini–Hochberg multiple-compar-ison correction was applied. We evaluated whether expres-sion quantitative trait loci (eQTL) analysis on genesdifferentially expressed in PBMCs of ADHD patients couldprovide additional biological evidence by conducting func-tional and pathway enrichment analyses with the IPA soft-ware (http://www.ingenuity.com). Top hits from eQTLresults were considered to construct polygenic risk scoreswith the PRSice software (http://prsice.info/) using subsetsof the total SNPs based on different P-value thresholds.Results: The genome-wide expression profiling in PBMCsof 32 adult medication-naive ADHD subjects and 57 controlsusing the Human Gene 1.1 Affymetrix array highlighted atotal of 2,527 differentially expressed genes, 888 of whichwere up-regulated and 1639 were down-regulated in ADHDpatients as compared to controls (Po0.05), and 53 of themremained significant after correcting for multiple compar-isons. This gene set was enriched for 52 canonical pathways,including “Synaptic Long Term Depression”, “GlutamateReceptor Signaling”, “Axonal Guidance Signaling” and“Synaptic Long Term Potentiation”, among others. We

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M. Barbu et al.4

focused on this set of differentially expressed genes tosearch for cis-eQTLs in 28 ADHD subjects. The eQTL analysisshowed a total of 1,174 SNP-gene pairs arising from 663SNPs and 660 genes (Po0.05; Figure 1), which weresubsequently considered to generate polygenic risk scoresto predict ADHD using the PGC+ iPSYCH meta-analysis data.The polygenic score significantly predicted ADHD at theP-value threshold of 5e-05 and highlighted the Syntaxin 8(STX8) gene as a strong candidate to be involved in ADHD.Discussion: eQTL analysis focused on genes differentiallyexpressed in PBMCs of ADHD provides preliminary evidencesupporting a role for the STX8 gene, which is involved in theregulation of protein trafficking via vesicle fusion andexocytosis, in the etiology of the disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.076

SA5. GAENETICS OF WORKING MEMORY AND VIGILANCEEDOPHENOTYPES IN ADHD

Beth Wilmotn

, Priya Bhatt, Peter Ryabinin,Hanna Gustafsson, Michael Mooney, Sarah Karalunas,Joel Nigg

Oregon Health & Science University

Background: Joint genetic analysis of correlated endo-phenotypes markedly enhances insight into the relationshipsamong them and the shared and distinct genetic influenceson phenotypically related complex traits. In addition,identifying pleiotropic effects among endophenotypes canhelp improve our biological understanding of the geneticarchitecture of a complex disease, namely childhood Atten-tion Deficit Hyperactivity Disorder (ADHD). Cognitive func-tions, in particular aspects of executive functioning, havelong been proposed as endophenotypes for ADHD, in somecases with distinct components of ADHD emphasized (hyper-activity and inattention-disorganization). This study identi-fies and characterizes the individual and shared geneticvariants associated with two major cognitive endopheno-types—Working Memory (WM) and arousal — in relation toboth ADHD sub-dimensions.Methods: Composite scores for working memory andarousal were created on the basis of a latent variable modelusing multiple laboratory-obtained measures of each con-struct. Inattention and hyperactivity were defined on thebasis of a composite of parental and teacher ratings. Aconfirmatory factor model fit well, supporting the internalvalidity of the composite scores. Subjects included 656unrelated community recruited volunteer children ranging7 to 13 years old (n=435 ADHD, 221 non-ADHD). SNPsincluded in our analysis (n=193,657) were from a polygenicrisk score (PGS) computed using the reported discoverysample of 20,183 ADHD cases and 35,191 controls from thePsychiatric Genetics Consortium. A linear regression analysisaccounting for age, sex and population stratification wasused to test for association to each endophenotype.

Pleiotropic relationships were identified using linear regres-sion analysis accounting for the correlation among all fourphenotype measures. A likelihood ratio test framework wasused for inferring the number of traits associated with agenetic variant and for partitioning traits associated withthe different SNPs.Results: The PGS was associated with ADHD diagnosis(Nagelkerke R2=.04, p=0.0000006) and multi-indicatordimensional ADHD latent variables by parent report(beta=.196, SE=.041) and teacher report (beta=.176,SE=.040). Univariate SNP associations (po0.0001) were:WM=23, arousal=21, hyperactivity=20, and inatten-tion=10. Two SNPs were significant in both hyperactivityand inattention, one located in EPHB1 which mediates axonalguidance. Hyperactivity was associated with genes involvedin energy metabolism and signaling processes. Inattentionwas associated with genes involved in regulation of geneexpression and GPCR signaling. WM was associated withgenes involved in differentiation, genes expression regulationand mitochondrial transcription. Arousal was associated withgenes involved in calcium binding, axon guidance andregulation of neurotransmitters. SNPs pleiotropic with WM(76 SNPs) or arousal (70 SNPs) were enriched for inorganiccation transmembrane transport (p=0.000041). SNPs pleio-tropic with hyperactivity (133 SNPs) or inattention (142 SNPs)were enriched for phosphate-containing compound metabolicprocess (p=0.027).Discussion: Our study provides motivation for pleiotropiceffects in ADHD endophenotypes and helps begin to accountfor the mechanism by which cognitive endophenotypesparticipate in ADHD development.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.077

SA6. COPY NUMBER VARIANTS IN BRAIN-RELATED GENESARE ASSOCIATED WITH NEUROPSYCHIATRIC TRAITS INCHILDHOOD

Christie Burtonn,1, Mehdi Zarrei1, Worrawat Enghuan1,

Daniele Merico2, Jeff MacDonald1, Bowei Xiao1,Andrew Paterson1, Lisa Strug3, Christian Marshall2,Jennifer Crosbie1, Paul Arnold4, Russell Schachar3,Stephen Scherer1

1The Hospital for Sick Children2The Centre for Applied Genomics3The Hospital for Sick Children, University of Toronto4University of Calgary

Background: Rare Copy Number Variants (CNVs) likelyplay an important role in common childhood neuropsychia-tric disorders such as ADHD and OCD. These disordersrepresent the extremes of broadly distributed behaviouraltraits that are influenced by underlying variation in funda-mental cognitive processes such as response inhibition.Using behavioural and cognitive trait-based approaches inpopulation samples can help reduce heterogeneity and

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5PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

improve power to detect rare CNVs associated with thesedisorders. Currently we do not know the prevalence of CNVsrelated to neuropsychiatric disorders in youth in the generalpopulation. Using the Spit for Science sample (Toronto,Canada), we examined the association of rare CNVs withADHD, OCD and response inhibition traits.Methods: We collected DNA and quantitative trait mea-sures from 16,718 youth (ages 6–17 years) at a local sciencemuseum. We measured ADHD traits using the Strengths andWeaknesses of ADHD and Normal Behavior (SWAN) scale,obsessive-compulsive traits using the Toronto Obsessive-Compulsive scale (TOCS) and response inhibition, a putativeendophenotype for ADHD, using the Stop-Task. We geno-typed unrelated Caucasians (n=5,320) using IlluminaHumanCoreExome beadchips. CNVs were called using threealgorithms: iPattern (ipn), PennCNV (pcnv), and QuantiSNP(qsnp) and a high confidence dataset was generated byretaining variants detected by two or more algorithms andat least 10 kb in size. We defined rare variants as those withless than 0.1% frequency against our population controls.Using linear regression, we examined whether CNV burden,overall and within psychiatrically relevant gene sets (e.g.,brain expression, synaptic function), is associated withresponse inhibition, ADHD and OCD traits.Results: After stringent quality control, 4815 (90.5%) ofparticipants remained with a total of 9,490 rare CNVs (1.97/individual on average). We observed CNVs affecting 23genomic loci previously implicated in neurodevelopmentalconditions (e.g. 22q11.2) in 59 (1.2%) of participants. Otherlarge CNVs affecting known psychiatric genes (e.g., ASTN2,NRXN1) were also identified. Significantly more deletions(4500 kb; p=0.04) and enrichment of deletions in genesinvolved in synapse structure, neuron projection and neu-rophenotypes in mice (p o 0.03) were observed for ADHDtraits. For response inhibition, there were significantly moreduplications (50–500 kb; p=0.004), a trend towards moredeletions (p=0.07), more deletions of genes related tobrain structure and function (p o 0.008) and duplicationsin genes highly and specifically expressed in the brain forresponse inhibition (p=0.006). There was no associationbetween overall burden and OCD traits but duplications ingenes related to synaptic function and neurotransmissionwere enriched for this trait (p o 0.01).Discussion: In a large pediatric general population sam-ple, brain-related CNVs were associated with neuropsychia-tric traits in children although the pattern of enrichmentdiffered between ADHD, OCD and response inhibition. Ourresults replicate several previous CNV burden findings forADHD and OCD suggesting a similar genetic architecturebetween traits and disorders. Our approach shows thefeasibility of CNV analysis and quality of CNV data from

the HumanCoreExome array in a large population basedsample.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.078

SA7. GENOME-WIDE ASSOCIATION STUDIES OF SUICIDALIDEATION DURING PSYCHOTROPIC MEDICATION

Clement Zain,1, Arun K. Tiwari1, Gwyneth Zai2,

Nicole Braganza1, Natalie Freeman1, James L. Kennedy1

1Centre for Addiction and Mental Health2Centre for Addiction and Mental Health, Universityof Toronto

Background: Suicidal behaviour can be a serious symptomof psychiatric disorder and may change during the course ofpsychotropic medication treatment. There have been anumber of published Genome-Wide Association Studies(GWASs) of treatment-emergent suicidal ideation, but therehas not been GWAS of resolution of suicidal ideation duringdrug treatment. Here we report on two such GWASs.Methods: From the STEP-BD study, we have 450 patientswith bipolar disorder assessed on the MADRS. We analyzedthe change in suicidality from baseline to six months.

From the IMPACT study (Individualized Medicine: Phar-macogenetic Assessment & Clinical Treatment), we have118 participants suffering from anxiety, depression, bipo-lar disorder, and/or attention-deficit hyperactivity disor-der. They were genotyped on the Illumina Omni 2.5 M chipand were followed for eight weeks on the Beck DepressionInventory. Of these participants, 69 experienced suicidalideation at baseline, and 23 of them did not experiencesuicidal ideation at their eight-week study visit. Conver-sely, 49 participants did not have suicidal ideation atbaseline, of which six reported suicidal ideation at theeight-week visit.

We analyzed the change in suicidal ideation duringthese studies, including baseline suicidality scores, age,and sex as covariates.Results: We did not observe genome-wide significant find-ings from either GWAS. We observed a possible genetic overlapbetween suicidal ideation in the STEP-BD bipolar disordersample and suicidal ideation in the IMPACT sample (p=0.047).Discussion: Suicide is a clinically important phenotype inclinical studies. Investigating the increases as well asdecreases in suicidal ideation during psychotropic

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M. Barbu et al.6

medication may be an interesting avenue for further geneticinvestigations.

Disclosure: Applications - Patent, Self.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.079

SA8. ACCELERATED EPIGENETIC AGEING ASSOCIATEDWITH MAJOR DEPRESSIVE DISORDER, NEUROTICISM,AND PSYCHOLOGICAL DISTRESS

Andrew McIntoshn

, Rosie Walker, Riccardo Marioni,Ian J. Deary, Chris S. Haley, Kathryn Evans, Heather Whalley

University of Edinburgh

Background: Major Depression (MDD), neuroticism andpsychological distress have each been associated with anincreased risk of several diseases commonly associated withageing. In the current study, we sought to identify which ofthese traits was associated with methylation age accelera-tion, and if any methylation age association with MDD ordistress survive correction for neuroticism.Methods: We conducted assessments of DNA methylationage in Generation Scotland (N=22,000 individuals), a familyand population-based cohort from Scotland. DNA methyla-tion was assessed genome wide using the Illumina EPIC arrayin 5000 individuals, of whom 500 were also assessedlongitudinally.Results: Associations were found between methylationage acceleration, MDD and psychological distress. Some-what contrasting results were found for the Hannum andHorvath epigenetic clocks.Discussion: These findings suggest that accelerated bio-logical ageing is associated MDD and psychological distress,and later analyses from this dataset will seek to determinethe directional relationship, and specifically whether MDD isleading to ageing acceleration, or whether acceleratedageing is increasing the likelihood to developing MDD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.080

SA9. EFFECT OF 5HT GENES IN CONFERRING RISK FORSUICIDE ATTEMPT AND SUICIDAL IDEATION

Vincenzo de Luca1, Ali Bani-Fatemi1, Charles F. Reynolds2,Eric Lenze3, James L. Kennedy

n,1, Benoit Mulsant1

1Centre for Addiction and Mental Health2University of Pittsburgh3Washington University in St. Louis

Background: Major Depressive Disorder (MDD) is a majorrisk factor for suicide. Familial, adoption, and twin studiessuggest that suicide is both genetic and heritable. However,

to date, there are no robust genetic predictors of suicide orsuicide attempt in MDD. Several serotonin genes have beenproposed as candidate genes in suicidal behaviour, includingHTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2, 5HTT, andMAOA. The findings from candidate gene studies in suicidalbehavior are inconsistent.Methods: In this study, we genotyped several functionalvariants of serotonin genes in a well characterized sampleof patients with MDD.Results: We found that the G allele in the HTTLPR regionis associated with a history of suicide attempt (po0.05). Onthe other hand, the G allele (rs25531) was not significantlyassociated with suicidal ideation measured using the SIS(p=0.955).Discussion: This suggests that this rare variant should beanalyzed independently from the nearby long/short polymorph-ism. However, all previous studies on suicide attempt haveneglected this rare variant or combined it with the long/shortpolymorphism. In conclusion, this study suggests that the Gallele in the HTTLPR region should be considered as a singlemarker in the studies of genetic predictors of suicide attempt.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.081

SA10. USING WHOLE GENOME SEQUENCING TO IDEN-TIFY DE NOVO VARIATION IN BIPOLAR DISORDER

Fernando Goesn

, Mehdi Pirooznia, Peter Zandi,Martin Tehan, Ann Pulver

Johns Hopkins University

Background: Although most gene-discovery efforts inBipolar Disorder (BD) have focused on inherited variation,the association of BD with increased paternal age and priorassociation of de novo copy-number variants with BD,suggests that de novo mutations may also play a role.Methods: We have performed deep whole genome sequen-cing of 97 trios selected specifically to have no family historyof bipolar disorder. Diagnoses were based on the DiagnosticInstrument for Genetics Studies with two independent best-estimate evaluations. Sequencing was performed on IlluminaHi-Seq with an average depth of 37X. Variant calling wasperformed according using the GATK using haplotype callerand best-practice recommendations. De novo calls wereindividually visualized with the Integrative Genomics Viewerand a subset, including all exonic variation, underwentconfirmatory Sanger sequencing.Results: We identified 6,882 de novo variants throughoutthe genome, representing an average of 73.3 de novo SingleNucleotide Variants (SNVs) and indels per family (range 43-106). As expected, the number of de novo variants corre-lated strongly with paternal age (Po4.8 � 10–14), with anaverage increase of �1.8 mutations per year. We identified105de novo coding mutations (average 1.06/trio), and ratesconsistent with Poisson expectations. Among these, therewere 12 de novo disruptive variants, including 6 disruptive

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variants in highly conserved genes. Meta-analysis with arecently published exome based de novo study of BD providedfurther evidence for enrichment (P=0.00594). Initial investi-gation of non-coding de novo variations shows an aggregationof variants within several candidate genes (CNTNAP2,CTNNA3, RBFOX1, GABRB1, GRID2, GRIK2) previously impli-cated by genetics studies of psychiatric disorders.Discussion: Our whole genome study of de novo variationprovides initial evidence for an association of disruptivemutations in highly conserved genes with BD. The consis-tency of our results with the only other study of de novovariation in BD highlights the need for further study of denovo variation in BD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.082

SA11. THE EXPRESSION OF KAINATE RECEPTORS IN THEHIPPOCAMPUS OF MATERNAL SEPARATION RAT PUPS

Hae Jeong Parkn

, Jin Kyung Park, Won Sub Kang

Kyung Hee University

Background: Adverse experiences during early life suchas social isolation, child abuse and parental loss is asignificant risk factor for neuropsychiatric diseases such ascognitive deficits, anxiety disorders, and depression. Mater-nal Separation (MS) in rats during the early postnatal period,which is a well-established animal model of early life stress,is served as a model of psychopathology for anxietydisorders and depression.Methods: To determine the molecular mechanism on thedevelopment of psychiatric problems following ELS, weassessed the alteration of molecules in the hippocampusof MS rats (during postnatal day 14–21) using microarraymethod.Results: MS decreased the 59 genes and increased 23genes more than two-fold. Interestingly, among them, weobserved that the expressions of kainate receptor 1 (KA1)and 2 (KA2) genes were up-regulated in MS pups. This resultwas also confirmed by RT-PCR. Additionally, the immunor-eactivities of KA1 and KA2 in the hippocampus wereincreased in the MS group compared to the control group.Discussion: Our studies showed that MS-induced ELSinduced the increased expressions of the hippocampal KA1and KA2 receptors. These findings suggest that the altera-tion of glutamate system induced by ELS may be involved inthe pathology of the psychiatric diseases such as depressionand anxiety disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.083

SA12. UNDERLYING DOMAINS OF ANXIETY TRAIT IN ACOSTA RICAN SAMPLE

Alejandro Ávila Aguirren

, Carolina Coto-Vílchez,Daniela Ugalde Araya, Henriette Raventós, Javier Conteras

University of Costa Rica

Background: Imprecision of the psychiatric phenotypemight partially explain the failure of genetic research toidentify genes that contribute to susceptibility of anxietydisorders. It has been suggested that using a broad anxietyphenotype instead of a DSM-IV anxiety disorder diagnosismight enhance the chance of finding candidate genes forthis complex group of symptoms. Previous research con-cluded that two underlying constructs, worry and rumina-tion may explain anxiety subsyndromic symptoms in CostaRican patients with history of mania or hypomania. There-fore, the goal of the current study is to explore thepresence of latent constructs for quantitative anxiety in agroup of subjects with a wide diagnostic phenotype (schizo-phrenia, schizoaffective disorder, bipolar disorder andmajor depressive disorder) and non-affected individuals.Methods: We conducted an exploratory factor analysis ofanxiety trait in 709 subjects originally recruited for a CostaRican study of Bipolar Disorder. Our sample was comprisedby 419 (59%) subjects with psychiatric disorders and 290(41%) non-affected individuals. The most frequent diagnoseswere bipolar disorder 167 (23%) followed by major depres-sive disorder 144 (20%). The sample was 57% female and hada mean age of 41.2 (SD 14.90). We used principal factorsextraction method with squared multiple correlations (SPSSv.20) of the STAI (trait subscale).Results: A three-factor solution with a good simple struc-ture and statistical adequacy was obtained with a KMO of0.92 (40.6) and Bartlett's Test of Sphericity of 5644,44(po0.05). The STAI items were grouped into three factors:1) anxiety-absent, 2) worry and 3) rumination based on thecharacteristics of the symptoms.Discussion: Two underlying constructs, worry and rumina-tion may explain anxiety subsyndromic symptoms in CostaRican subjects. Responses to items associated with factor1 describe people with emotional stability, meaning noanxiety. The items associated to the factor 2 indicateanxiety about actual and future events and stressful situa-tions, meaning worry. On the other hand, the factor 3 clustercomponents associated with thoughts about past events andrecurrent situations, namely rumination. How the type ofsymptoms affects the clinical presentation and prognosis ofthe mania/hypomania raise an important line of research.Our proposed underlying structure of subsyndromal anxietyin individuals should be considered as an important factor indefining better phenotypic characterizations on a broaderdiagnostic concept. Worry and rumination as a phenotypiccharacterization may assist in genotyping; however, itspredictive value on actual illness outcome still requiresmore research. The Genome-Wide QTL analysis for anxietytrait in the same sample is ongoing.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.084

SA13. INVESTIGATION OF NOVEL RARE VARIANTS INNRXN1 CONTRIBUTES TO THE INCREASED RISK OFAUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA

Kanako Ishizukan,1, Branko Aleksic2, Norio Ozaki3

1Nagoya University Hospital2Nagoya University3Nagoya University Graduate School of Medicine

Background: NRXN1 is a transmembrane protein having afundamental role in synaptogenesis, synaptic maintenance,neurotransmitter release, and the function of voltage-gatedcalcium channels in the synapses of brainstem and neocor-tex. Impairments in NRXN1 caused by genetic variants arethought to be critical for the pathomechanisms in neurop-sychiatric disorders including autism spectrum disorders andschizophrenia.Methods: In this study, we conducted exon-targeted rese-quencing of the NRXN1 gene with next-generation sequen-cing technology in 562 Japanese patients (192 withidiopathic autism and 370 with schizophrenia). We thenperformed in silico analyses, trio analyses, and associationanalyses on 1,892 cases (381 autism and 1,511 schizophre-nia) and 1,291 controls with these variants.Results: We detected six heterozygous variants with allelefrequencies of r1%. We regarded three missense variants(p.T777M, p.D812G, p.R896W) as novel ones because theywere predicted to be damaging based on in silico predic-tions and because each was not registered in either HGVD oriJGVD, the Japanese public databases. Among these threecases, two involved transmission from a healthy mother toher autistic son, and one involved transmission from ahealthy mother to her schizophrenia daughter. We foundno statistically significant association for any of three rarepoint variants in NRXN1 with case-control analysis.Discussion: We explored the role of rare NRXN1 variantsin Japanese neuropsychiatric disorders. To assess the impactof the variants discovered here, further investigation bysample size expansion and biological analysis will beperformed.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.085

SA14. WHOLE EXOME TRIO SEQUENCING IDENTIFIESNOVEL VARIANTS FOR AUTISM SPECTRUM DISORDER

Ricardo Harripauln,1, Nasim Vasli1, Ashlyn Rodrigues1,

Ansa Rabia2, Saqib Mahmood2, Abolfazl Heidari3,Laila Al Ayadhi4, Bita Bozorgmehr1, Roksana Sasanfar5,Muhammad Ayub6, John Vincent1

1Centre for Addiction and Mental Health2University of Health Services3Qazvin University4King Saud University5University of Massachusetts Memorial Hospital6Queen's University

Background: Autism Spectrum Disorder (ASD) affects 1%of the population and it is characterized by social impair-ment and repetitive behaviors. Usually, signs of ASD occurbefore the age of three years and are often comorbid withother psychiatric disorders such as epilepsy and IntellectualDisability (ID) (25–70% of ASD cases have ID). ASD is believedto have a high degree of genetic heterogeneity with manyrare variants contributing to the disorder. Thus far, mostASD research has focused on de novo and dominant variantsbecause emphasis is placed on smaller Western familieswhere recessive variants are hard to identify. This has led toa substantial knowledge gap on the effects recessivevariants have on diseases such as ASD. The aim of this studyis to assess the role recessive variants play in ASD andneurodevelopmental disorders.Methods: We used Whole Exome Sequencing (WES) for asubset of samples so far. In addition, we have DNA from 257Iranian, 115 Pakistani, and 20 Saudi ASD trios that will beanalyzed over the next few months. The analysis pipelineconsists of genome alignment using SNAP and the GenomeAnalysis Toolkit GlobalHaplotyper (GATK) implemented on ahigh performance Hadoop infrastructure. Variant calls areannotated using recently released databases and pathogeni-city scores including M-CAP, Intervar, Sift, Polyphen2, Muta-tionTaster and comparing against 123 000 exomes in gnoMADand 2497 exomes in the GME Server.Results: We have identified de novo variants in known IDor ASD genes ZNF292, MYT1L, CHD8, DYRK1A, and novelgenes such as ANXA4; also an X-linked variant in known IDgene THOC2. Biallelic mutations have been found in theknown ID/ASD gene CC2D1A, and new candidate geneFAXDC2. The FAXDC2 is a homozygous truncating mutationthat has not been associated with ASD or ID previously.FAXDC2 is a fatty acid hydroxylase domain containingprotein with no known function or previous associationswith disease. ANXA4 is part of the annexin family of genespreviously associated with ID/ASD. It is a calcium dependentphospholipid binding protein and is expressed in the brain.

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Mouse models of ANX4 indicate behavioral and neurologicalimpairments when knocked out.Discussion: We are in the process of analyzing 300 triosthe results of which will be available in next few months.Once the function of these mutations and the associatedclinical features is characterized, these genes can beutilized for molecular diagnosis, better clinical managementand in the long-term may act as potential targets forpersonalized therapeutics.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.086

SA15. THE EMORY 3Q29 DELETION PROJECT: PROFILESOF NEURODEVELOPMENTAL AND NEUROPSYCHIATRICPHENOTYPES

Rebecca Pollakn

, Sherly Boddu, Joy Park, Michael Zwick,Celine Saulnier, Jennifer Mulle

Emory University

Background: 3q29 Deletion Syndrome (3q29DS) is a rare(�1:30000) genomic disorder characterized by a 1.6 Mbdeletion on chromosome 3, and is associated with develop-mental delay, intellectual disability, and a significantlyincreased risk for neuropsychiatric disorders, includingAutism Spectrum Disorders (ASD). The clinical presentationof these phenotypes is highly variable, which combined withthe low frequency of the deletion has resulted in a poorunderstanding of 3q29DS. In a previous study, we found that24% of 3q29DS registry participants self-reported a formaldiagnosis of ASD, a 16-fold increase versus the generalpopulation. However, many more patients report “autism-like symptoms” without a formal diagnosis of ASD. In thecurrent study, we use additional registry data to test thehypothesis that the true prevalence of ASD is underesti-mated in 3q29DS.Methods: The 3q29DS registry (3q29deletion.org) is an IRB-approved, HIPPA-compliant patient ascertainment website.After informed consent, registrants fill out several question-naires, primarily a custom medical and demographic ques-tionnaire that includes prior diagnosis of ASD. In addition,several standardized surveys were adapted for the onlineplatform: the Social Responsiveness Scale (SRS); the SocialCommunication Questionnaire (SCQ); the Autism SpectrumScreening Questionnaire (ASSQ); and the Child BehaviorChecklist (CBCL). Data from 3q29DS patients was de-identi-fied and securely downloaded for analysis. Responses to allquestionnaires were hand-scored by three independentexaminers and cross-checked to ensure identical scores.Statistical testing and data visualization was performed in R.Results: Self-report data from 3q29DS registry partici-pants shows a significantly increased prevalence of ASDdiagnosis versus the general population (21.4% vs. 1.47%,po2.22e-16). Further, 3q29DS patients without a diagnosisof ASD scored significantly higher on the SRS, SCQ, and CBCLversus non-ASD, non-3q29DS children (p=1.18e-5, 0.003,

9.00e-7). We identified 2 3q29DS patients that did notreport a formal diagnosis of ASD but scored in the clinicalrange on all scales, and an additional 15 3q29DS patientsthat did not report a formal diagnosis of ASD but scored inthe clinical range on at least one scale, indicating sub-stantial impairment in the absence of a formal diagnosis.Male and female 3q29DS patients show comparable impair-ment, with similar scores on all four measures, and maleand female 3q29DS patients report a similar frequency offormal ASD diagnosis, unlike ASD patients in the generalpopulation.Discussion: We have shown that the 3q29DS population issignificantly enriched for ASD features measured via fourASD surveys. Self-report data confirms the increased pre-valence of ASD in 3q29DS; however, several patients scoredin the clinical range on all scales, despite reporting nodiagnosis of ASD. These data support our hypothesis that thetrue prevalence of ASD in 3q29DS may be underestimated,and suggest that ASD testing should be the standard of carefor 3q29DS patients. We have also identified differences inASD presentation in 3q29DS patients versus the generalpopulation: male and female 3q29DS patients are equallyimpaired according to the scales employed in the presentstudy, and males and females report similar proportions offormal ASD diagnoses. This implicates 3q29DS as a promisingline of investigation into the underlying mechanisms of ASD,due to both the enrichment of ASD features and thereduction in gender bias.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.087

SA16. PATHWAY INTERACTIONS FOR AUTISM-RISK GENESLC9A9: IN VITRO CONFIRMATION OF BIOINFORMATICASSOCIATIONS

Jameson Patakn

, Stephen Faraone, Yanli Zhang-James,Jonathan Hess, Stephen Glatt

SUNY Upstate Medical University

Background: Na+/H+ exchanger 9 (SLC9A9) is an aut-ism-risk gene localized in the endosomal system, which is anovel biological pathway that over-represents autism-riskgenes. SLC9A9 regulates the endosome-recycling compart-ment through alkalinizing the endosomal lumen; although,it's broader biological functions have not been elucidated.Objectives: Achieve a broader biological understandingof SLC9A9 through co-expression analysis and providein vitro data confirming the endocytic regulation of autop-hagy and cell survival.Methods: We use bioinformatics techniques to determinegene co-regulations, protein-protein interactions and path-way enrichments and confirm those results in an in vitrosystem. We perform WGCNA on human RNA-sequencing datafrom Allen Brain Atlas focusing on SLC9A9 co-expressionmodules in the pre- and postnatal hippocampus, cortex andamygdala. We use N2a cells as a neuronal model system to

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provide evidence that SLC9A9 gene-dosage affects autop-hagy induction and cell survival signals through lipofecta-mine 2000 transfections of SLC9A9 cDNA constructs. Weassess immunoblots of N2a protein lysate for critical autop-hagy protein LC3-I/II, and cell survival protein BCL2. Inaddition, we challenge N2a cells with chloroquine to assesstheir viability at increasing levels of dosage.Results: Our bioinformatics study shows SLC9A9 co-expres-sion modules are enriched with mTOR and autophagic inter-mediates, as well as Bcl-2 pathway constituents. Our in vitrowork demonstrates that SLC9A9 overexpression in N2a cellssignificantly decreases LC3-I to LC3-II conversion and signifi-cantly increases Bcl-2 levels. In addition, it increases phos-pho-AKT and phospho-mTOR levels, decreases LC3-II punctaformation and autophagic rate and provides resistance todrug treatments that typically result in cell death.Discussion: Our results confirm the co-regulation of SLC9A9and autophagic molecules. The in vitro data better defines therole of SLC9A9 in autophagic regulation, in that it inhibits theconversion of LC3-I to LC3-II and reduces the rate of autophagy.Although in need of replication in a true neuronal model, ourdata suggests that SLC9A9 expression could be a signaling andion-transport brake, effectively inhibiting autophagic processes.When dysregulated, this has the potential to impact pruningand thus neuronal morphology and function. Conclusions: theseresults provide further insight into how SLC9A9 is impactingneuronal function that eventually leads to autistic phenotypes.We provide preliminary evidence as to how SLC9A9 couldpotentially be associated with autism spectrum disorders viaautophagy and cell survival pathways.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.088

SA17. PATERNAL AGE AFFECTS OFFSPRING'S BEHAVIORPOSSIBLY VIA EPIGENETIC MECHANISM RECRUITING ATRANSCRIPTIONAL REPRESSOR REST

Kaichi Yoshizaki, Ryuichi Kimura, Kentaro Mochizuki,Takako Kikkawa, Hitoshi Inada, Niroko Osumi

n

Tohoku University Graduate School of Medicine

Background: Paternal age has deleterious effects on thetransmission of phenotypes to offspring, including higherprevalence of major psychiatric and neurodevelopmentaldisorders.Methods: Here, we examined transgenerational transmis-sion of selected somatic and cognitive phenotypes in miceand explored a possible epigenetic mechanism.Results: F1 offspring of aged fathers had lower bodyweight and showed impairment in pup's vocalization, sensor-imotor gating and spatial learning. From comprehensivemethylome analyses, we identified in aged sperm 16 hyper-methylated and 96 hypomethylated genomic loci. Motifanalysis identified 19 potential REST/NRSF-binding sites inhypomethylated regions, which was confirmed as 37 motifswith actual binding of REST in the ChIP-seq database using

ES-derived neural stem cells. Since we also found reductionof thickness in the neocortex, especially in the deep layer,we analyzed expression of potential REST-target genes.Discussion: All of the data consistently support thescenario that hypomethylation in sperm due to paternalage may eventually result in ectopic binding of RESTrepressor to its target genes, downregulating their expres-sion during brain development, thereby inducing behavioralabnormalities in the offspring.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.089

SA18. ANALYSIS OF GENETIC VARIANTS IN MEXICANCHILDREN WITH AUTISM SPECTRUM DISORDER: ANIMMUNGENOMIC APPROACH

Mirna Moralesn,1, Paulina Apra2, Carla Márquez2,

Lorena Orozco1, Humberto García1, Humberto Nicolini1,Helios Cárdenas1

1National Institute of Genomic Medicine INMEGEN2National Institute of Genomic Medicine, National Autono-mous University of Mexico

Background: Autism spectrum disorders encompass a largenumber of symptoms such as difficulty in social interaction,poor communication skills and repetitive behaviors. Recently,new hypotheses have emerged about the relationship betweenpsychiatric diseases and abnormalities in the immune system,where evidence suggests that a part of the etiology can beexplained by immunological alterations. Genomic wide associa-tion studies in Latino and Mexican populations are scarce, so inthis study we used a sample of pediatric patients of Mexicanmestizo origin with ASD diagnosis.Methods: As a first approach to the study of geneticvariants in 120 mexican children with ASD, using a highdensity microarray (Psycharray, Illumina) and 45 controls.This array contains variants related to common psychiatricconditions and immune system. For the analysis, the Plinkand Eigensoft softwares were used. Genotypic values o97%,the samples in equilibrium of HW and a P 4 1� 10-4 weretaken. A logistic regression was carried out and adjusted forgender and ancestry.Results: As we expected, immune system genes areinvolved in ASD. Further, we found some genes associatedwith mental diseases. Some SNPs are close to immune genesas TNFRSF19 (P=4� 10-4), ATG16L1 (P=2� 10-4) withingenes as MLIP (P=4� 10-5), NUBP1 (P=4� 10-4) and ATP9A(P=3� 10-4). SNPs located at intergenic regions were foundstatistically significant either. In chromosome 4 and 7 werefound a signal of several intergenic SNPs with a significant P.Discussion: This is the first study in children with ASDperformed in Mexican population. These results give us anidea of the SNPs contained in genes that can explain part ofthe etiopathogenesis of the disorder. Pathway analyses arenecessary to elucidate gene interaction. Intergenic SNPs

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with significant P need to minucious analyses. In addition, itlays the foundation for future functional studies on thegenes involved.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.090

SA19. GENE EXPRESSION SIGNATURES FROM PERIPH-ERAL BLOOD DISCRIMINATE THE MAJOR PSYCHOSES

Jonathan Hessn,1, Stephen J. Glatt2

1SUNY Upstate Medical University2Medical Genetics Research Center, SUNY Upstate MedicalUniversity

Background: Bipolar Disorder (BD) is a complex andhighly heritable psychiatric disorder with a world-wideprevalence near 1%. There is converging evidence fromgenetic, molecular, and clinical studies of BD that implicatenumerous neurotransmitter and immune signaling abnorm-alities. These abnormalities have been described previouslyin Schizophrenia (SZ), which has close genetic and molecu-lar ties to BD.Methods: The purpose of this investigation was to uncovergeneralizable biomarkers for BD using a cross-study analysis ofsix microarray data sets comprising peripheral blood tran-scriptomes for patients with a DSM-diagnosis of BD (n=77) andunaffected comparison subjects (n=81); furthermore, wesought to compare transcriptomic signatures between BDand SZ (obtained from a prior study). We performed acombined-subject differential expression mega-analysis withregression models applied per gene, each adjusted for clinicalfactors and study heterogeneity. In addition, we surveyedgene sets and gene networks for consistent differentialexpression in BD.Results: Three genes were associated with BD at a level ofsignificance that withstood rigorous statistical correction formultiple testing. In addition, differential expression of genesets in BD was found; functions of these gene sets includedinnate immunity, energy production in mitochondrial com-plexes, and metabolism of RNA and proteins, among otherbiological pathways previously related to BD or psychosis.Lastly, we deployed a machine-learning pipeline, whichdiscriminated BD patients from unaffected comparison sub-jects and SZ patients with high accuracy based on 77 genes(mean AUCROC=0.849, 95% CI=0.837 – 0.859).Discussion: Our study provides strong evidence in supportof candidate biomarkers for BD and introduces potentiallygeneralizable blood-based classifiers for BD. Our findingshave relevance for cross-disorder genomic analyses. Thiswork warrants expansion to identifying gene signatures thatdiscriminate other adult and childhood neuropsychiatricdisorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.091

SA20. PRSice 2: POLYGENIC RISK SCORE SOFTWARE(UPDATED) AND ITS APPLICATION TO CROSS-TRAITANALYSES

Shing Wan Choin

, Paul O'Reilly

King's College London

Background: In 2015, we published PRSice (‘precise’), asoftware for the calculation, application and evaluation ofpolygenic risk scores (PRS). PRSice has been widely used inthe field of psychiatric genetics since. Here we describe anupdated version – PRSice 2 – which contains several impor-tant new features. While a key feature of the originalversion was its identification of the most predictive PRS viaits ‘high resolution scoring’, the inherent over-fittinginvolved meant that we recommended using a significancethreshold of P o 0.001 for testing based on permutation.PRSice 2 deals with this problem more directly by perform-ing permutations on user data and thus estimating bothempirical P-values and empirical R2 values. This is madefeasible by the speed-up in PRSice 2 via its C++ imple-mentation - the algorithmic improvements in PRSice 2 leadto more than 30 times improvement in speed. Other newfeatures include support for the binary oxford BGEN fileformat and a correction of the estimated R2 of model fitaccording to the ascertainment in the selection of cases(i.e. whether mild or severe cases).Methods: We demonstrate the performance of PRSice 2 herewith our latest cross-trait PRS analysis results, and, inparticular, investigate how confounding typically associatedwith non-genetic studies can be re-introduced in such studiesand give rise to misinterpretation of their results.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.092

SA21. USING CHROMATIN CONFORMATION DATA TOINFER THE FUNCTIONAL IMPACT OF DISEASE-ASSO-CIATED (SNPs)

Michael Mooneyn

, Joel Nigg, Beth Wilmot

Oregon Health & Science University

Background: Thousands of SNP-trait associations havebeen reported in published GWAS. However, taking the nextstep to identify the functional impact of these SNPs remains

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a significant challenge, due in part to the fact that manyassociated SNPs are located in non-coding regions of thegenome.

We have developed a new framework for annotatingintergenic SNPs to target genes; we do this by integratingdata about the 3D structure of chromosomes with informa-tion about predicted regulatory regions. This frameworkbuilds upon evidence that (a) chromatin looping eventsfacilitate long-range interactions between enhancers andpromoters, and (b) these interactions are important forregulating gene expression. We used results from two GWAS(ADHD and schizophrenia) conducted by the PsychiatricGenomics Consortium to investigate whether this novelannotation method can reveal new candidate genes tar-geted by regulatory variants.Methods: SNPs were assigned to genes if they met any ofthe following criteria: 1) the SNP was located strictly withinthe boundaries of the gene, 2) the SNP was located within apromoter region that overlaps the TSS of any of the gene'stranscripts, 3) the SNP was located within an enhancer that isbrought into close proximity of the gene's promoter throughchromatin looping. We required that both regulatory ele-ments (promoters and enhancers) be within 100 kb of theloop anchors (the region of direct chromatin contact).

Publicly-available high-resolution chromatin contact data,and promoter and enhancer regions from the ENCODE Projectwere used. GWAS summary statistics were retrieved fromlarge-scale meta-analyses conducted by the PsychiatricGenomics Consortium. The schizophrenia meta-analysisincluded 36,989 cases and 113,075 controls. The ADHDmeta-analysis included 20,183 cases and 35,191 controls.Results: For the ADHD and schizophrenia analyses, respec-tively, 158,650 (59 with p r 1e-5) and 187,867 (1005 with pr 1e-5) SNPs were located within predicted enhancerregions. A substantial proportion (N=45,247, or 29% forADHD; N=53,233, or 28% for schizophrenia) of these enhan-cer SNPs could be mapped to target genes through chroma-tin looping events. For ADHD, 18 SNPs with a p-value r 1e-5 were mapped to 19 target genes through chromatin loops.Of these 19 genes, 11 are farther than 100 kb from theassociated SNP, making it unlikely that they would beidentified by conventional methods. Similarly, for schizo-phrenia, 85 target genes farther than 100 kb away from anassociated enhancer SNP (p r 1e-5) were identifiedthrough chromatin loop events.

Using a manually curated PPI network of high-confidenceinteractions, subnetworks containing candidate genes and allcommon interactors (gene's connecting two candidate genes)were extracted. For both disorders, subnetworks that includedgenes implicated by chromatin looping events showedincreased mean connectivity compared to subnetworks con-taining only genes near (within 1 kb) an associated SNP.Discussion: Our results show that integrating data on the3D structure of the genome with information about genomicregulatory elements has the potential to greatly improvethe knowledge gained from GWAS and to generate newhypotheses about the genetic mechanisms of susceptibilityto complex diseases.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.093

SA22. PERFORMANCE OF POLYGENIC SCORES ACROSSANCESTRALLY DIVERSE POPULATIONS: SCIENTIFIC ANDETHICAL CONSIDERATIONS

Laramie Duncann,1, Hanyang Shen1, Jonathan Pritchard1,

Marcus Feldman1, Kerry Ressler2, Kathleen Harris3,Ben Domingue1

1Stanford University2Harvard Medical School, McLean Hospital3University of North Carolina at Chapel Hill

Background: Polygenic scores (i.e. weighted metrics ofphenotype-associated alleles) are now widely used inresearch and by companies like 23&Me. The majority ofthe Genome-Wide Association Studies (GWAS) on whichthese scores are based were conducted in European Ances-try (EA) individuals, and questions remain regarding howwell scores work in non-EA populations and whether, likeMendelian phenotypes, ancestry-related differences in phe-notype-associated alleles may partially explain phenotypicdifferences across populations. The interpretation of poly-genic scores raises ethical questions because distributions ofpolygenic risk scores (as typically calculated) vary consider-ably across ancestry groups.Methods: To address these questions, we extracted dataabout predictive performance of polygenic scores (mea-sured in phenotypic variance explained) from a review of450 published papers and analyzed genotype and phenotypedata in the Adolescent Health dataset. We also tested thecorrelation between means of polygenic score distributions(for each of the 1000Genomes populations) with epidemio-logical data about mean height for relevant countries oforigin, for the 1000Genomes populations.Results: Across multiple phenotypes, polygenic predictionin African Americans (AA) was less strong than in EAindividuals (AA on average 31% of variance explained inEA). The same was not true for Latino and Asian samples;predictive performance was usually better than in EAsamples. Across the 1000Genomes populations, mean poly-genic scores for each population were positively correlatedwith average height of individuals in regions from which the1000Genomes data were obtained (r=.63, p=.009).Discussion: Consistent with population genetic models(e.g. Scutari et al. 2016), polygenic prediction was worsein AA individuals when using EA GWAS data to weightpolygenic scores. The same was not true for Latino andAsian samples. This could be due to sampling error, but alsosuggests that the relative importance of genetic andenvironmental effects may vary across populations. Thepositive correlation between mean polygenic scores forheight in the 1000Genomes populations, and mean height

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for relevant populations, suggests that differences in poly-genic scores across populations may contribute to popula-tion level differences in phenotypes. However, withoutevaluation of relevant environmental factors, it would beinaccurate to conclude that genetic differences explainobserved phenotypic differences. Here we use the exampleof height, but this caveat is just as important for othercomplex genetic phenotypes including psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.094

SA23. BIOLOGICAL PATHWAYS AND DRUG GENE-SETS:ANALYSIS AND VISUALIZATION

Helena Alexandra Gasparn

, Christopher Hübel,Gerome Breen

King's College London

Background: Here, we use summary statistics from Gen-ome-Wide Association Studies (GWAS) to find significantbiological pathways, disease pathways, drug targets anddrug gene-sets in schizophrenia, BMI, Body Fat % (BF%), andFat Free Mass (FFM). We introduce a workflow encompassingdata collection and curation, pathway analysis of drug gene-sets and biological pathways, drug class enrichment analy-sis, and visualization of "pathway landscapes".Methods: We used the schizophrenia GWAS from the PGCSchizophrenia working group phase 2 (35,476 cases), andnew GWASs of BMI, BF% and FFM based on UK Biobank data(N=83,477). We curated drug/gene interactions from var-ious databases: DGIdb, DSigDB, Ki DB, PHAROS, and ChEMBL.Biological pathways were collected from MSigDB (GO andcanonical pathways) and disease/phenotype pathways fromthe Open Targets platform. The software MAGMA was usedto produce gene-wise and pathway-wise associations, andMetaXcan for transcriptome prediction based on GTEx data(Genotype-Tissue Expression project). The enrichment ofdrug classes was estimated by grouping drugs by ATC class(Anatomical Therapeutic Chemical) and estimating theenrichment using Wilcoxon-Mann-Whitney test and theAUC (area under the enrichment curve). Pathway land-scapes were generated using the kernel Generative Topo-graphic Mapping (GTM), a probabilistic dimensionalityreduction algorithm. On these maps, gene-sets are repre-sented by points and the background color is derived fromGWAS pathway analysis p-values.Results: Results show new Bonferroni-significant pathwaysin schizophrenia. Antipsychotics and antiepileptics areenriched in the latest and largest schizophrenia GWAS fromthe PGC Schizophrenia working group. Different disease/phenotype pathways are found in BMI and BF% - e.g., “bingeeating” and “age at menarche” for BMI. 47 disease/pheno-type pathways and 24 biological pathways are significantlyassociated with FFM: anthropometric measures, height,myopathies, midgut development, bone development, etc.Pathway landscapes reveal that many significant pathways

overlap in “pathway clusters”, such as the skeletal systemcluster or the myopathy cluster on FFM maps.Discussion: A comprehensive approach is necessary toinvestigate drug repurposing opportunities and biologicalpathways using GWAS results. New visualization approachesmay help to highlight the overlap between pathways andthe genes driving the association. Two key issues are dataavailability (drug/target affinities, gene annotations) andsample sizes for GWAS studies. Growing public databasesand increasing sample sizes will help us to improve ourunderstanding of the genetic etiology of complex diseases.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.095

SA24. COMBINED WHOLE EXOME SEQUENCING ANDLINKAGE ANALYSIS REVEALS LINKAGE TO 10Q11-10Q21 LOCUS WHICH IS NOT EXPLAINED BY GWAS-ASSOCIATED SNP OR RARE VARIANTS IN ANK3

Alex Shaw1, Claudio Toma1, Richard Allcock2, Anna Heath1,Kerrie Pierce1, Philip B. Mitchell3, Peter Schofield1,Janice Fullerton

n,1

1Neuroscience Research Australia2University of Western Australia3School of Psychiatry, University of New South Wales

Background: Bipolar Disorder (BD) is a common, complexpsychiatric condition characterized by recurrent fluctua-tions of mood. Historically, linkage approaches implicated anumber of genetic loci, but signals typically failed to bereplicated due to heterogeneity of family samples inindividual studies and lack of power. Recent Genome-WideAssociation Studies (GWAS) have implicated common var-iants in CACNA1C, ODZ4 and ANK3 as increasing risk of BD,although those individual variants have small effect sizes.Sequencing studies are underway to characterise the impactof common and rare variants in these and other genes. Herewe perform a combined whole exome sequencing andlinkage study, with the aim of identifying linkage signalsand dissecting the contribution of common and rarevariants.Methods: Whole Exome Sequencing (WES) was performedin 117 subjects from 15 Australian multiplex BD families ofEuropean origin (72 affected, of whom 62 had diagnoses ofBD type-1 or schizoaffective disorder-manic type). Geno-types were called using samtools pileup and filtered toinclude haplotype-informative markers (HapMap CEU) usingLINKDATAGEN. Familial relationships were confirmed bypair-wise identity-by-descent in PLINK. Genome-wide link-age analysis was performed (using �6,000 WES-derivedSNPs) under non-parametric Kong & Cox linear and expo-nential models in Merlin. To reduce clinical heterogeneitywe considered patients with severe forms of illness asaffected (n=62), and subjects with BD-II or depressionconsidered unknown. Regions with suggestive linkage(LOD42) were fine mapped to reduce inter-marker intervals

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to o1 cM. Empirical significance of linkage was calculatedusing 10,000 simulated data sets and permuting phenotypes.Linkage analysis conditioning on GWAS-associated SNPs wasperformed using LAMP. To assess contribution of potentiallydamaging functional variation, an allele frequency weightedgene-based rareFBAT test was used.Results: Linkage analysis across 15 extended BD familiesfound a peak on chromosome 10q11-21 (maxSNP=rs10761725;LODlinear=2.52, empirical p=0.045; LODexp=3.03, empiricalp=0.046). The 95% confidence interval spanned 15.9 cM(chr10:51,588-67,727 Mb; hg19) and included top GWAS-asso-ciated gene ANK3 and 38 other protein-coding genes capturedby WES. Conditional linkage analysis with ANK3 GWAS-asso-ciated SNP (rs10994397, MAF=0.076 in CEU) demonstratedthat this risk variant did not explain the linkage signal, withonly a small contribution (LOD=0.63, p=0.089). Examinationof haplotype breakpoints did not establish a clear localisationof the gene/s driving the signal. We identified 56 missense ortruncating variants (regardless of frequency) informative forassociation analysis across 23 protein-coding genes, including5 in ANK3. Preliminary analysis using rare FBAT gene-basedtests find no significant evidence for association with any ofthe 23 genes after multiple testing correction.Discussion: We found no evidence that variants increasingrisk to BD are constrained within any single gene in the10q11-21 region, including ANK3. Our findings are consistentwith the 10q11-21 region containing multiple functionalvariants that contribute to BD susceptibility with modesteffects. Our study suggests heterogeneity within 10q11-21,and highlights the need for examination of genetic variantsbeyond the ANK3 common risk variants previouslyidentified.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.096

SA25. AN INHERITED DISTAL 16P11.2 DELETION DEMON-STRATES VARIABLE EXPRESSIVITY AND INCOMPLETE PENE-TRANCE FOR PSYCHIATRIC ILLNESS AS WELL AS ASSO-CIATION WITH RHIZOMELIC SHORTENING: A CASE REPORT

Emily Morrisn

, Barbara McGillivray, Anna Lehman,Jehannine Austin

University of British Columbia

Background: The most commonly reported 16p CopyNumber Variant (CNV) - 16p11.2 deletion syndrome(16pDS) (�600 kb; 29.5 -30.1 Mb) – has been robustlyassociated with schizophrenia (SZ), as well as IntellectualDisabilities (ID)/Developmental Delays (DD), congenitalanomalies, dysmorphic features and obesity. Non-overlap-ping “distal” 16p11.2 deletions (�200 kb; 28.7 -28.9 Mb)are less commonly reported, but have a variable phenotypesimilar to that of 16pDS, including emerging data suggestinga psychiatric phenotype. We report here on a parent/childdyad who share a distal 16p11.2 deletion.

Methods: Patient 1 (index) was assessed (for indicationsincluding seizures, DD, and short limbs) at ages 2, 17, and36, when she had clinical Chromosomal Microarray (CMA)(Affymetrix Cytoscan HD array, clinical thresholds: 200 kb(deletions), 400 kb (duplications), Chromosome Analysissuite (v2.0.0 195)). Fluorescence in Situ Hybridization (FISH)was used to confirm the deletion and determine origin.Results: Patient 1 was born at term to non-consanguineousparents. A 46XX karyotype was confirmed at age 2 and 17(testing indications: myoclonic seizures, DD, rhizomelic short-ening of upper limbs). At age 17, she was also noted to havesmall hands (o3rd %ile) and feet (-3.5 SD), large posteriorlyrotated ears (+3 SD), brachycephaly, high nasal bridge, andlow posterior hairline. She had developed psychosis at 13, andreceived diagnoses of bipolar disorder type I, ADHD, possibleASD and ID. At 37, she is obese with impaired fasting glucose,and ongoing psychiatric symptoms. CMA revealed a 238Kbdeletion at 16p11.2 (28 819 028 – 29 056 973; hg19)) confirmedby FISH as being paternally inherited. Patient 2 is the 69 year-old father of Patient 1. He completed high school despitedifficulties, and is not obese but has diabetes mellitus type II.He has rhizomelic shortening of both upper limbs but nohistory of psychiatric illness.Discussion: While distal 16p11.2 deletions have been shownto increase risk for schizophrenia, this report contributes to theemerging evidence that this CNV is also associated with broaderpsychiatric phenotypes, such as bipolar disorder. The father'smilder cognitive and metabolic phenotype supports variableexpressivity of distal 16p11.2 deletions, even when inherited;his negative psychiatric history reinforces the incompletepenetrance of this CNV for psychiatric disorders. This reportalso contributes to the generation of a more thorough clinicaldescription of the phenotypic range of distal 16p11.2 deletion,which we suggest, includes rhizomelic limb shortening.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.097

SA26. SPARSE CANONICAL CORRELATION IN APPLICA-TION TO BIPOLAR PSYCHOTIC PHENOTYPES AND SCHI-ZOPHRENIA GENOME-WIDE SIGNIFICANT GENETIC LOCI

Ganna Leonenkon,1, Arianna Di Florio1, Judith Allardyce1,

Liz Forty2, Sarah Knott1, Lisa Jones3,Katherine Gordon-Smith3, Nicholas Craddock2,Michael Owen4, Michael O'Donovan2, James Walters2,Ian Jones2, Valentina Escott-Price4

1Cardiff University School of Medicine2Cardiff University3University of Worchester4MRC Centre for Neuropsychiatric Genetics & Genomics,Cardiff University

Background: The aetiology of Bipolar Disorder (BD) andSchizophrenia (SZ) involves a complex gene-environmentinterplay and this involves common risk alleles that are

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shared across the disorders. Bipolar disorder is heteroge-neous in presentation and we and others have postulatedthat the particular clinical presentation is in part deter-mined by the particular risk alleles carried. To investigatethis, we have employed sparse Canonical Correlation Ana-lysis (sCCA), to seek patterns of correlation betweenpsychotic symptoms and schizophrenia risk alleles in a large(N=3903) deeply phenotyped sample of subjects with BD.Methods: Canonical Correlation Analysis (CCA) seeks lin-ear relationships between two sets of multi-dimensionalvariables. In the psychiatric genetics field, this approachcan be adapted to enable the analysis of both phenotypeand genetic variables in one framework. This has theadvantage of minimizing the number of statistical testsrequired. A recent extension of CCA to sparse canonicalcorrelation analysis (sCCA) allows application of the generalapproach to high dimensional genomic data (Witten et al.,2009). sCCA has advantages compared to CCA in terms ofprecision of parameter estimates and statistical power.

We employed sCCA to analyse 30 psychotic symptomsassessed with the OPerational CRITeria checklist (OPCRIT)and 82 independent genome-wide significant SNPs that wereidentified by the SZ PGC2 study (The Psychiatric GenomicsConsortium, 2014) for which we had data in our BD sample.We applied the sCCA as a purely data driven approach toindividual OPCRIT psychotic symptoms and also to groups ofOPCRIT psychotic symptoms (“positive”, “negative”, “dis-organised”) defined by a previously published factor analysisstudy of schizophrenia.Results: sCCA analysis of the individual OPCRIT items withthe set of significantly associated with SZ 82 sCCA analysisbased on individual psychotic symptoms revealed a signifi-cant association (p=0.045) with the largest weights attrib-uted to delusions of influence, bizarre behaviour andgrandiose delusions and an indel SNP on chromosome 3(3:180594593, build 37). sCCA analysis on the same set ofSNPs and OPCRIT symptom groups confirmed associationwith the same SNP and the “disorganised” group of OPCRITsymptoms (p=0.01). The results also show significant asso-ciation when we use less stringent p-value thresholds in SZ.In this case the most heavily weighted SNP remains3:180594593, but other SNPs also contribute to the analysis.Discussion: Our results suggest the CCA canonical corre-lation approach might be a useful tool to explore pheno-type-genotype relationships. It can be applied to generatedata-driven hypotheses with the potential to providefurther insights into the complex architecture of psychiatricdisorders. To the best of our knowledge, this is the firststudy to apply this approach in analysing phenotypes andgenotypes together. sCCA offers the potential to beextended to include a larger number of fine grainedsystematic descriptors of BD, and for testing for correlationwith genetic profiles from other co-morbid disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.098

SA27. EXOME SEQUENCING OF MULTIPLY AFFECTEDBIPOLAR DISORDER FAMILIES AND FOLLOW-UP RESE-QUENCING IMPLICATE RARE VARIANTS IN NEURONALGENES CONTRIBUTING TO DISEASE ETIOLOGY

Andreas J. Forstnern,1, Anna Maaser1, Jana Strohmaier2,

Kerstin U. Ludwig1, Franziska Degenhardt1, Fabian Streit2,Holger Thiele3, Peter Nürnberg3, Stefan Herms4,Per Hoffmann4, Sven Cichon4, Marcella Rietschel5,Markus M. Nöthen1

1University of Bonn2University of Heidelberg Medical Faculty Mannheim3Cologne Center for Genomics, University of Cologne4University of Bonn, University of Basel5Central Institute of Mental Health, Medical FacultyMannheim/University of Heidelberg

Background: Bipolar Disorder (BD) is a complex neurop-sychiatric disorder characterized by recurrent episodes ofmania and depression. It is a severe disorder of mood with alifetime prevalence of about 1% and a high heritability ofabout 70%.

Models of illness are most consistent with a polygeniccontribution of common and rare variants to disease sus-ceptibility. As the cumulative impact of common alleleswith small effect may only explain around 25–38% of thephenotypic variance for BD, rare variants of high pene-trance have been suggested to contribute to BD suscept-ibility. One way to evaluate this hypothesis is to investigatelarge pedigrees densely affected with BD, in which theexistence of a genetic variant of strong effect inheritedfrom a common ancestor may be more likely.Methods: In the present study, we investigated 226 indi-viduals of 68 large multiply affected families of Europeanorigin using Whole Exome Sequencing (WES). In each family,two to five affected individuals with BD or recurrent majordepression were selected for sequencing. WES was per-formed on the Illumina HiSeq. 2500 platform and theVarbank pipeline of the Cologne Center for Genomics wasused for data analysis. All identified variants shared withineach family were filtered for a minor allele frequencyo0.1% using data of the Exome Aggregation Consortium(http://exac.broadinstitute.org, non-psychiatric subsets)and potentially damaging effects predicted by at least fourof five different bioinformatics tools (Purcell et al., 2014).Results: We identified a total of 1214 rare, segregatingand functional variants implicating 1122 different genes, ofwhich 903 were brain expressed. Subsequently, we appliedthe Residual Variation Intolerance Scores (Petrovski et al.,2013) and identified 294 genes that were ranked among the20% most “intolerant” genes in the genome. Gene enrich-ment analysis of these genes showed a significant enrich-ment for 18 pathways (po0.001) including neuronprojection, axon development and cell adhesion.

We prioritized genes that were (i) found in at least twounrelated families in the present study, (ii) previouslyreported in next generation sequencing or GWAS studies of

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BD, or (iii) predominantly driving the significant pathways inour gene enrichment analysis.

The different approaches of prioritization yielded 42promising candidate genes including CDH22 which encodesa calcium-dependent cell adhesion protein that plays animportant role in the morphogenesis of neural cells duringbrain development.Discussion: Our preliminary results strongly suggest thatrare and highly-penetrant variants in neuronal and celladhesion genes contribute to BD etiology.

The 42 prioritized candidate genes are currently beingfollowed up by resequencing in cohorts of about 2500independent BD cases and 2500 controls of Europeanancestry. For resequencing, we use the single moleculemolecular inversion probes (smMIPs) technology thatenables multiplex targeted resequencing in large cohorts.The smMIPs sequences have been designed with the empiri-cally trained design algorithm MIPgen (Boyle et al., 2014)and sequencing is currently performed on the IlluminaHiSeq. 2500 platform. The resequencing results will providefurther insights into the particular genes and pathwayswhich are involved in BD development.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.099

SA28. ASSOCIATIONS IN THE UK BIOBANK COHORTBETWEEN GENETIC RISK SCORE FOR CALCIUM VOL-TAGE-GATED CHANNEL SUBUNIT ALPHA 1 C (CACNA1C)POLYMORPHISMS AND BOTH MOOD DISORDER PHENO-TYPES AND CHRONOTYPE PREFERENCE

Amy Fergusonn

, Joey Ward, Nicholas Graham, Jill Pell,Mark Bailey, Daniel Smith

University of Glasgow

Background: Variants of the Calcium Voltage-GatedChannel Subunit Alpha 1 C (CACNA1C) gene have beenassociated with several neuropsychiatric disorders, mostnotably Bipolar Disorder (BD) (Cross Disorder Group ofPGC., 2013). Previous studies of the function of BD-asso-ciated CACNA1C SNPs have tended to study single SNPs inisolation within relatively small samples (Bigos et al., 2010).Circadian rhythm disruption is recognised as a core clinicalfeature of BD, with BD individuals commonly reporting anevening chronotype preference (Bellivier et al., 2015).Given that CACNA1C has a key role in the regulation ofcircadian rhythms (Shi et al., 2008), we hypothesised that aCACNA1C Genetic Risk Score (GRS) would be associated bothwith mood disorder phenotypes and chronotype preferencewithin 95,073 UK Biobank participants.Methods: A Genetic Risk Score (GRS) combining several BD-associated CACNA1C SNPs was used to investigate the associa-tion between CACNA1C, several mood disorder-related phe-notypes (mood instability, neuroticism, BD status, MDD status)and chronotype. In light of evidence of a potential sex-specific

effect of CACNA1C variants, secondary analyses were stratifiedby sex (Dao et al., 2010; Heilbronner et al., 2015).Results: There was no association between CACNA1C GRSand any of the mood disorder phenotypes, or chronotype,after adjusting for confounding factors (age, sex, socialdeprivation and genetic principal components). However,there was preliminary evidence of an association betweenhigher CACNA1C GRS score and BD status in females (p=0.03).Discussion: Overall, we did not find association betweenCACNA1C GRS and a range of mood disorder phenotypes orchronotype preference within the UK Biobank cohort, butthere was evidence of a potential sex-specific effect ofCACNA1C variants on BD status in females. There is cur-rently considerable interest in the repurposing of calciumchannel blockers (CBBs) as new treatments for BD (Keerset al., 2009). Our findings, which require replication inother cohorts, suggest that there may be a sex difference intherapeutic effect of CCBs used to treat BD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.100

SA29. ADDRESSING THE IMPACT OF RARE GENETICVARIANTS IN EXTENDED/MULTIPLEX BIPOLAR FAMILIES

Claudio Toman,1, Alexander D. Shaw1, Richard J.N. Allcock2,

Anna Heath1, Kerrie D. Pierce1, Philip B. Mitchell3,Peter R. Schofield1, Janice M. Fullerton1

1Neuroscience Research Australia2Lotterywest State Biomedical Facility Genomics, Universityof Western Australia3Black Dog Institute, Prince of Wales Hospital

Background: Bipolar Disorder (BD) is a complex psychia-tric condition with high heritability, the genetic architec-ture of which likely comprises both common variants ofsmall effect and rare variants of higher penetrance. Multi-plex families with high density of illness provide an oppor-tunity to map novel risk genes or consolidate evidence forexisting candidates, by identifying genes carrying patho-genic rare variants.Methods: We performed Whole Exome Sequencing (WES)in 15 BD families (117 subjects: 72 affected, 28 unaffectedrelatives), augmented with Copy Number Variant (CNV)microarray data, to examine contributions of: i) predictedpathogenic SNVs and likely-gene-disruptive variants sharedin affected versus unaffected relatives; ii) genome-wideburden of likely-gene-disruptive variants; iii) de novo var-iants; iv) rare CNVs; and v) rare highly penetrant variantsunder family-specific linkage peaks. Linkage analysis andhaplotype reconstruction using WES-derived genotypesenabled elimination of false-positive SNVs, CNV inheritance,and candidate gene prioritisation. Gene Ontology and Gene-sets enrichment analyses were performed after correctionfor WES-covered ORF length and genic constraint using anull distribution of overlap with randomly drawn gene sets

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matching on these characteristics. Spearman's correlationassessed relationships between genome-wide burden oflikely-gene-disruptive variants in brain-expressed genesand age of onset.Results: Rare predicted pathogenic variants shared amongstZ3 affected relatives were over-represented in PostsynapticDensity (PSD) genes (P=0.002, PBonf=0.024), with no enrich-ment in unaffected relatives. Burden of likely-gene-disruptivevariants was no different in affected versus unaffected relatives(P=0.24), but correlated significantly with age of BD onset(P=0.017). The number of de novo variants in affected versusunaffected offspring was no different (P=0.23), although wenote a higher overall rate (1.44/individual) than previousreports. We identified novel BD candidate genes, includingthe X-linked IRS4 with a stop mutation in all 5 affected siblingswhich mapped within a family-specific linkage peak. IRS4displays a restricted pattern of expression in the amygdala,and IRS4-/- mice show compromised maternal nurturing beha-viours. Further, our study implicates the protocadherin family ofgenes, which act to mediate neuronal connectivity. Weobserved heterogeneity within and between families, withalleles of modest effect and reduced penetrance being themost likely genetic model.Discussion: Genetic approaches that combine WES, CNVand linkage analyses in extended families is an effectivemethod for detection of potential pathogenic variation,pinpointing genes and pathways that may contribute to thepathophysiology of BD. A high burden of brain-expressedloss-of-function variants may expedite symptom onset in BDindividuals, and further investigation of this relationshipwith other measures of BD severity are warranted.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.101

SA30. GENETIC HETEROGENEITY OF BIPOLAR DISOR-DER: A FOCUS ON MANIC PSYCHOSIS AND THE SIMILA-RITIES TO SCHIZOPHRENIA

Brandon Coombesn,1, Matej Markota1, Beth Larrabee1,

Susan McElroy2, Colin Colby1, Mark Frye1, Joanna Biernacka1

1Mayo Clinic2Lindner Center of HOPE

Background: Bipolar Disorder (BD) is highly heteroge-neous contributing to challenges in identifying geneticcontributions to risk of illness. Narrowing the clinicalphenotype may help identify risk genes. This study wasdesigned to identify genetic components of psychotic maniain bipolar disorder, and potential genetic overlap betweenbipolar disorder with psychosis and schizophrenia.Methods: We studied a Mayo Clinic Bipolar Disorder Biobankcohort of 695 BD type I (BD-I) cases and 777 controls. Of the695 BD-I cases, 336 had a history of manic psychosis, and 309had no history of psychosis. A Polygenic Risk Score (PRS)analysis was performed by using Psychiatric Genomics

Consortium Schizophrenia genome-wide summary statisticsas training dataset to create PRS. Schizophrenia PRS was thenused to predict BD-I vs controls, BD-I with manic psychosis vscontrols, BD-I without psychosis vs controls, and BD-I withmanic psychosis vs BD-I without psychosis. A genome-wideanalysis was performed comparing BD-I patients with a historyof manic psychosis with BD-I cases with no history of psychosis.We also performed gene-level and pathway-level analysesusing MAGMA in the same case-only sample.Results: PRS analysis showed that the schizophreniagenetic risk score was more predictive of BD-I with manicpsychosis than of BD-I without psychosis (BD-I with manicpsychosis vs controls: p=1.1� 10e-12, R2=6.6%; BD-I with-out psychosis: p=0.0001, R2=1.9%). Our GWAS showed noSingle Nucleotide Polymorphisms (SNPs) with genome-widesignificance; the top SNP was rs11126581 from the LRRTM4gene (OR=2.17, p=1.08� 10-6). LRRTM4 was also amongthe top genes in the gene-level analysis. The pathwayanalysis identified one significant pathway: the GO paranoderegion of the axon (p=0.008).Discussion: Our results show that patients with schizo-phrenia are genetically more similar to bipolar patients whodevelop psychotic mania than those who never developpsychosis. This study was underpowered to detect SNPsassociated with psychotic mania; however, the marginallysignificant association with LRRTM4 and the significantpathway, which contains ANK3, are potentially interestingfindings. The LRRTM family and ANK3 have been previouslyimplicated in schizophrenia and therefore could be involvedin development of psychosis, regardless of schizophrenia orbipolar disorder distinction.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.102

SA31. GENETIC VARIANTS AS MODIFIERS OF THE ASSO-CIATION OF BODY MASS INDEX WITH BIPOLAR DISORDER

Stacey Winhamn,1, Alfredo Cuellar-Barboza2,

Anthony Batzler1, Rolf Adolfsson3, Martin Alda4,Ole Andreassen5, Arianna Di Florio6, Andreas J. Forstner7,John Kelsoe8, Mikael Landen9, John Vincent10, PsychiatricGenomics Consortium (PGC) Bipolar Disorder WorkingGroup, Susan McElroy11, Mark Frye1, Joanna Biernacka1

1Mayo Clinic2UANL3UME University4Dalhousie University5University of Oslo6Cardiff University7University of Bonn8University of California, San Diego9Gothenburg University10Centre for Addiction and Mental Health11Lindner Center of HOPE

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Background: Bipolar Disorder (BD) is associated withhigher Body Mass Index (BMI). In a prior Genome-WideAssociation Study (GWAS) of BD, we found that rs12772424in TCF7L2, a transcription factor in the Wnt signalingpathway, modified the association between BMI and BD(Winham et al., 2014), and subsequently replicated thisfinding in an independent sample (Cuellar-Barboza et al.,2016). Preliminary data further suggested that the TCF7L2-BMI interaction association with BD may be sex-specific,with stronger effects observed in females. Additional stu-dies are needed to validate these findings and determinethe role of other clinical factors and genetic modifiers in theBMI-BD association. Here, using data from the PsychiatricGenomics Consortium (PGC), we seek to identify additionalgenetic variations that may be contributing to the associa-tion of BD with elevated BMI.Methods: Data from nine PGC sites were included in thisstudy (3165 cases, 2645 controls); five sites provided BMIdata for cases and controls, whereas four sites had BMI dataonly for cases. In all analyses, BMI was log-transformed.Separately for each site, case-only GWAS analyses wereconducted to investigate SNPnBMI interaction effects byexamining SNP effects with BMI as the outcome variableusing linear regression, for SNPs that have not shownevidence of genome-wide significant BMI association in priorstudies. Additionally, for sites with controls, case-controlanalyses were conducted using logistic regression, adjustedfor BMI. Two tests were performed: 1 df test of SNPnBMIinteraction, and 2 df test of SNP effect and the SNPnBMIinteraction effect. Results of the site-specific analyses werethen meta-analyzed for SNPs observed across all sites. Sex-stratified analyses were also conducted.Results: No evidence of study heterogeneity was observedfor the top SNPs. In case-only and case-control analyses ofSNP-BMI interaction effects, no results were genome-widesignificant (overall or sex-stratified). The top result in thecase-control analysis for SNP-BMI interaction was rs736893in GLIS3 (OR=1.03, P=3.6E-5), with a stronger result inmales in sex-stratified analyses (OR=1.07, P=5.7E-6). Thetop result in the case-only analysis of SNP-BMI interactionwas rs4285452 in GSDMC (beta=0.02, P=3.3E-6), whichshowed similar results in males and females. In sex-strati-fied case-only analyses, the strongest result was in femalesfor rs7994174 in DCLK1 (beta=0.05, p=4.5E-6), where noeffect was observed in males.Discussion: Although no genome-wide significant findingswere identified in analyses of SNPnBMI effects on BD risk,overall or stratified by sex, interesting candidate variantswere observed in genes including GLIS3 and DCLK1. GLIS3encodes a zinc finger protein that has been associated withneonatal diabetes and congenital hypothyroidism. DCLK1encodes doublecortin like kinase 1, which is involved inneuronal migration, transport, neuronal apotosis, and neu-rogenesis; it is upregulated by BDNF, previously implicatedin both BD and BMI. The retrospective data analyzed herecan only identify associations, and does not allow us todetermine directionality of these associations, so furtherinvestigation is needed to determine if SNP effects modifythe effect of BMI on BD or vice versa. Future directionsinclude analysis of imputed data, gene set analyses, ana-lyses of secondary phenotypes related to BMI (e.g. binge

eating disorder and weight gain), and analyses to investi-gate possible medication effects.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.103

SA32. GSK-3B 50 T/C POLYMORPHISM AND ASSOCIATEDCLINICAL PARAMETERS IN BIPOLAR DISORDER

Bharathram Raghuramann

, Pradip Paul, Ravikumar Nadella,Vaisnvy Kapur, Somdatta Sen, Lakshmi Narayanan Kota,Biju Viswanath, Meera Purushottam, Sanjeev Jain

National Institute of Mental Health & Neurosciences

Background: Of the genes that are implicated in BipolarDisorder (BD), GSK -3B is important, especially because ofthis gene playing a vital role in various neurological net-works, cell cycle, and circadian rhythm. All the above, arethought to play a role in the evolution of BD though theindividual contributions of each are yet to be delineated.GSK-3B 50 T/C Polymorphism (SNP) is important for itsproposed association with various clinical parameters ofBD including age at onset, presence of psychotic symptomsand total number of episodes.

We aimed at studying this genetic polymorphism and lookfor its association with the above mentioned clinical para-meters of BD in Indian population.Methods: 175 patients with Diagnosis of Bipolar Disorderaccording to DSM-IV were recruited from all patientsattending Outpatient Services of National Institute ofMental Health and Neurological Sciences (NIMHANS). Thediagnosis was confirmed using Clinical Interview and MINI5.0.0. Genotype analysis for 175 patients selected was donefor GSK-3B -50 T/C using PCR-RFLP method. Clinical vari-ables including Age at Onset, Total number of episodes andPresence of Psychotic Symptoms were assessed.Results: Of all the 175 patients who were selected for thestudy, demographic analysis was done with the mean age atonset being 19.31 years (SD-4.32). Lifetime psychoticsymptoms were noted among 153 subjects (87.4%). TheMedian of the total no of episodes in the studied subjectswas 4 episodes (SD -4.94).

The genotype Frequencies for the GSK-3B 50 T/C polymorph-ism CC-24.6%, TC-48.6%, TT-26.9% for 175 patients, did notdeviate from Hardy-Weinberg equilibrium. No statistically sig-nificant correlation was found between GSK-3B 50 T/C SNP andthe clinical parameters that were studied including age at onset(N=175), presence of psychotic symptoms(N=175) and Totalnumber of episodes(N=175) (all p40.05).Discussion: No significant association was found betweenTT genotype and an earlier age at onset of illness. However,the mean age at onset of the subjects in the TT genotypegroup being 18.80 years (SD-6.2 years) was the lowest.

This result did not replicate the favorable association ofTT genotype and earlier age at onset from an earlier studyby Benedetti et al. in 2004 which was conducted inCaucasian population. The frequency of the CC genotype

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19PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

(5%) of their 60 cases was unlike in our population where CCgenotype was found in 24.6% of the subjects.

In a study by Serretti et al. in 2007, a trend was notedwith CC genotype carriers having higher delusion scoreswhile no significant association was noted with presence ofCC genotype and the presence of psychotic symptoms in ourstudied population.

No association was found between GSK-3B 50 T/C andtotal number of episodes in our studied population which isconsistent with study by Szczepankiewiczi et al., 2006.

We are also in the process of doing gene expression analysisfrom cell lines derived from patients with this SNP along withassessment of response to Lithium to obtain further insights intothe functions of this SNP in bipolar disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.104

SA33. VARIABILITY IN EXPRESSION OF TMEM163 INBRAIN CORTEX IS ASSOCIATED WITH RESILIENCE TOMULTIPLE BRAIN DAMAGE PHENOTYPES IN A BIOBANKPOPULATION

Jessica Dennisn

, Nancy Cox, Xue Zhong

Vanderbilt Genetics Institute, Vanderbilt University MedicalCenter

Background: Resilience to brain damage describes theimperfect correlation between clinical symptoms and theextent of brain injury, whether traumatic, degenerative, orvascular in origin. DNA samples linked to electronic medicalrecords (biobanks) offer unique opportunities to identifygenes that underlie multiple brain resilience phenotypes.We use Traumatic Brain Injury (TBI) as our discoveryphenotype, since over 8 million Americans sustain a TBIannually, and the pathology underlying TBI is hypothesizedto overlap that of other neurological diseases, ranging frompersistent headache to dementia.Methods: We report the first GWAS of TBI risk, conductedin the Vanderbilt University Biobank, BioVU, which includes4270,000 patients. Results from single SNP analyses can bedifficult to interpret and pay a heavy multiple testingburden. We therefore applied a gene-based tool, PrediXcan,to predict gene expression levels in 9155 European-ancestryBioVU patients from genome-wide genotype data in thetarget sample (BioVU) and a reference transcriptome data-set (GTEx). We tested 11005 genes in whole blood and 9164genes in brain cortex for association with TBI defined by CDCcriteria as one or more ICD codes for ‘Cerebral lacerationand contusion’, ‘Concussion’, ‘Intracranial hemorrhage fol-lowing injury’, ‘Skull fracture’, and ‘Other intracranialinjury’. Analyses were adjusted for sex, age (at first TBI orat last ICD code in the medical record), and principalcomponents 1–3. Genes significantly associated with TBIwere tested for association with 1309 phenotype codes in aPhenome-Wide Association Analysis (PheWAS).

Results: TBI was diagnosed in 503 of 9155 patients. Themedian age at first TBI was 51.7 years, 6.8% of patients wereo18 years of age at first TBI, and 57.8% of TBI patients weremale. No genes expressed in whole blood were associatedwith TBI or any of its sub-categories after applying Bonfer-roni correction. Conversely, expression of TMEM163 incortex was associated with an increased risk of ‘Otherintracranial injury’ (odds ratio, OR=1.59, p=1.68� 10-7)and was marginally associated with TBI overall (p=0.001).TMEM163 is a transmembrane zinc transporter implicated bymeta-GWAS in Parkinson disease (PD) risk. In PheWAS, eightcodes passed Bonferonni correction, including three codesunder the umbrella ‘Delirium dementia and amnestic andother cognitive disorders’ (OR=1.58, p=2.84� 10-5), andone code for ‘Abnormality of gait’ (OR=1.40, p=2.30� 10-5). Increased expression of TMEM163 was marginally asso-ciated with reduced risk of PD (OR=0.46, p=0.10). Whilethe top-ranked neurodegenerative codes were more com-mon in TBI patients than in controls, the associationbetween TMEM163 expression and TBI persisted when westratified by neurodegenerative disease.Discussion: Our analyses suggest that TMEM163 expres-sion in cortex is associated with resilience to multiple typesof brain damage. Further research is warranted to disen-tangle the complex temporal and potentially confoundingrelationships between phenotypes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.105

SA34. MITOCHONDRIAL DYSFUNCTION IN ALZHEIMER'SDISEASE

Lakshmi Narayanan Kota, Rashmitha Nayak, Pradip Paul,Biju Viswanath, Mathew Varghese, Sanjeev Jain,Meera Purushottam

n

National Institute of Mental Health and NeurologicalSciences

Background: Alzheimer's Disease (AD) is a neurodegenera-tive disorder characterized by progressive decline in memoryand executive functions. APOE4 allele increases the risk for ADby 2.5 times in the Indian population. Previous reports showAPOE4 is cleaved to produce toxic fragment, in neurons, whichis associated with mitochondrial dysfunction. APOE4 is alsoassociated with elevated mitochondria‐associated EndoplasmicReticulum (ER) Membranes (MAM) dysfunction, similar to that ofpresenilin‐deficient cells.

Further, an intronic poly T variant (L allele) of the TOMM40gene (Translocase of Outer mitochondrial membrane) isreported to be associated with AD, and along with APOE4,seems to influence the age of onset in the disease (AAO). Thispoly Trepeat acts as an enhancer, and influences the expressionof both Tomm40 and APOE. Longer repeats are associated withincreased expression of Tomm40 which in turn increases thereactive oxygen species production.

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Methods: Subjects diagnosed with AD (n=167) at theclinical services of NIMHANS were invited to participateand provide blood samples after informed consent. Controls(n=179) were volunteers with no family or past history ofneuro-psychiatric illness. APOE genotype was determinedusing allele specific primers. Mitochondrial DNA (mt DNA)copy number was estimated using SYBR Green. The relativecopy number of mt DNA was assessed after ND1 and CytBnormalization by a nuclear encoded housekeeping gene PK1.TOMM40 repeat length was estimated by polymerase chainreaction followed by fragment length analysis. Based onlength the poly T polymorphism was divided into short allele(So19), long allele (L=19 to 29) and very long (VL429).Results: There is a significant association of APOE4 withAD (0.26) compared to controls (0.09). (po0.05). There isan increased occurrence of the L allele in association withAPOE4. Forty percent of APOE4 carriers have L allelecompared to seven percent in APOE4 non carriers. The ‘L’allele of Tomm40 shows association with AD as compared tocontrols after correcting for APOE.(Poo.o5).

The mitochondrial DNA content was not significantlydifferent between AD cases and age matched controls.However, APOE4 carriers showed significantly reduced mito-chondrial DNA content than their non APOE4 counterpart.There was no significant correlation with age of onset ordisease severity seen in the AD group.Discussion: We explored the effect of the E4 allele onmitochondrial copy number, and find a diminished copynumber in E4 carriers. Since the mitochondrial DNA copynumber is known to affect expression of the mitochondrialgenes, this might explain the changed bioenergetics in thecontext of AD.

The L allele shows an increased allele frequency in APOE4carriers. Further, AD cases that lack the APOE4 allele showpresence of L allele. We conclude that the L allele of TOMM40might have an additional role in pathogenicity in the ADcontext.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.106

SA35. PPD ACT, AN APP-BASED POSTPARTUM DEPRES-SION GENETIC STUDY

Jerry Guintivanon,1, Holly Krohn1, Carol Lewis1,

Alexander Ploner2, Patrick Sullivan1,Samantha Meltzer-Brody1

1University of North Carolina at Chapel Hill2Karolinska Institutet

Background: Postpartum Depression (PPD), a subtype ofMajor Depressive Disorder (MDD), has a lifetime prevalenceof 10–15% and is one of the most frequent complications ofchildbirth. PPD is particularly suited to genetic investigationas it is a more homogenous phenotype than MDD occurringoutside of the perinatal period (i.e., women of childbearingage exposed to a similar biopsychosocial stressor).

Therefore, we developed an iOS app (PPD ACT) with thegoal of recruiting 100,000 women with a lifetime history ofPPD to sufficiently power Genome-Wide Association Studies(GWAS). We used Apple's ResearchKit platform to put ourresearch study in the hands of thousands of women inter-nationally, becoming the first mobile health study focusedon psychiatric genetics.Methods: PPD ACT is a study with two basic components:1) participant screening for PPD and 2) collection of DNAfrom PPD cases. Women who believe they may have had PPDdownload the app, complete a basic eligibility quiz, and arepresented with Informed Consent (IC) for PPD screening. Toassess for comprehension of study procedures, women mustcomplete a quiz prior to finger-signing the IC document.Participants are then screened for PPD using the lifetimeversion of the EPDS and those identified as cases are theninvited to participate in DNA collection. If they wish toparticipate, they complete another IC process (presentationof IC contents, quiz, signature) and are sent a spit kit viaUSPS. To validate app findings, we performed clinicalvalidation in UNC Hospitals and assessed recall validity usinga second PPD screen (6 – 8 months after initial assessment).Results: PPD ACT was released to the US App Store onMarch 21, 2016. The data presented here are from the first-year post-launch. PPD ACT was downloaded 13,869 times.Following download 10,473 participants completed a basiceligibility screen and consent for phenotyping, with 7,607PPD cases identified. After one year, 3,038 saliva sampleshave been biobanked. The lifetime EPDS threshold for PPDcase status was Z 13 but the median score in cases was 23(IQR: 20 – 25). This sample of PPD cases was notablyseverely affected. PPD ACT had a sensitivity of 100% in aclinical validation sample (n=43). In addition, 2,149 womenparticipated a second lifetime EPDS assessment. There wasa 92% agreement in case status (AC1=0.92, 95% CI: 0.91 –

0.93) among participants who took place in reassessment.Discussion: PPD ACT is the first mobile health applicationfor a psychiatric genetics study, screening and collectingsamples directly from participants. Overall, we enrolled apopulation of cases that experienced severe episodes of PPDand a large proportion of cases reported symptoms so severethey sought professional help or were prescribed medica-tion. With the response we obtained in just the first year ofour study, we are confident that we are well on the way tohelping all women who suffer with postpartum depression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.107

SA36. ASSESSMENT OF PERCEPTION OF STRESSFULLIFE EVENTS AS IMPORTANT FACTORS IN MAJORDEPRESSIVE DISORDER (MDD)

Liliana Galeano Petro, Alejandra Gaviria,Catalina Cañizares, Catalina Uribe, Eugenio Ferro,Alvaro Arenas, Yvonne Gómez, Claudia Lattig

n

Universidad de los Andes

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Background: Major Depressive Disorder (MDD [MIM:608516]) is a multifactorial disease that affects morbidity,mortality and quality of life. It is a chronic and recurrentphenotype of a complex etiological relationship betweengenetic and environmental factors where early childhoodadversity and stressful life events are recognized environ-mental risk factors for MDD. However, early-life adversitydoes not always end in MDD but the individual stressassessment may be a determining factor in the presenta-tion of MDD symptoms. Additionally, Brain-Derived Neuro-trophic Factor Gene (BDNF) Val66Met (rs6265) variant hasa well-established role in neuronal plasticity anddecreased levels have been observed in individuals withMDD. Previous studies present evidence that support theidea that vulnerability to environmental stress is mediatedby the rs6265 variant. However, there is still some con-troversy on the topic, mainly because most of thesestudies have been carried out in non-clinical populations.This study aimed to stablish if the number and individualresponse to adverse events together with the Val66Metvariant may predict MDD.Methods: Here we present a case-control study using aclinical population from two psychiatric clinics and matchedcontrols. An initial inclusion criterion was establishedthrough the M.I.NI interview. Subsequently, the ESV ques-tionnaire and event assessment was applied. The rs6265variant was genotyped using real time PCR with Taqmanprobes from Applied Biosystems 7500/7500.Results: This study was approved by the ethics commit-tee of all the participant institutions. We did not find anyassociation or gene x environment interaction betweenthe rs6265 variant and MDD. Early stress events andrecent stressful live events are significant risk factorsfor MDD.Discussion: When analyzing the response to these eventswe found that the experimental group had a significantincrease in negative affectivity, frequency of stressfulevents and the level of stress the event provoked. Inconclusion, the assessment given to each individual stressevent are determinant for the phenotypic expression onMDD and should be analyzed together with other knowngenetic variants involved in MDD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.108

SA37. NEUROINFLAMMATORY GENE EXPRESSION IN HIP-POCAMPUS IN MAJOR DEPRESSIVE DISORDER

Gouri Mahajann,1, Eric Vallender1, Michael Garrett1,

Lavanya Challagundla1, James Overholser2, George Jurjus3,Lesa Dieter4, Ham Benghuzzi1, Craig Stockmeier4

1University of Mississippi Medical Center2Case Western Reserve University3Louis Stokes Cleveland VA Medical Center4University of Mississippi Medical Center; Case WesternReserve University

Background: Major Depressive Disorder (MDD) is a com-mon psychiatric disease for which available medications areoften not effective. Full remission from depression isachieved by less than 50 percent of patients using medica-tions that mainly target serotonin or norepinephrine sys-tems (Berton and Nestler, 2006; Rush et al., 2006). Theeconomic burden of depression in the U.S., along withcomorbid conditions, is estimated at over $170B anddepressive disorders are the leading contributors to globalburden of disease (Greenberg et al., 2015; Whiteford et al.,2013). The high prevalence of MDD and modest response toexisting therapies compels efforts to better understand andtreat the disorder. One promising avenue of researchsuggests that decreases in hippocampal volume withincreasing duration of depression results from a decreasein neurogenesis or altered gene expression (Sheline et al.,1996, Cobb et al., 2013).Methods: Tissue punches from the dentate gyrus werecollected from 23 subjects (MDD, medication-free) and 23demographically-matched normal controls. Of the 23 sub-jects with MDD, 17 died by suicide and 17 had multipledepressive episodes. High quality total RNA, RNA QualityIndex 4 6, was isolated and whole transcriptome paired-end shotgun sequencing was performed using an IlluminaNextSeq. 500. For each sample, raw RNA-seq reads (adap-ter-trimmed fastq files) were aligned to the EnsemblGRCh38 human reference genome using GSNAP (GenomicShort-read-Nucleotide Alignment Program). Differentialgene expression was determined using cuffdiff, and corebiological processes, molecular networks, and pathwayspathologically disrupted in MDD were identified using Inge-nuity Pathway Analysis.Results: For each sample, 37 to 112 million reads wereobtained and 64 to 96% were mapped successfully to thehuman genome, with most samples mapping above 85%.‘Cuffdiff’ analysis in the Tuxedo suite revealed 30 significantgenes differentially expressed in all MDD compared tocontrols (Lumenogix™, FDR o 0.05). Genes down-regulatedin MDD included several with inflammatory function (ISG15,IFI44L, IFI6, NR4A1) and GABBR1. Genes up-regulated inMDD included those with cytokine function (CCL2/MCP-1),inhibiting angiogenesis (ADM, ADAMTS9), and the KANSL1gene, a histone acetyltransferase. Similar analysis of spe-cific subsets of MDD subjects gave analogous results.Discussion: The key finding in the primary MDD dataset aswell as in the subsets is the overrepresentation of neuroin-flammation related genes. Inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways were significantlyaltered in the hippocampal dentate gyrus in MDD, withcytokine signaling and inflammatory pathways preferen-tially altered in MDD-suicide vs. MDD-non-suicide. Togetherthis suggests that neuroinflammation, mediated by micro-glia and astrocytes may play a crucial role in majordepressive disorder. These findings suggest a novel approachby seeking targets for new treatment of MDD that includesanti-inflammatory and neuroprotective properties.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.109

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SA38. GWAS-BASED MACHINE LEARNING APPROACH TOPREDICT DULOXETINE RESPONSE AND REMISSION INMAJOR DEPRESSIVE DISORDER

Malgorzata Maciukiewiczn,1, Victoria Marshe1,

Anne-Christine Hauschild2, Jane A Foster3, Susan Rotzinger3,James L. Kennedy1, Sidney H. Kennedy4, Daniel J. Müller1,Joseph Geraci5

1Centre for Addiction and Mental Health2IBM Life Sciences Discovery Centre, Princess MargaretCancer Centre, University of Toronto, University HealthNetwork3University Health Network4University of Toronto, University Health Network and St.Michael's Hospital5Queen's University

Background: Major Depressive Disorder (MDD) is one ofthe most prevalent psychiatric disorders and is commonlytreated with antidepressant drugs. However, large variabil-ity is observed in terms of response to antidepressants.GWAS based Machine Learning (ML) models may be useful topredict treatment response, thus improving antidepressanttreatment.Methods: A sample of 186 MDD patients received treat-ment with duloxetine for up to 8 weeks were categorized as“responders” based on a Montgomery-Åsberg DepressionRating Scale (MADRS) change 450% from baseline; or“remitters” based on a MADRS score of 10 or lower at endpoint. The initial dataset (N=186) was randomly dividedinto training and test sets (70% and 30%, or 130 and 56individuals respectively), resulting in ten different trainingand test set pairs. A genome-wide logistic regression wasperformed to identify potentially significant variants relatedto duloxetine response/remission and extracted the mostpromising predictors using LASSO regression. Subsequently,Classification-Regression Trees (CRT) and support vectormachines (SVM) were applied to construct models, usingten-fold, repeated cross-validation.Results: For the response phenotype, LASSO regressionsuggested twenty SNPs to be entered in prediction models.Calculated models for response achieved accuracy of 63.43%for CRT and 78.93% for SVM. For the remission phenotype,LASSO filtering suggested five SNPs. Best models werecharacterized by an accuracy of 65.45% with a sensitivityof 69.31% and specificity of 61.43%.Discussion: In this study, the potential of using GWAS datato predict duloxetine response was examined using MLmodels. These models managed to capture a fraction ofresponders and remitters (i.e. moderate sensitivity), butfailed to filter out non-responders and non-remitters (i.e.low specificity). Inclusion of additional non-genetic vari-ables to create integrated models may help improve pre-diction results.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.110

SA39. A CLUSTER RANDOMIZED CONTROLLED TRIAL OFA PSYCHOEDUCATIONAL INTERVENTION FOR PEOPLEWITH A FAMILY HISTORY OF DEPRESSION FOR USE INGENERAL PRACTICE

Bettina Meisern,1, Llewellyn Mills2, Raghib Ahmad1,

Peter Schofield3, Michelle Peate4, Charlene Levitan1,Lyndal Trevena2, Kristine Barlow-Stewart2,Timothy Dobbins1, Helen Christensen1, Kerry A. Sherman5,Kate Dunlop6, Philip B. Mitchell1

1University of New South Wales2University of Sydney3Neuroscience Research Australia4University of Melbourne5Macquarie University6Centre for Genetics Education

Background: Many individuals with a family history ofdepression are concerned about their risks of developing majordepressive disorder and/or bipolar disorder and the risks totheir offspring. They report a range of unmet educational andpsychological support needs in relation to their familial risk.Several high-quality websites delivering therapy for, and educa-tion about, depression have been developed. However, noonline interventions are available that specifically target peoplewith a family history of depression.Methods: A cluster randomised controlled trial was carriedout in the primary health care setting. GP attendees with atleast one first-degree relative with major depressive disorderor bipolar disorder were eligible to participate. Twentygeneral practices were randomised to provide eligiblepatients access to either the intervention (n=10) or controlcondition (n=10). Participants completed outcome measuresat baseline and 2-week follow-up. The primary outcome wasintention to undergo or actually undergoing psychologicaltherapy as a risk reduction strategy for development ofdepression. Secondary outcomes were: knowledge of riskfactors and risk reduction strategies, perceived risk ofdeveloping major depressive disorder or bipolar disorder,depression symptoms, and perceived stigma.Results: 211 patients completed both questionnaires andwere included in the analyses. Compared to the controlgroup, the intervention group participants were more likelyto intend to use or use therapy (OR=3.45, 95% CI: 1.28–11.20, p=.016), had a significantly greater increase inknowledge (mean difference 0.47, 95% CI: 0.09–0.88,p=.022) and were more likely to accurately estimate theirlifetime risk of developing bipolar disorder (mean differ-ence 11.2, 95% CI: -16.19–-5.48, p o.001). There were nosignificant differences in the other outcomes measured.Discussion: This psychoeducational website can play animportant role in improving the outcomes of individuals atfamilial risk for depression. Testing of the intervention inother health practitioner settings (e.g. psychologists, psy-chiatrists, genetic counsellors) appears warranted.

Disclosure: Astrazeneca – Consultant, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.111

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SA40. A TWO-DIMENSIONAL APPROACH FOR A VENLA-FAXINE TREATMENT EFFICACY PREDICTION MODEL

Dekel Taliazn

, Omri Teltsh

Taliaz, Ltd.

Background: Patient response to antidepressant treatmentis frequently defined at the end of treatment, as an improve-ment of 50% or greater from the initial depression score.However, this definition does not take into account the ‘timeto response’, therefore not allowing for any differentiationbetween response rates. Of course, time to response can be animportant factor when trying to determine features influencingthe efficacy to antidepressant treatments as the genetic back-grounds of ‘fast’ and ‘slow’ responders may be different. Bytaking into consideration both depression scores and time toresponse, we can find new features that may serve aspredictors. Additionally, many genetic differences may impactthe efficacy to antidepressants, and analysis of combinations ofgenetic factors is needed to define novel predictors of responseto antidepressant treatments. We applied novel methods, basedon this logic, to design a prediction model of efficacy toVenlafaxine treatment.Methods: Using the raw data of the Sequence TreatmentAlternatives to Relieve Depression (STARnD) clinical trial, wehave designed two response models for the Venlafaxinetreatment group: 1. A percentage of depression score reduc-tion using the first and last scores. 2. An exponential formula,taking into account all depression scores for each patient, andplotted against their number of days in treatment. For geneticfeature selection, we have applied a genome–wide associationapproach, and then developed a prediction model by applyingmachine learning algorithms to define combinations of para-meters that predict response for Venlafaxine.Results: Out of the 135 patients who were treated withVenlafaxine, the 50% depression score reduction approachfound that 51 patients were responders and 84 patientswere non-responders. The exponential approach however,labeled 66 patients as responders and 69 patients as non-responders. We split the Venlafaxine group into train andvalidation groups. The split was performed randomly toremove bias. Genome-wide association analysis identifiedtwo genetic features for the Venlafaxine model only for theexponential response model groups, but not for the 50%depression score reduction approach. After feature selec-tion was performed, a Support Vector Machine (SVM)machine learning algorithm with a linear kernel wasapplied. The prediction model yielded the following resultson the validation group: Area Under the Curve (AUC) of0.8511, accuracy of 77.50%, sensitivity of 76.19%, specificityof 78.95%, positive predictive value of 80.00% and negativepredictive value of 75.00%.Discussion: Genome-wide association analysis on a two-dimensional response model taking into consideration bothchanges in depression score and time of response, revealednovel features which predict the response to Venlafaxine.These features could not be found using the commonly usedone-dimensional 50% depression score reduction model,emphasizing the strengths of using a two-dimensionalapproach. Furthermore, by using machine learning

algorithms we have managed to design a highly accurateprediction model of response to Venlafaxine, based on thecombinatorial approach between the genetic features weidentified by genome-wide association. Applying new mod-els and new algorithmic methods on currently availablelarge datasets can lead to novel findings which will advanceour understanding of psychiatric disorders, and advance thedesign of accurate prediction models for psychiatricmedications.

Disclosure: Taliaz, Ltd. – Stock / Equity, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.112

SA41. DIFFERENTIAL GENE EXPRESSION IN THE PRE-FRONTAL CORTEX ASSOCIATED WITH SUICIDE

Xiao Zhang1, Robert Gilmore1, Shaurita Hutchins1,Gouri Mahajan1, Alison Athey2, James Overholser2,Craig Stockmeier3, Eric Vallender

n,1

1University of Mississippi Medical Center2Case Western Reserve University3University of Mississippi Medical Center; Case WesternReserve University

Background: Suicide is one of the top five causes of deathfor individuals between the ages of 10 and 54; however,unlike many other causes of death, it is preventable ifrecognized and treated. Evidence from family studiessuggest that suicide has a genetic basis, though specificassociated genes are less well understood. Although suicideis a complicated, multi-factorial behavior, one importantassociated endophenotype is trait impulsivity. Trait impul-sivity and behavioral inhibition is controlled by the pre-frontal cortex. While the complexity and circuitry of theseregions are still being explored, two regions, the dorsolat-eral prefrontal cortex (dlPFC) and the Orbitofrontal Cortex(OFC) are consistently associated with impulsive action andloss of impulse control as well as suicidal behavior.Methods: The dlPFC and OFC was isolated from 60 demo-graphically similar that had either died from suicide or fromnatural causes. A psychological autopsy was performed onall individuals, assessing for major depressive disorder andother psychiatric disease. Complete screening was alsoperformed for the Behavioral and Emotional Impulsivitysubscales of the SIDP-IV and the MLES. Total RNA wasisolated from these regions and next generation sequencingwas performed using an Illumina NextSeq. 500 with a 150 bppaired-end protocol. Data was processed using the ‘tuxedo’pipeline and functional enrichment was performed withIngenuity Pathway Analysis.Results: As with previous studies, an association wasobserved between behavioral and emotional impulsivity asmeasured by the SIDP-IV and suicidal behavior. This associa-tion held when controlling for gender, alcohol or tobaccouse, or major depressive disorder. RNA quality and subse-quent next generation sequencing was unaffected by differ-ences in post-mortem death interval, tissue pH, or age at

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M. Barbu et al.24

death. Differential gene expression was observed betweenindividuals who died from suicide and those who died fromnatural causes, regardless of whether the latter werediagnosed with major depressive disorder. These genespartially, though not entirely, overlapped with genes asso-ciated with behavioral and emotional impulsivity indepen-dent of cause of death. Additional work is ongoing furthercharacterizing the interactions between these factors andtheir impact on gene expression.Discussion: Identifying individuals most at risk for suicideallows for proactive intervention that can directly savelives. By focusing on impulsivity as an endophenotype, it ispossible to better identify genetic effects. By using geneexpression analyses, it is possible to better place thesegenetic effects in context. This study allows for a betterunderstanding of the molecular factors underlying executivecontrol in the prefrontal cortex and offers insight into thedysregulation that occurs leading to suicidal behaviors.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.113

SA42. POLYGENIC DISSECTION OF T2DM AND DEPRES-SIVE SYMPTOMS

Carol Kann,1, Niamh Mullins1, Divya Mehta2, Yuri Milaneschi3,

Christopher Garrett1, Maciej Trzaskowski4, Hans J. Grabe5,Sandra Van der Auwera5, Gerome Breen1, Major DepressiveDisorder Working Group of the Psychiatric Genomics Con-sortium, Khalida Ismail1, Cathryn Lewis1

1King's College London2Queensland University of Technology, School of Psychologyand Counselling3Amsterdam Public Health and Amsterdam Neuroscience,VU Amsterdam Medical Center/GGZinGeest4Institute for Molecular Bioscience, University ofQueensland5University Medicine Greifswald

Background: The association between Type 2 Diabetes(T2DM) and depression has been consistently reported inepidemiological studies. The T2DM-depression link may besymptom-specific. We therefore examined whether poly-genic risk scores for T2DM predict specific depressivesymptoms in the Psychiatric Genomics Consortium MajorDepressive Disorder Phase 2 (PGC-MDD-29) dataset.Methods: T2DM-polygenic scores were constructed fromthe association summary statistics of Diabetes GeneticReplication And Meta-analysis Consortium (DIAGRAM; 12,171cases and 56,862 controls) at association p-value threshold of0.5 (PTo0. 0.5). Stepwise regression was used to test forassociation between T2DM-polygenic scores at PTo0.5 andnine specific depressive symptoms in PGC-MDD-29 dataset,adjusting for ancestry principal components and study.Results: The four cohorts from PGC-MDD-29 datasetincluded in this study were: i) CoFaMS, ii) PsyCoLaus, iii)NESDA/NTR and iv) SHP0. The combined data consists of

6,542 participants of European ancestry, with 2,360 cases ofdepression and 4,182 controls. Feelings of guilt/worthless-ness is the only significant depressive symptom predictor forT2DM-polygenic scores (β=-0.0041; p=0.0037). It is presentin 1,771 (75%) cases and 120 (3%) controls. This effect cameprimarily from depression cases (β=-0.0058; p=0.0002), withlimited information from controls (β=-0.0003; p=0.7903).Discussion: This study provides the first evidence of ashared genetic aetiology between T2DM and feelings ofguilt/worthlessness, particularly in people with depression.No association was found between T2DM-polygenic scoresand depressive symptoms which are more related to T2DM,such as changes in appetite/weight. Previous studies havereported an association between appetite/weight andinflammatory markers but not with glucose-related mea-sures. Longitudinal prospective studies examining the asso-ciation between specific symptoms of T2DM and depressionare needed to clarify the underlying mechanism.

Disclosure: Novo Nordisk UK Research Foundation –

Honoraria, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.114

SA43. ARE SOME MALTREATED INDIVIDUALS 'IMMUNE'TO LATER LIFE DEPRESSION? AN INVESTIGATION OF 41INFLAMMATORY MARKERS IN OVER 600 U.K. ADULTS

Alish Palmosn,1, Stuart Watson2, Allan H. Young1,

Rebecca Strawbridge1, Anthony J. Cleare1,Raymond Chung1, Matthew Hotopf3, Hong Wang4,David A. Collier4, Sandrine Thuret1, Gerome Breen1,Timothy R. Powell1

1King's College London2ADD Study Team3SELCoH Study Team4Eli Lilly and Company

Background: Childhood maltreatment is widely reportedacross the world and the incidence of child cruelty andneglect offences is reportedly on the rise. Childhood mal-treatment is strongly associated with a range of negativehealth outcomes in adulthood and represents the strongestenvironmental risk factor for Major Depressive Disorder(MDD). Immuno-inflammatory activation is one biologicalmechanism activated in response to maltreatment, and apossible mediator of this increased risk for MDD. Immunemodulators, such as the inflammatory cytokines arereported to be increased in patients with MDD and play arole in brain development, neurogenesis and synapticremodelling. We hypothesize that: (i) maltreatment sub-types will have effects on specific inflammatory markers inadulthood; and (ii) maltreatment will have differentialeffects on inflammatory markers in adulthood dependingon whether or not an individual develops MDD.Methods: 616 U.K. participants (276 MDD cases and 340controls) were recruited as part the South East LondonCommunity Health Study (SELCoH) and the Antiglucocorticoid

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augmentation (metyrapone) of antiDepressants in Depression(ADD) Study. MDD status was defined using either DSM-IV, orthe Clinical Interview Schedule-Revised (which generatesICD-10 diagnoses). Childhood maltreatment was determinedusing the Childhood Trauma Questionnaire and ordinal mea-sures of maltreatment subtype severity were generated. Theexpression of 41 inflammatory markers were quantified usingmultiplex electrochemiluminescence methods applied toparticipant serum samples. General linear models were usedto investigate the main effects of maltreatment severity onimmune marker expression, and MDD case-control by mal-treatment interactions whilst covarying for a broad range ofpotential confounders. Within each test we performed, wecorrected for the number of inflammatory markers assessedusing the False Discovery Rate (qo0.1).Results: 34 out of 41 inflammatory markers wereexpressed in over 70% of our sample, and these were carriedforward into downstream analyses. Main effect analysesshowed that a higher severity of emotional neglect inchildhood was associated with higher Vascular EndothelialGrowth Factor D (VEGF-D) levels in adulthood (qo0.1).Interaction analyses revealed that higher childhood emo-tional and physical neglect in childhood was associated withhigher Interleukin 12 heterodimer (IL-12p70) levels in con-trols only, with lower levels found in MDD subjects (qo0.1).Discussion: VEGF-D is a cytokine responsible for vascular-isation and angiogenesis. The effect we observed wasirrespective of MDD case-control status, suggesting that ifhigher levels of VEGF-D levels do have a long-lasting impacton health, this may relate to disorders other than MDD, or itrequires interaction with other factors to lead to MDD. OurMDD case-control by maltreatment interaction analysesrevealed heightened levels of IL-12p70 in control subjectsrelative to depressed cases in association with emotional andphysical neglect severity. IL-12p70 has been shown to haveneuroprotective properties and we hypothesise that thismarker may be involved in a mechanism which confersresilience to MDD in response to childhood neglect, or thatit represents a biological proxy for a protective environmen-tal factor (e.g. social support). Further work is now neededto understand if IL12p70 represents a novel drug target totreat MDD in those who have experienced childhood neglect.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.115

SA44. THE IDENTIFICATION OF HETEROGENEOUSGENETIC SUBGROUPS FOR MAJOR DEPRESSIVE DISORDER

David Howardn,1, Toni Clarke1, Mark Adams1,

Jonathan Hafferty1, Eleanor Wigmore1, Yanni Zeng1,Jude Gibson1, Thibaud Boutin1, Pippa Thomson1,David Porteous1, Major Depressive Disorder Working Groupof the Psychiatric Genetics Consortium2, Chris Haley1,Ian Deary1, Heather Whalley1, Andrew McIntosh1

1University of Edinburgh2King's College London

Background: Major Depressive Disorder (MDD) is a leadingcause of disability worldwide with an estimated heritabilityof 37%. MDD is clinically heterogeneous and has frequentlybeen shown to be comorbid with a variety of other condi-tions. Both of these factors have potentially confoundedprevious attempts to elucidate MDD's genetic architecture.To investigate causal heterogeneity within MDD we soughtto identify genetic subgroups associated with other traitswithin MDD cases.Methods: We examined two cohorts comprising of unre-lated individuals, Generation Scotland: Scottish FamilyHealth Study (GS:SFHS; n=6,946) and UK Biobank(n=25,035), for evidence of heterogeneous genetic sub-groups within MDD cases. Within GS:SFHS, a diagnosis ofMDD was made by trained researchers using the StructuredClinical Interview for the Diagnostic and Statistical Manualof Mental Disorders. UK Biobank participants completed atouchscreen assessment of depressive symptoms and pre-vious treatments from which a probable diagnosis of MDDwas determined. We obtained risk alleles for a total of 34traits and used the software package Buhmbox to determinewhether there was a sharing of risk alleles associated witheach trait and a subgroup within our MDD cases.Results: There was evidence (P o 0.05) of genetic sub-groups for 10 traits within MDD cases across both GS:SFHSand UK Biobank cohorts. This included subgroups for alcoholconsumption, migraine, eczema, blood pressure and cho-lesterol and triglyceride levels. The most notable subgroupswere for the metabolic traits with P r 2.57� 10�8 acrossboth cohorts. There was evidence (P o 0.05) of a further4 genetic subgroups within MDD cases within one cohort, butnot both cohorts, which included Alzheimer's disease,neuroticism and schizophrenia.Discussion: As far as we are aware, ours is the first studyto identify the existence of genetic subgroup heterogeneitywithin MDD. In our study, the strongest evidence of geneticsubgroups within MDD cases were for blood pressure,cholesterol and triglyceride levels. Our study has providedreplicable evidence of subgroup heterogeneity within MDDfor a number of traits underlining the potential of usinggenomic data to develop stratified approaches for thediagnosis and treatment of depression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.116

SA45. AFFECTIVE TEMPERAMENTAND DEPRESSIVE SYMP-TOMS IN OBESE INDIVIDUALS IN THE CONTEXT OF SER-OTONERGIC TRANSCRIPTIONAL GENE POLYMORPHISMS

Alina Borkowska, Maciej Bielińskin

, Natalia Lesiewska

Nicolaus Copernicus University

Background: Patients with obesity experience many psy-chological burdens. Some of them result directly from theload that jets excessive weight. Nevertheless, it seems thatthe susceptibility of obese people to accompanying mental

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M. Barbu et al.26

disorders can be ingested not only by the environment, butalso genetically.

The aim of this work was to determine the correlation ofthe genetic aspects of serotoninergic (SERT, 5-HT2A) trans-mission with the severity of depressive symptoms and theaffective temperament profile in subjects with simpleobesity.Methods: The study included 506 patients with simpleobesity who were excluded secondary causes of obesity andsignificant mental illness. Clinical, psychological and geneticanalyzes were performed. To assess the severity of depres-sive symptoms, Beck Depression Inventory and the HamiltonDepression Scale were used. Affective temperament wasassessed using the TEMPS-A questionnaire. Polymorphism ofserotonin transporter (SERT 44-bp insertion/deletion) andserotonin receptor 2 A type (1438 G/A) were evaluated aspotential genetic markers of psychological factors.Results: The long allele of SERT gene was associated withsignificantly higher BMI and more pronounced depressive,cyclothymic and hyperthymic dimensions of affective tem-perament. Interestingly, these subjects obtained the lowestscores of both scales, which measured the severity ofdepressive symptoms. Adenine homozygotes in examined5-HT2A polymorphism were characterized by higher BMI andmore pronounced anxious and, in particular, hyperthymicdimension of temperament. Carriers of particular polymorph-isms in this gene did not differ significantly in the clinical scaleevaluating the severity of depressive symptoms.Discussion: Polymorphisms of both examined genesrevealed correlations in affective temperamental dimen-sions. Acknowledgments in the SERT polymorphism seemsto play a more important role in the regulation of reactivedepressive symptoms.

Disclosure: Group Medical Practices – Employee, Self &Spouse

http://dx.doi.org/10.1016/j.euroneuro.2017.08.117

SA46. THE GENETIC RISK UNDERLYING SYNAPSE PLAS-TICITY AND NEUROINFLAMMATION IN MAJOR DEPRES-SIVE DISORDER (MDD): A JOINT WHOLE EXOMESEQUENCING (WES) AND STRUCTURAL MRI STUDY

Yamin Zhangn,1, Mingli Li1, Jacob Hsu2, Qiang Wang1,

Pak Sham3, Tao Li1

1Psychiatric Laboratory and Mental Health Center, TheState Key Laboratory of Biotherapy, West China Hospitalof Sichuan University2University of Hong Kong3Li Ka Shing Faculty of Medicine, University of Hong Kong

Background: Major Depressive Disorder (MDD) is amongthe leading causes of disability and becoming increasinglyprevalent with modernity. Although it has a prominentheritability from Twin studies, genome-wide associationstudies have long been struggling with replicated results.At the same time, efforts to explore the effects of rare

variants are in lack. In addition, phenotype heterozygosity isone of the main challenges of genetic study of MDD.Methods: We sequenced the whole exome of 77 patientswith MDD and 255 healthy controls. All patients wereunmedicated with 17-item Hamilton Depression Rating Scale≥ 18. Hypothesis-free analyses were performed on gene andpathway level to identify those with higher burden ofdeleterious rare variants in patients. Structural MagneticResonance Imaging (sMRI) data was collected from 75patients and 107 controls, leveraging the endophenotypesof MDD to dissect the genotype-phenotype relationship inbetter resolution. Gray Matter Volume (GMV) was used as anendophenotype in multivariate parallel Independent Com-ponent Analysis (pICA) to find genetic underpinnings of GMVabnormalities of MDD.Results: Two genes with critical functions, CSMD1 andCNTNAP5, achieved marginal significance in burden test ofrare variants (p = 5.32E-06 and p = 1.32E-06 respectively).The CSMD1 protein is involved in synapse plasticity andneuroinflammation through regulating the classical com-plement cascade. CNTNAP5 encodes one member of theneurexin family which are regulators of synapse forma-tions. Additionally, rare and disruptive variants in MDDpatients over-represented in Neuroactive Ligand ReceptorInteractive pathway, which implicates neurological func-tion disturbance. Moreover, one pair of imaging-geneticcomponents achieved significant correlation (r = 0.38, p =9.92E-06), which remained stable in validation and per-mutation. The imaging component reflected decreasedGMV in precuneus, temporal gyrus and posterior cingulatefor patients. The genetic component over-represented intwo gene sets of which one was singling by G-protein-coupled receptors and the other one consisted of geneswith increased expression in patients with Alzheimer’sDisease. All pathways identified above hit several geneswith a role in synapse plasticity and neuroinflammation.Discussion: Two genes with critical functions, CSMD1 andCNTNAP5 achieved marginal significance in burden test ofrare variants (p = 5.32E-06 and p = 1.32E-06 respectively).The CSMD1 protein is involved in synapse plasticity andneuroinflammation through regulating the classical comple-ment cascade. CNTNAP5 encodes one member of theneurexin family which are regulators of synapse formations.Additionally, rare and disruptive variants in MDD patientsover-represented in Neuroactive Ligand Receptor Interac-tive pathway, which implicates neurological function dis-turbance. Moreover, one pair of imaging-geneticcomponents achieved significant correlation (r = 0.38, p =9.92E-06), which remained stable in validation and permu-tation. The imaging component reflected decreased GMV inprecuneus, temporal gyrus and posterior cingulate forpatients. The genetic component over-represented in twogene sets, of which one was singling by G-protein-coupledreceptors and the other one consisted of genes withincreased expression in patients with Alzheimer’s Disease.All pathways identified above hit several genes with a rolein synapse plasticity and neuroinflammation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.118

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27PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

SA47. QUANTIFYING THE EFFECT OF COPY-NUMBERVARIANTS ON GENERAL INTELLIGENCE IN UNSELECTEDPOPULATIONS

Guillaume Huguet1, Catherine Schrammn,1, Elise Douard1,

Lai Jiang2, Aurélie Labbe3, Jean-Baptiste Poline4, Eva Loth5,Roberto Toro6, Gunter Schumann5, Patricia Conrod1,Zdenka Pausova7, Celia Greenwood2, Tomas Paus8,Thomas Bourgeron6, Sébastien Jacquemont1

1Sainte Justine Hospital2Lady Davis Institute for Medical Research, Jewish GeneralHospital3HEC Montreal4Berkeley University5Institute of Psychiatry, Psychology and Neuroscience, King'sCollege London6Institut Pasteur7The Hospital for Sick Children, University of Toronto8Rotman Research Institute, University of Toronto

Background: Detection of Copy Number Variants (CNVs) areroutinely performed in patients with NeurodevelopmentalDisorders (NDs) and “Clinically significant” CNVs, defined asrare and large CNVs contributing to disease, are identified in 10to 15% of patients. Effects of these clinically significant CNVs oncognitive traits have been studied for only a small number ofrecurrent CNVs. In addition, case-control studies are impossibleto perform for 4 75% of CNVs that are non-recurrent. As aresult, their effects on neurodevelopment are neither charac-terized nor understood.Objectives: To examine the effect of CNVs on measures ofPerformance and Verbal Intelligence Quotient (PIQ and VIQ) ingeneral populations. To model and predict the effect of CNVs onPIQ and VIQ using variables that characterize gene content andnoncoding regions involved in CNVs.Methods: We called CNVs from genotyping data withPennCNV and QuantiSNP on two cohorts drawn for thegeneral population: Imagen (n=1804) and the SaguenayYouth Study (n=968). Rare (o1/1000) CNVs Z 50 kb werevalidated by visual inspection. Gene and regulatory contentwere annotated for all CNVs based on scores of intolerancesto mutation, temporal and tissue expression, as well as genefunction. We tested several models to select the indepen-dent variables most predictive of CNV effect on IQ usinginformation based criteria.Results: We identified rare deletion and duplications largerthan 250 kb in 10% of individuals. Both the size and genecontent of rare deletions decrease IQ, eg. deletions Z250Kbdecrease IQ by 6 points (p=2.10–3). We were unable todetect a significant effect of rare duplications on IQ. Forestimating the effect of all deletions on IQ, a stepwise linearmodel procedure converged on a model including mutationintolerance scores (pvalue o10-4). To validate our modelwhich is built mainly on rare non-recurrent deletions, wecompared its predictions to empirical measures of IQ lossfrom the literature for 12 known recurrent CNVs. TheIntraclass Coefficient Correlation shows that predictionsreliably match known IQ losses (ICC 4 80%, pr2.10–3).Discussion: Our results suggest that the effects of dele-tions on general intelligence can be reliably modeled and

represent a new perspective for the study of non-recurrentCNVs. These results will also help clinicians estimate theimpact of non-recurrent CNVs on cognition in their patients.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.119

SA48. STRESS, DEPRESSIVE STATUS AND TELOMERELENGTH: DOES SOCIAL INTERACTION AND COPINGSTRATEGY PLAY A MEDIATING ROLE?

Jiajia Liun,1, Yabin Wei2, Yvonne Forsell3,

Catharina Lavebratt3

1Peking University Health Science Center2Karolinska Hospital3Karolinska Institutet

Background: Telomeres have been reported to be shorterin individuals exposed to psychosocial stress and in thosewith depression. Since negative environmental stress is arisk factor for depression, the present study tested whetherstressors in childhood (CA) and recent adulthood (NLE)predicted telomere attrition directly and/or indirectlythrough individuals’ depressive status 3-6 years before TLmeasurement; and then if social interaction and copingstrategies in adulthood influenced the relationship betweendepressive status and TL.Methods: Participants were 337 individuals with a recentdepression diagnosis and 574 screened controls that derivedfrom a longitudinal population-based cohort study con-ducted in Stockholm, Sweden. Relative TL was determinedusing qPCR. Relationships between key variables stressors,depressive status, social interaction, coping strategies andTL were explored by path analysis in males and females,adjusting for age.Results: The key variables were correlated in expecteddirections. In females, depressive status and age had directnegative effects on TL (po0.05) and both CA (p=0.025) andNLE (po0.003) had indirect negative effects on TL. Formales, the effects of stressors and depressive status on TLwere mediated by social interaction (p=0.005) and thecoping strategy worry (p=0.005). In females, no mediationeffect of social interaction and coping strategy wasdetected.Discussion: Our study consolidates previous findings thatTL is shorter in depression. In other words, exposure toenvironmental stress is associated with higher risk ofdepression, which in turn associates with shorter TL. Whilein females there was no statistically significant pathwaythrough social interaction or coping strategy, in males,depressive status was associated with TL through AVSI, AVATand the coping strategy worry. In addition, in males CA hada significant indirect effect on TL through AVSI, AVAT anddepressive status. This sex difference in pathways might beexplained by the sex differences in social-cognitive styles,coping or reaction to stress and relationship provisions.Good social relationships play a positive role in reducing the

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impact of stress and in turn enhance well-being and healthhabits, whereas weak social interactions and correspondingimproper coping relate with the dysregulation of stress-responsive biological systems e.g. the HPA axis and inflam-mation. Previous studies have linked the dysfunction ofthese biological systems to accelerated telomere erosion.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.120

SA49. A QUANTITATIVE ANALYSIS OF DISCREPANCIESBETWEEN CANDIDATE GENE AND GENOME-WIDE STU-DIES OF COMPLEX TRAITS AND RELATEDENDOPHENOTYPES

Richard Bordern,1, Emma Johnson2, Patrick Sullivan3,

Noah Berley4, Matthew Keller4

1Institute for Behavioral Genetics2Washington University in St. Louis3University of North Carolina at Chapel Hill4University of Colorado Boulder

Background: Candidate gene and genome-wide investiga-tions of complex traits and related endophenotypes areboth fundamentally concerned with elucidating the biolo-gical pathways underlying individual differences in behavior.However, these two methods have produced disparateliteratures and have often reached contradictory conclu-sions about the genetic architectures of target traits. Thusfar, the polarizing attempts to reconcile these discrepancieshave been largely rhetorical. In contrast, the presentresearch uses rigorous quantitative methods to evaluateplausible explanations for the current disagreement in theliterature: poor measurement and simplistic models ingenome-wide studies versus publication bias and methodo-logical errors in candidate gene work. Results aim to aidinvestigators in parsing previous findings and selectingfuture research targets.Methods: We present closed form representations of thedependencies between statistical power in genome-wideassociation studies and endophenotype studies, measure-ment error, and endotype-complex trait associations. Theresulting theory is used to critically evaluate the existingcandidate gene literature. Additionally, we present novelmethods for falsifying gene-by-environment interactionhypotheses in genome-wide samples where the environ-mental variable is unobserved and apply this method to datafrom large genome-wide studies of Schizophrenia and MajorDepressive Disorder conducted by the Psychiatric GeneticsConsortium. Finally, we evaluate the evidence for publica-tion bias in the candidate gene literature as a competingexplanation for observed discrepancies.Results: Attenuation of true genetic associations in gen-ome-wide studies vis-a-vis those reported in smaller candi-date gene studies (regardless of whether caused bymeasurement error, biological distance, or any combinationthereof) is only likely to explain observed discrepancies in

the literature when the association between the candidate-gene study trait and the genome-wide association studytrait is weak, leaving endophenotype candidate generesearchers in a paradoxical position. Moreover, even afterallowing for the possibility of extreme measurement error ingenome-wide data, leading candidate gene-by-environmentinteraction hypotheses are incompatible with recent gen-ome-wide association study findings. Finally, an overwhelm-ing ratio of positive to null findings and the ubiquitousfailure to cite mainstream genetics findings suggest thatprevalent publication bias and interdisciplinary fragmenta-tion characterize the existing candidate gene literature.Discussion: Candidate gene research, especially endo-phenotype and gene-by-environment interaction literaturecontinue to gain popularity across the behavioral sciences.However, empirical support for the findings these methodshave produced is weak. By making common arguments forcontinuing candidate gene research mathematically preciseand then evaluating evidence for their unacknowledgedimplications, we conclude that neither measurement error,overly-complex or heterogenous phenotyping, nor unmea-sured environmental moderators can explain discrepanciesbetween candidate gene and genome-wide findings.Instead, widespread publication bias and false positivefindings provide a likely alternative explanation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.121

SA50. CHARACTERISING COGNITIVE ENDOPHENOTYPESRELATED TO NEUROPSYCHIATRIC DISEASES

Annette Milnikn

, Tobias Egli, Bianca Auschra,Francina Hartmann, Klara Spalek, Eva Loos,Dominique J.F. de Quervain, Andreas Papassotiropoulos

University of Basel

Background: Deep phenotyping aims at measuring largenumbers of phenotypes per subject, which enables us todescribe more comprehensively the subjects’ physical orcognitive state; the increased information-depth allows usto gain insight in the underlying neurophysiological andneuropsychological relationships. The concept of endophe-notypes is an important link between phenotyping based ondiseases and phenotyping based on healthy subjects, espe-cially in the field of neuropsychiatric diseases. The cognitivedomains episodic memory, working memory and attentionare examples for endophenotypes that can be assessed in adeep-phenotyping approach; all these domains are heritabletraits that are affected in neuropsychiatric disorders, suchas Schizophrenia, Depression, or Posttraumatic stress dis-order. These domains are based on shared but also ondomain-specific neurophysiological and neuropsychologicalmechanisms and can be measured with a variety of differenttasks.Methods: Here, we conjointly analysed data of five dif-ferent studies investigating cognitive performance

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29PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

measurements in healthy young adults from the generalpopulation. Importantly, each of the included studies used avarying set of tasks from different domains, which hampersthe usage of common multivariate approaches, like e.g.factor analysis. Instead, we applied a multitrait-multi-method approach that allowed us to successfully integratethe different datasets in one analysis.Results: Our results illustrate a continuous phenotypicclassification ranging from tasks comprising more attention-related processes on one hand to tasks comprising moreepisodic memory-related processes on the other hand.Discussion: In summary, by applying a multitrait-multi-method approach to a heterogeneous database, we canvisualize the putative underlying neurophysiological andneuropsychological mechanisms of cognitive tasks. Thesetasks can further be used as endophenotypes for neuropsy-chiatric diseases.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.122

SA51. ASSOCIATIONS OF MONOAMINE OXIDASE A GENEFIRST EXON METHYLATION WITH SEXUAL ABUSE ANDCURRENT DEPRESSION IN WOMEN

Dave Checknitan,1, Megha Bendre1, Tomas Ekström2,

Erika Comasco1, Jari Tiihonen2, Kent W. Nilsson1,Sheilagh Hodgins2

1Uppsala University2Karolinska Institutet

Background: Childhood maltreatment interacts with afunctional polymorphism in the monoamine oxidase A(MAOA) gene promoter region to modify the risk of aggres-sive behaviour. In females, the high-expressing variant(MAOA-L) interacts with maltreatment, whereas in malesit is the low-expressing variant (MAOA-S) that interacts withmaltreatment, highlighting a key sex-difference in thebiology of aggression. It has been suggested that epigeneticprocesses, such as DNA methylation, may be one of thebiological mechanisms underlying such gene-environmentinteractions. We investigated whether MAOA-uVNTR geno-type, and methylation in a region spanning the MAOA firstexon and part of the first intron, moderated associationsbetween childhood physical and sexual abuse and aggressivebehaviours in women and men.Methods: A sample of 117 Swedish women and 77 mencompleted standardized diagnostic interviews, question-naires to report maltreatment and aggressive behaviours,and provided saliva samples for DNA extraction. The MAOA-uVNTR polymorphism was genotyped, and methylation of aregion of interest in MAOA (ChrX: 43,515,544 - 43,515,991)was analyzed.Results: In women who experienced childhood maltreat-ment, MAOA-L and lower exonic methylation were associatedwith an increased number of aggressive behaviours. By con-trast, among men who had experienced maltreatment, MAOA-

S and higher exonic as well as lower intronic methylation wereassociated with an increased number of aggressive behaviors.Discussion: Our study offers initial evidence that alteredDNA methylation of MAOA may be one underlying biologicalmechanism accounting for gene-environment interactions ofMAOA in aggressive behaviour. Further, our findings highlightthe importance of considering sex-differences in the patho-physiology of aggression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.123

SA52. EFFECTS OF TRANSCRANIAL DIRECT CURRENTSTIMULATION ON COGNITIVE CONTROL AND DNAMETHYLATION

Ariane Wiegandn

, Christof Brückmann, Christian Plewnia,Vanessa Nieratschker

University of Tuebingen

Background: Coping with the complexity of our daily liferequires cognitive flexibility and control over emotions andbehavior. Deficits in cognitive control are often involved inthe psychopathology of psychiatric diseases, e.g. MajorDepressive Disorder (MDD), a severe mental illness charac-terized by increased receptiveness for negative stimuli andunbalanced emotion processing. On a neural basis, MDD aswell as deficient cognitive control are associated withhypoactivity of the Dorsolateral Prefrontal Cortex (dlPFC).

Transcranial Direct Current Stimulation (tDCS) is a well-established brain stimulation technique inducing targetedmodulation of cortical activity. It is discussed as promisingapproach to support conventional psychiatric therapies butso far little is known about the underlying molecularmechanisms. Epigenetic changes might be a potentialmechanism how tDCS effects manifest as long-lasting cog-nitive improvements and amelioration of psychiatric symp-toms. In two previous stimulation genetics studies, wedemonstrated an influence of the COMT genotype, whichrenders this gene an interesting candidate for a stimulationepigenetics study.Methods: For the present study, healthy male participantsperformed a potentially frustrating and challenging task, a2-back version of the Paced Auditory Serial Addition Task(PASAT), once under sham stimulation and once underanodal tDCS over the left dlPFC. Participants’ affectivestates were assessed several times throughout the experi-ment. To investigate epigenetic effects of the stimulationprotocol, one blood sample was collected before the PASATand five blood samples were collected after task comple-tion. DNA methylation status of the COMT gene promoterregion was assessed by pyrosequencing.Results: Our results provide further evidence that anodaltDCS applied to the left dlPFC improves task performance.In addition, tDCS seems to prevent task-induced decline inpositive affect, whereas task-related negative affect wassuppressed. Furthermore, our data suggest a dynamic

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M. Barbu et al.30

increase in DNA methylation of the COMT gene promoterregion in response to the task. Depending on the type ofstimulation (anodal or sham) participants received duringtheir first session, they showed different methylation levelsin their second session.Discussion: Together, our data extend previous findingsshowing improved cognitive performance under anodalstimulation, which correlates with enhanced control overemotions. In response to stimulation, we observed increasedpositive affect and reduced negative affect, which supportsthe idea of tDCS as a potential treatment approach for MDDtargeting the negativity bias.

In addition, we observed dynamic methylation changes inthe COMT gene promoter region in response to a challengingcognitive task, which might be differentially modulated bytDCS. COMT is an enzyme involved in the degradation ofdopamine and dopamine levels are critical in executivefunctioning. Therefore, the observed changes in COMTpromoter methylation might indicate an adaptive processto the task and they might indicate an underlying mechan-ism to induce long-lasting tDCS effects.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.124

SA53. METHYLOME IMPACTS OF CANNABIS USE IN THECHRISTCHURCH HEALTH AND DEVELOPMENT STUDY

Amy Osborne, John Pearson, Neil Gemmell, Joseph Boden,John Horwood, Martin Kennedy

n

University of Otago

Background: Cannabis has been very much in the news oflate, with controversy and debate surrounding legalisationand medicinal uses purposes. However, there is also strongevidence for negative consequences of prolonged cannabisuse. Significant contributions in this area have been made bythe Christchurch Health and Development Study (CHDS), alongitudinal study of a birth cohort of 1265 children born in1977 in Christchurch (New Zealand), who have been studiedon 23 occasions from birth to the age of 35 (n=987).Methods: It is now clear that many environmental factors,including drugs, impact on the pattern of epigenetic marksthroughout the genome. We sought to explore the impactsof heavy cannabis use on the methylome in participants ofthe CHDS. We selected DNA (purified from peripheral bloodsamples) of 96 CHDS subjects including 49 heavy long-termcannabis smokers (25 of whom also smoked tobacco), and 47non-smoking, non-cannabis using controls. Epigenome wideanalysis of methylation was carried out using Illumina 850 KEPIC arrays.Results: Our key observations were that for the cannabisplus tobacco smokers compared with non-smoking controls,the most differentially hypermethylated sites were in theAHRR and F2RL3 genes (adjusted P 4.4� 10-8, 4.9� 10-6respectively), replicating multiple previous studies onmethylomic effects of tobacco. For those sites (�15000)

significantly showing greater than 5% differential methyla-tion after multiple comparison adjustment, 99% werehypermethylated. Comparing cannabis only users withnon-smoking controls, for those sites (�4500) significantlyshowing greater than 5% differential methylation aftermultiple comparison adjustment, 99% were hypomethy-lated. The differentially methylated sites which werehypermethylated in tobacco smokers but hypomethylatedin cannabis only users were most strongly represented inPI3K-Akt and oxytocin KEGG pathways (FDR corrected pvalues o10-22 and 10-11 respectively.Discussion: These data suggest that cannabis has quitedifferent methylome effects to tobacco smoking, and thatthere may be interaction effects which modify the methylomeimpacts when both cannabis and tobacco are smoked. We areseeking to validate a proportion of these methylation changesusing bisulfite-amplicon sequencing in a wider selection ofsamples from the CHDS and other cohorts. These analyses mayhelp to identify epigenome impacts of cannabis use, and pointto gene regulatory processes that underlie both potentiallypositive as well as adverse consequences of its use.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.125

SA54. DNA METHYLATION AND ADOLESCENT TRAJEC-TORIES OF PSYCHOTIC SYMPTOMS

Susanna Robertsn,1, Matthew Suderman2, Stanley Zammit3,

Sarah H. Watkins2, Eilis Hannon4, Caroline Relton2,Jonathan Mill4, Helen Fisher1

1King's College London2University of Bristol3Cardiff University4University of Exeter Medical School

Background: Psychotic Symptoms (PS) are often distres-sing and can be predictive of schizophrenia, other psychia-tric disorders and suicide attempts in adulthood,particularly if they persist during adolescence. Previousresearch in diagnosis-discordant monozygotic twin-pairsand patient-control samples has demonstrated that changesin epigenetic processes could be potential biomarkers of theemergence and persistence of PS. Investigation in large,pre-clinical population-based samples is urgently required.The aim of this study is to explore the association betweenDNA methylation and the emergence, persistence, andremission of PS in childhood and adolescence.Methods: DNA methylation data (Illumina 450k) wereobtained from the ARIES subsample of the ALSPAC birthcohort at birth, age 7, and age 15/17 (N=901). PS wereassessed in private interviews with the participants at ages12 and 18. EWAS were conducted to determine the associa-tion between DNA methylation at each time-point andreports of PS at ages 12 and 18, controlling for pregnancyand birth-related covariates and cell-type composition.Gene Ontology (GO) term enrichment analyses of the top

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probes were performed to identify important pathways. Thetop probes from each EWAS were used to investigate therole of DNA methylation in the persistence and remission ofPS by comparing individuals with no history of PS, thosewhose symptoms persisted, and those whose symptomsremitted. Multilevel models were then constructed to testthe association between the longitudinal methylomic tra-jectory of the top CpG sites and the trajectory of psychoticsymptoms. Results from a replication of the top findings inan independent cohort will also be presented.Results: A number of probes were differentially methy-lated (po5� 10-5) at each time-point between those whoexperienced PS at age 12 and age 18, although these werenot significant after applying stringent correction for multi-ple testing (po1.3� 10-7). The top ranked GO terms fromenrichment analyses at each time-point included thoserelated to neuronal development, immune processes, andthe Wnt signalling pathway. Investigation of the top probesrevealed differences in DNA methylation profiles betweenPS trajectories in adolescence, in both a time-point specificmanner and longitudinally across development. At many ofthese probes, individuals whose symptoms remittedbetween 12 and 18 showed DNA methylation profiles moresimilar to those with no history of PS, and those whosesymptoms persisted showed the largest difference in DNAmethylation.Discussion: Findings from this large, population-basedstudy suggest that epigenetic processes at multiple stagesof development may be associated with the emergence,remission, and persistence of PS in late childhood andadolescence. Research uncovering biomarkers associatedwith pre-clinical PS is important as it has the potential tofacilitate early identification of individuals at increased riskand target preventive interventions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.126

SA55. NEURAL CELL ADHESION MOLECULE 1 (NCAM-1)IS ASSOCIATED TO LONG-TERM AVERSIVE MEMORY INNEMATODES AND HUMANS

Vanja Vukojevicn,1, Pavlina Mastrandreas1, Virginie Freytag1,

Thomas Elbert2, Iris Kolassa3, Dominique J.F. de Quervain1,Andreas Papassotiropoulos1, Attila Stetak1

1University of Basel2University of Konstanz3University of Ulm

Background: The Neural Cell Adhesion Molecule 1 (NCAM-1) has been implicated in several brain-related biologicalprocesses, including neuronal migration, axonal branching,fasciculation, and synaptogenesis, with a pivotal role insynaptic plasticity. Here, using an interdisciplinary approachwe investigated the evolutionary conserved role of NeuralCell Adhesion Molecule 1 (NCAM-1) in learning and memory.

Methods: First, we examined the temporal transcriptomeprofiles during C. elegans aversive olfactory long-termmemory in a large-scale gene expression study (up to24 hours upon conditioning). We observed sustained changesin NCAM-1 expression and thus we further investigated itsassociation with aversive memory by using molecular genet-ics methods. Following, we examined the link betweenmolecular signatures of the NCAM-1 gene and aversivememory in two independent human samples of Europeandescent, by using genome-wide expression and methylationprofiling. Finally, in a population of genocide survivors ofAfrican descent we investigated the link between NCAM-1promoter DNA methylation and PTSD.Results: NCAM-1 expression showed sustained expressionchanges up to 24 hours upon aversive olfactory conditioning.Loss of NCAM-1 function selectively impaired long-termmemory in a negative but not in positive olfactory associa-tive memory paradigm, without causing acquisition, sen-sory, motor or short-term memory deficits. Finally, both C.elegans and human NCAM-1 expression in nematodes res-cued loss of C. elegans NCAM-1 gene function. Consideringthe conserved role of NCAM-1 in higher complex organisms,we next expanded our C. elegans findings in human. In twosamples of European descent, we showed a negativecorrelation between DNA methylation of the NCAM-1 pro-moter and aversive memory (i.e., recognition of negativepictures) as well as a strong positive correlation betweenNCAM-1 expression and the same recognition performance.In the second sample, we could also show a strong correla-tion between NCAM-1 expression and long-delayed recall ofnegative pictures. Finally, in a population of genocidesurvivors DNA methylation at NCAM-1 gene promoter wasinversely correlated with intrusive memories symptoms andPosttraumatic Stress Disorder (PTSD) risk.Discussion: Taken together, our results support a con-served role of NCAM-1 in negative associative memory fromnematodes to humans and might, ultimately, prove to behelpful in elucidating diagnostic markers and suggest noveltherapy targets for memory-related disorders, like PTSD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.127

SA56. DNA METHYLATION SIGNATURES OF CHRONICALCOHOL DEPENDENCE IN PURIFIED CD3+ T-CELLSOF PATIENTS UNDERGOING ALCOHOL TREATMENT

Mara Thomasn,1, Christof Brueckmann2, Sumaiya A. Islam3,

Julia L. Maclsaac4, Alexander M. Morin4, Kathrin N. Karle2,Adriana Di Santo2, Richard Wuest2, Immanuel Lang2,Anil Batra2, Michael S. Kobor3, Vanessa Nieratschker2

1University of Tuebingen2University Hospital of Tuebingen3University of British Columbia4BC Children's Hospital

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Background: Alcohol Dependence (AD) is a severe dis-order that has long-lasting detrimental consequences,resulting in considerable health, economic and societalburden. According to the World Health Organization, alco-hol related diseases account for approximately 3.3 milliondeaths per year (WHO, 2014). The pathogenesis of AD iscomplex, as the disease arises from the interaction ofgenetic as well as environmental factors. One of the mostcompelling candidate mechanisms for the mediation of suchgene x environment effects is epigenetic regulation, amongwhich DNA methylation is the most frequently studiedmechanism. In fact, several recent studies have shown anassociation of alcohol dependence with DNA methylation(DNAm), suggesting that environmentally-induced changeson epigenomic variation may play an important role inalcohol dependence.Methods: In the present study, we assessed genome-wideDNAm profiles of purified CD3+ T-cells of a well-character-ized cohort of long-term chronic AD patients participating ina clinical 3-week alcohol treatment program, along with theprofiles of healthy controls closely matched for sex, age,ethnicity and smoking behaviour. 42,43 Furthermore, bycomparing the patients before and after 3 weeks ofparticipating in a clinical alcohol treatment program, wesought to identify differentially methylated sites that mayplay a potential role in alcohol withdrawal and earlyrecovery. In order to test whether our findings were robust,we validated four of our top-ranked hits by pyrosequencing,replicated the top-ranking hits in an independent secondcohort of AD patients and matched controls and additionallyconfirmed the top-ranking hits in whole blood DNA of ourcohort samples.Results: We identified 59 differentially methylated CpGsites comparing patients prior to treatment with healthycontrols and were able to confirm 8 of those sites inadditional analyses for differentially methylated regions.Comparing patients before and after a 3-week alcoholtreatment program we revealed another unique set of 48differentially methylated CpG sites. Additionally, we foundthat the mean global DNAm was significantly lower inpatients prior to treatment compared to controls, butreverted back to levels similar to controls after treatment.We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated twoof them in an independent cohort and confirmed differentialDNAm of HECW2 and SRPK3 in whole blood.Discussion: The reduction in mean global DNAm observedin AD patients and our finding that DNAm in patients revertsback to levels comparable to those in controls after alcoholtreatment are supported by previous studies. However, thetop hits of differentially methylated sites derived fromT-cells did not overlap with previously reported associationsof AD with DNAm.This can at least in part be explained by theuse of heterogeneous biological material (i.e. whole blood,PBMCs), differences in the cohorts used or in the strategiesapplied to match patients and controls as well as by varyingmethodologies for DNAm measurement, with reduced ordiscordant coverage of CpG sites in previous studies. Still,our top-ranking hits in HECW2 and SRPK3 might contribute toreveal mechanisms that may play a role in AD.

This study is the first to show widespread DNAm variationin a disease-relevant blood cell type and implicates HECW2

and SRPK3 DNAm as promising blood-based candidates tofollow up in future studies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.128

SA57. GENETIC AND EPIGENETIC INVOLVEMENT OF THEFKPB5 GENE IN POSTTRAUMATIC STRESS DISORDERAFTER COMBAT TRAUMA

Jee In Kangn,1, Tae Yong Kim2, Hae Gyung Chung2,

Jin Hee Choi2, Eun Hee Hwang3, Se Joo Kim1

1Yonsei University College of Medicine2Veterans Health Service Medical Center3Institute of Behavioral Science in Medicine, YonseiUniversity College of Medicine

Background: FK506 binding protein 5 (FKBP5) is a majorregulatory protein of the HPA axis, which binds to theglucocorticoid receptors and modulate glucocorticoid sensi-tivity. The FKBP5 genes have been implicated in dysregula-tion of human stress responses, contributing to vulnerablephenotypes such as depression and anxiety. The presentstudy aimed to investigate whether genetic and epigeneticfactors of the FKBP5 are a predictive biomarker of Post-traumatic Stress Disorder (PTSD) among veterans exposed tocombat. In addition, the influence of potentially associatedfactors, including combat exposure levels and alcoholproblem, was examined in the pathophysiology of PTSD.Methods: All subjects were Korean male veterans whoserved on active duty during the Vietnam War and theCombat Exposure Scale (CES) was used for assessing thelevel of wartime stressors experienced by combatants.Using the Clinician-Administered PTSD Scale (CAPS), combatveterans were grouped into those with (n=124) and without(n=120) PTSD. Three SNPs of the FKBP5 locus (rs9296158,rs1360780, and rs9470080) were genotyped with single baseprimer extension assay using the ABI PRISM SNaPShot Multi-plex kit. DNA methylation levels at two CpG sites in theFKBP5 intron 7 region were quantified in the peripheralblood using the bisulfite pyrosequencing method. Theeffects of FKBP5 variants, the DNA methylation levels andclinical factors on the diagnosis of PTSD were tested usingbinary logistic regression analysis.Results: Since a significant interaction effect betweenalcohol problem and FKBP5 variants was found for PTSDsymptom, logistic regression analyses stratified by presenceof alcohol problem were performed. Among combat-exposed individuals without alcohol problem, the risk alleleof FKBP5 rs1360780, higher methylation levels at the FKBP5CpG1 site, high combat exposure significantly predictedPTSD diagnosis in combat-exposed individuals (Model Sum-mary: -2 Log likelihood=144.07, Nagelkerke R2=0.279;Overall percentage of correct classification resulting fromthe model=72.9%). In the logistic model among subjectswith alcohol problem, the combat exposure level was anonly significant predictor of PTSD status.

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Discussion: The present study demonstrated the involve-ment of FKBP5 genetic variants and higher DNA methylationof the FKBP5 in PTSD status without alcohol problem. Thepresent findings suggest that the external traumatic eventsmay influence PTSD pathophysiology via genetic and epige-netic modulation of the FKBP5 and alcohol problem may bea moderating factor of PTSD. Further prospective researchexamining genetic variants and epigenetic changes of FKBP5locus in people exposed to trauma might shed light on therole and the biological basis of FKBP5 in susceptibility toPTSD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.129

SA58. DIVERSITY OF INFORMATIONAL PREFERENCES OFGENOMIC INFORMATION RESULTS OF A SURVEY OF 860INDIVIDUALS MAKING (HYPOTHETICAL) DECISIONS CON-CERNING GENOMIC INFORMATION

Laura Flatau, Thomas G. Schulzen

University of Munich

Background: Undoubtedly, genomic information is gettingmore and more available via new technologies and becomespart in clinical every-day life. The very personal and fore-telling character of genomic information is unique and there-fore medical, juridical and ethical implications are widelydiscussed (Ayuso et al. 2013; Knoppers et al. 2015; Ryan et al.2017). In addition, there are psychosocial aspects such as self-fulfilling prophecy that might influence an individual s reac-tion towards genomic information (Colloca und Finniss 2012;Hagerty et al. 2005). In our study, we surveyed various groups(e.g. patients, experts, and the general population) on theirfears, expectations, and their attitudes towards genomicinformation and their personality traits.Methods: Using a 68-item online questionnaire, we askeddifferent stakeholders in Germany about their knowledge ofgenetics, professional experiences in the genetic contextand their personal attitudes, fears, and expectations. Wespecifically focused on the disclosure and the confrontationwith genomic findings. In addition, we measured the BigFive Personality traits (e.g. Neuroticism, Extraversion) witha short version of NEO-FFI (Fruyt et al. 2004). The recruit-ment started in May 2016 and so far the sample includes1271 subjects in total, 860 out of which completed thesurvey. Another focus of our study was to find out whetherchanges in the information given, as subtle as they mightbe, lead to divergent decisions.Results: When we asked individuals with a (live-timehistory of) psychiatric disorder if they would wish to receivegenomic information about a psychiatric disorder 31%agreed, whereas only 15% of individuals with no psychiatricdisorder agreed. Presenting a scenario in which a personreceives the information that he or she is likely to developAlzheimer's disease, 75% of non-medical participants

expected the person to promote healthy behavior afterthe finding, whereas only 53% of people who studiedmedicine agreed to that statement. Furthermore, weanalyzed if specific personality traits were related tospecific attitudes (e.g. neuroticism and openness towardsgenomic information). Analysis showed a low positivecorrelation between scoring higher on neuroticism andwanting a physician to have the legal duty to discloseincidental findings in research context (r=.138, p=.000).Discussion: Our survey sheds light on the diversity ofattitudes towards genomic information. For clinical prac-tice, it is crucial to understand that the way how genomicinformation is presented and communicated to a stake-holder as well as the personality of the individuals them-selves (expectations, fears and personality) might impact onthe consequences of disclosing genomic information andresulting individual medical decisions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.130

SA59. LOCAL AND GLOBAL CHROMATIN INTERACTIONSARE ALTERED BY LARGE GENOMIC DELETIONS ASSO-CIATED WITH HUMAN BRAIN DEVELOPMENT

Alexander Urbann,1, Ying Zhang2, Xianglong Zhang1,

Xiaowei Zhu1, Carolin Purmann1, Michael Haney1,Thomas Ward1, Jie Yao3, Sherman Weissman3

1Stanford University2Mount Sinai3Yale University

Background: Large Copy Number Variants (CNVs) in thehuman genome are strongly associated with common neu-rodevelopmental, neuropsychiatric disorders such as schizo-phrenia and autism. However, given that these large CNVseach affect many genes directly and an often even largernumber of genes indirectly, understanding the molecularmechanisms that connect these loci with the clinicalphenotypes is a considerable challenge.Methods: Using Hi-C for the genome-wide analysis of long-range chromosome interactions and ChIP-Seq for the analysisof regulatory histone marks we studied the epigenomiceffects of the prominent large deletion CNV on chromosome22q11.2, in a cohort of Lymphoblastoid Cell Lines (LCLs), andalso replicated a subset of the findings in LCLs with thecommon large deletion CNV on chromosome 1q21.1.Results: We found that, in addition to local and globalgene expression changes, there are pronounced and multi-layered effects on chromatin states, chromosome foldingand topological domains of the chromatin that emanatefrom the large CNV locus.

Regulatory histone marks are altered in the deletion prox-imal regions, and in opposing directions for activating andrepressing marks. There are also significant changes of histonemarks elsewhere along chromosome 22q and genome wide.

Chromosome interaction patterns are weakened within

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M. Barbu et al.34

the deletion boundaries and strengthened between thedeletion proximal regions. We detected a change inthe manner in which chromosome 22q folds onto itself,namely by increasing the long-range contacts between thetelomeric end and the deletion proximal region. Further,the large CNV affects the topological domain that isspanning its genomic region.

Finally, there is a widespread and complex effect onchromosome interactions genome-wide, i.e. involving allother autosomes, with some of the effect directly tied tothe deletion region on 22q11.2.Discussion: These findings outline novel principles of howsuch large genomic deletions can alter nuclear organizationand affect genomic molecular activity. Our work demon-strates that there are molecular mechanisms other than thegene expression changes that result from the alteration ofthe copy number of a given gene, that should be taken intoaccount when studying this problem. Multiple molecularlevels of control should be assayed and analyzed in anintegrated fashion when studying this essential phenomenonof human genome biology and pathophysiology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.131

SA60. TRANSCRIPTIONAL CHANGES IN MOUSE MODELSOF THE 15Q13.3 MICRODELETION SYNDROME

Annika Forsingdaln,1, Thomas Werge2, Jacob Nielsen1

1H. Lundbeck A/S2Institute of Biological Psychiatry, MHC Sct. Hans, MentalHealth Services–Copenhagen

Background: The 15q13.3 microdeletion syndrome iscaused by a 1.5 MB hemizygous microdeletion at chromo-some 15q13.3 affecting seven genes: FAN1, MTMR10,TRPM1, MIR211, KLF13, OTUD7A, and CHRNA7. The15q13.3 microdeletion increases the risk of intellectualdisability, epilepsy, autism spectrum disorder and schizo-phrenia, though the clinical profile varies considerably.

Mouse models of the 15q13.3 microdeletion recapitulatea number of the behavioral and physiological deficits thatcharacterize the human condition. Still, little is known ofthe underlying biological mechanisms.Methods: We have performed RNA sequencing (RNA-seq)of five brain areas, frontal cortex, striatum, parietal cortex,hippocampus and cerebellum from 15q13.3 homozygousknockout mice and wild type littermates, with an averageof 9 samples per group.Results: Our transcriptomic analysis identified about 100genes that were differentially expressed in 15q13.3 homo-zygous knockout mice compared to wildtype littermatesafter correction for multiple testing. The majority of thesegenes were regulated in the same direction in hemizygous15q13.3 deletion mice, indicating that the changes we seeare also relevant for the hemizygous deletion syndrome.

Discussion: Further investigation of the biological func-tions affected by these transcriptional changes can guidetarget identification and drug discovery efforts for intellec-tual disability, epilepsy, autism spectrum disorder andschizophrenia.

Disclosure: H. Lundbeck A/S - Employee, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.132

SA61. THE ROLE OF MUSASHI RNA BINDING PROTEINSIN ASSOCIATIVE LEARNING AND MEMORY

Pavlina Mastrandreasn

, Vanja Vukojevic, Csaba Boglari,Fabian Peter, Dominique de Quervain,Andreas Papassotiropoulos, Attila Stetak

University of Basel

Background: The Musashi family of RNA binding proteins,MSI-1 and MSI-2, retain a pivotal role in stem cell mainte-nance, nervous system development and tumourigenesis.Recently, we demonstrated that the C. elegans sole ortholog,MSI-1, can regulate forgetting upon associative learning via a3’ UTR dependent translational repression of the Arp2/3 actinbranching complex. Based on these findings, here we opted todecipher the role of human MSI-1 and MSI-2 in the regulationof associative learning and memory; and investigated whethera conserved mechanism of action exists across species.Methods: Based on the homology shared between thehuman and nematode musashi proteins, we first constructedtwo transgenic C. elegans lines expressing the humanproteins in an msi-1 knockout background by using mole-cular genetic techniques. Moreover, learning and memory(both short-term and long-term) phenotypes were assessedin a paradigm known as negative olfactory chemotaxis assay.Following, using pharmacological manipulations, the func-tion of human musashi proteins were studied both on themolecular and behavioral level.Results: Introduction of both human MSI-1 and MSI-2proteins fully rescued the previously seen forgetting defectof msi-1 (lf) mutant worms, during C. elegans aversiveolfactory short-term and long-term memory. Since musashiwas shown to regulate gene expression at the translationallevel via its highly conserved RRM domain, we next soughtto disrupt binding to its downstream targets and assessedthe effects at the behavioral level. Pharmacological pertur-bation of both human MSI-1 and MSI-2 function suppressedthe memory rescue phenotype previously observed; withoutcausing locomotion, chemotaxis or learning deficits.Discussion: Taken together, our results support a con-served role of musashi in negative associative memory fromnematodes to humans and might, ultimately, prove to behelpful in elucidating novel therapy targets for the treat-ment of memory-related disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.133

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SA62. TRANSCRIPTIONAL CONSEQUENCES OF REDUCEDEXPRESSION OF THE SCHIZOPHRENIA SUSCEPTIBILITYGENE SETD1A

Darren Cameronn

, Derek Blake, Nick Bray, Matthew Hill

Cardiff University

Background: Loss of function alleles in SETD1A are agenetic risk factor for developing schizophrenia. SETD1Aencodes a protein possessing histone methyltransferaseactivity. Specifically, it catalyses the methylation of histoneH3 at Lys4, a modification indicative of active regulatoryDNA function. Reduced SETD1A expression is therefore likelyto have a major impact on global gene expression viaalterations to the histone code. To understand the down-stream genes and pathways altered by SETD1A expressionwe performed gene expression profiling of a neural cell linein which SETD1A expression had been reduced.Methods: SETD1A expression was reduced in the SH-SY5Yneuroblastoma cell line using two non-overlapping siRNAs. Anon-targeting siRNA was used as a control. Four days aftertransfection cells were harvested for RNA extraction.Transcriptional profiling was performed using Illuminamicroarrays. Differential expressed probes were identifiedusing t tests and gene ontology enrichment analysis per-formed using DAVID. Quantitative PCR was used to verify themicroarray findings for a subset of gene transcripts. Wetested for enrichment of association with schizophreniaamongst the differential expressed probes using MAGMA.Results: Both targeting siRNAs reduced SETD1A RNAexpression �50% compared to control. Gene expressionprofiling identified 1131 differentially expressed probes (po0.05) common to both siRNA conditions compared tocontrol. Amongst the most upregulated probes were DCXand GAP43, known markers of early neuronal development.However, gene ontology analysis of these upregulatedprobes did not to identify significantly enriched biologicalannotations. Down regulated probes were enriched for‘GO:0005739�mitochondrion’ and the KEGG pathway‘hsa01100: Metabolic pathways’. The set of differentialexpressed genes were also significantly enriched for asso-ciation with common variant schizophrenia risk genes(p=0.015).Discussion: Reduced SETD1A levels lead to widespreadchanges in the expression of genes involved in diverseprocess, consistent with its role in general transcription.However, we observed altered expression of known regula-tors of neuronal development and function. Our results alsohighlight mitochondrial function as important downstreamconsequences of reduced SETD1A expression. Importantly,we show that gene expression changes after knock-down ofa rare variant schizophrenia risk gene are enriched for acommon variant association signal, indicating a point ofmolecular convergence in risk mechanisms.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.134

SA63. HIGH RATES OF NEURODEVELOPMENTAL RISKCNVs IN PATIENTS WITH INTELLECTUAL DISABILITIESAND CO-MORBID PSYCHIATRIC DISORDERS

Kate Wolfen,1, Johan Hilge Thygesen1, Andrew McQuillin1,

Marina Viñas-Jornet2, Nathalie Brison3,Susanna Esteba-Castillo4, Núria Ribas-Vidal4,Ramon Novell4, Griet Van Buggenhout3, Andre Strydom1,Nick Bass1, Miriam Guitart Feliubadaló2, Annick Vogels3

1University College London2Genetic Laboratory, UDIAT-CD, Corporació Sanitària ParcTaulí3University Hospital Leuven4Institut Assistència Sanitària

Background: Rare Copy Number Variants (CNVs) areknown to be important risk factors for NeurodevelopmentalDisorders (NDDs). Pathogenic CNVs identified to date confermoderate to large effect sizes (OR 1.5 - 50 or higher) andhave important clinical implications for affected individualsand at-risk family members. Several studies have investi-gated pathogenic CNVs in paediatric cohorts with Intellec-tual Disabilities (ID), or in schizophrenia/Autism SpectrumDisorders (ASD) only samples. However, adult populations –

in particular those who exhibit ID and co-morbid psychiatricdiagnoses – are less well characterised.Methods: We undertook Chromosomal Microarray Analysis(CMA) and clinical phenotyping in 599 adults with ID and co-morbid psychiatric disorders recruited from three Europeanresearch sites (Catalonia, Spain; Leuven, Belgium; andEngland, UK). We compared the carrier frequency of 63established NDD CNV risk loci to reported frequencies inhealthy controls, schizophrenia and ID/ASD populations. Wedetermine the clinical diagnostic yield of CMA in our sampleand describe likely pathogenic CNVs affecting NDD candi-date genes.Results: We identified 58 carriers of NDD risk CNVs at 23 ofthe 63 risk loci investigated. The five most frequent CNVswere: 22q11.2 deletion (N=7, 1.2%), 15q11.2 (Prader-Willisyndrome/Angelman syndrome region) duplication (N=6,1%), 16p11.2 duplication (N=5, 0.8%), 15q13.3 deletion(N=5, 0.8%) and 16p12.1 deletion (N=4, 0.7%). The fre-quency of NDD risk CNVs was significantly higher in ourcohort (10%), compared to healthy controls (1.2%,po0.0001) schizophrenia (3.1%, po0.0001) and ID/ASD(6.5%, po0.0008) only populations. The yield of pathogenicand likely pathogenic CNVs was 13% (n=78) and 21.5%(n=129) respectively. We provide clinical phenotype datafor likely pathogenic CNV duplications at 3p26.3 (CNTN6)and 9q21.32q21.33 (SLC28A3 & NTRK2), deletions andduplications at 14q11.2 (CHD8 & SUPT16H) and 15q26.1(CHD2), and deletions at 16p12.1.Discussion: There is a paucity of research on CNVs inadults with ID and co-morbid psychiatric diagnoses. Thisposes a challenge for genetic counselling of rare CNVs, asdescriptions of later-life phenotypes are largely unavail-able. In our sample, the largest multi-population sample ofits kind to date, we find a significantly higher rate of NDDrisk CNVs compared to schizophrenia and ID/ASD only

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cohorts. Our high diagnostic yield of 13% pathogenic CNVsdemonstrates the diagnostic utility of CMA in this patientgroup. We also find a high yield of likely pathogenic CNVs(21.5%), which enables us to phenotypically characteriserare recurrent CNVs. Increased clinical testing and researchin this population should be a priority for both clinicians andresearchers in the field of psychiatric genetics.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.135

SA64. FOLLOW-UP STUDY OF WHOLE-GENOME DNAMETHYLATION EPIGENETIC PROFILES IN THE REMISSIONOF ANOREXIA NERVOSA

Nicolas Ramozn,1, Sébastien Guillaume2, Philippe Courtet2,

Boris Chaumette3, Philip Gorwood4

1INSERM2CHU Montpellier3McGill University4Sainte-Anne Hospital CMME

Background: Anorexia Nervosa (AN) is a severe psychia-tric disorder with a strong heritability (about 0.6). Thereare no drug treatments available for AN. Interestingly, onethird of patients evolved to remitters after hospitalizationsand multiple adapted cares but, to date, there are nobiological markers that could help to propose a prognosticto this remission. Even the genetic component to AN, thereis no major gene that has been identified in AN. Themechanisms of epigenetic regulations could play a majorrole in the involvement in AN. We and other groups haverecently performed a whole-genome DNA methylation study(methylome) in AN. We found that the differentially methy-lated CpG sites are located around genes involved inbiological processes in link with embryonic morphogenesis,brain development and its plasticity, in particular adhesionand axon guidance. In the present study, we have screeneda novel independent group of 40 AN patients. Furthermore,we have done a follow-up during more than one year, tocompare the methylation profiles between the patientscurrently with AN and subjects that evolve to the remission.Methods: Our objective is to characterize a specificmethylome in AN patients that convert to remitters in thegoal to identify prognostic epigenetic signatures for AN. Ofthe 40 AN patients, 18 evolved to the remission after oneyear of follow-up. The blood samples of the subjects werecollected at the 2 times of the follow-up. Methylations ofthe DNA were measured by using the Infinium HumanMethy-lation450 BeadChip technology and analyzed according tothe Chip Analysis Methylation Pipeline (ChAMP).Results: Comparisons of AN patients to controls showedsimilar profiles of methylation has previously found withother patients, including the same biological processes aspreviously identified. We are now comparing the differ-ence of methylation between the 18 remitters and the 18current AN.

Discussion: We expect to characterize specific methyla-tion signatures of the prognostic of the AN remission.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.136

SA65. IDENTIFYING VARIANTS IN NF1A GENE TO BEASSOCIATED WITH SEASONAL PATTERN AND SUSCEPT-IBILITY FOR DEPRESSION THROUGH A CANDIDATE GENEAPPROACH

Teng-Yu Fann,1, Ming-Chyi Huang2, Mong-Liang Lu3,

Hsi-Chung Chen4, Shih-Jen Tsai5, Yu-Li Liu6,Chun-Hsin Chen3, Po-Hsiu Kuo7

1Institute of Epidemiology and Preventive Medicine,College of Public Health, National Taiwan University2Taipei City Psychiatric Center, Taipei City Hospital3Taipei Municipal Wan Fang Hospital4National Taiwan University Hospital5National Yang-Ming University6National Health Research Institutes7Institute of Epidemiology and Preventive Medicine,National Taiwan University

Background: Seasonal Pattern (SP) was reported indepressive patients of both Bipolar Disorder (BD) and MajorDepressive Disorder (MDD). In this study, we aimed toinvestigate genetic contributions of seasonal pattern ofmajor depressive episodes in both BD and MDD patients,including genes in relevant biological pathways indicated inprevious studies. To further clarify the roles of the variantsin depression, we conducted analyses using a case-controlstudy design to examine whether the genetic variants for SPalso possess effects on susceptibility to depression.Methods: We recruited 472 BD (83%) and MDD (17%)patients in Taiwan. SP of depressive episode were definedaccording to interview questions as “Which season do youfeel the worst?” in their first, the most serious, and themost recent episode within a year. Subjects answered aspecific season in two of the three episode categories wereconsidered SP+, while others were categorized as non-SP(SP-). The other dataset for depression was obtained fromthe Taiwan biobank with about 10,000 people. Cases weredefined by self-report MDD history or having the sum-scoregreater than 3 in the Patient Health Questionnaire-4.

We examined 15 genes (824 single nucleotide variants)including the melatonin pathway (MTNR1a, MTNR1b,AANAT), serotonin pathway (TPH2, HTR2A, HTR2B, SLC6A4),circadian feedback loop (NPAS2, CRY2, ARNTL, ARNTL2,RORA, RORB, PER) and NF1A gene that identified from aprevious genome-wide association study of seasonal mania.Association analyses were performed by multivariate logis-tic regression, adjusting for gender, age, and diagnosis. Wecorrected for multiple testings using false discovery ratemethod.Results: After excluding subjects with missing covariates,there were a total of 464 subjects with 162 (35%) in the SP+

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and 302 (65%) in the SP- groups. No differences wereobserved in gender, age or diagnosis distribution betweenthe two SP groups. Nominal associations with p-valueo0.01was observed in 20 markers for SP of depressive episodes, 19of them located in NFA1 gene and 1 locus in RORA gene.Marker rs1547849 in the NFA1 gene showed the highestsignificant level (P=6.37n10-5), followed by rs1777546(P=1.52n10-4) and rs1779868 (P=1.83n10-4). These geneticvariants remained significant (P-values=0.05) after multipletesting correction.

The 20 markers were tested again for depression in 9862individuals from Taiwan biobank. Although none of themshowed genome-wide significance, 6 SNPs had nominalp-valueso0.05, and rs334724 in NFA1gene had the smallestp-value (P=1.08n10-3).Discussion: We found that NF1A gene maybe a susceptiblegene for depression and modifiable gene for SP. Somegenetic variants in this gene are related to both seasonalpattern of depressive episodes and depression with nominalsignificance, indicating partially shared genetic componentsbetween the development of mood symptoms and season-ality in depression. Further investigation is needed forreplication with more stringent seasonal pattern evaluation,and for exploring the exact biological functions of theidentified genetic variants.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.137

SA66. PRECISION MEDICINE FOR SUICIDALITY: FROMUNIVERSALITY TO SUBTYPES AND PERSONALIZATION

Alexander Niculescun

Indiana University School of Medicine

Background: Objective and quantitative markers wouldpermit better and more precise assessment, tracking, andprediction of suicidal risk, which would enable preventivetherapeutic interventions. Previous work by our group hasidentified blood biomarkers and phenotypic predictors forsuicide risk in men, and separately in women, showing somegender similarities as well as differences. An essentialquestion remained to be answered, of high relevance fordeveloping this area of research and carrying it to fullclinical applicability: would a quest for more universalpredictors or a quest for more personalized predictors bemore productive? We endeavored to answer this questionthrough our current work.Methods: First, we sought to investigate whether bloodgene expression biomarkers can be identified that are moreuniversal in nature, working across psychiatric diagnosesand genders, starting with a powerful longitudinal within-participant design, and using larger cohorts than in previousstudies. Second, we identified subtypes of suicidality basedon mental state (anxiety, mood, psychosis) at the time ofhigh suicidal ideation. Third, we used a more personalizedapproach, by gender and diagnosis, with a focus on the

highest clinical risk group, male bipolars. We examined theability of the candidate biomarkers to predict suicidalideation and future hospitalizations for suicidality, in com-pletely independent cohorts. We also used the lists of topbiomarkers we identified as a window into the biology ofsuicidality, by conducting biological pathways and networkanalyses. Additionally, we leveraged these lists for thera-peutics and drug discovery purposes.Results: We were successful in this endeavor, using acomprehensive stepwise approach, leading to a wealth offindings. Step 1, 2 and 3 were discovery, prioritization, andvalidation for tracking suicidality, resulting in a top dozenlist of candidate biomarkers comprising the top biomarkersfrom each step, as well as a larger list of 148 candidatebiomarkers that survived Bonferroni correction in thevalidation step. Step 4 was testing the top dozen list andBonferroni biomarker list for predictive ability for suicidalideation and for future hospitalizations for suicidality inindependent cohorts, leading to the identification of com-pletely novel predictive biomarkers, as well as reinforce-ment of ours and others previous findings in the field.Discussion: The biomarkers we identified also provide awindow towards understanding the biology of suicide,implicating biological pathways related to neurogenesis,programmed cell death, and insulin signaling from theuniversal biomarkers, as well as mTOR signaling from themale bipolar biomarkers. Finally, based on the totality ofour data and of the evidence in the field to date, aconvergent functional evidence score prioritizing biomar-kers that have all around evidence (track suicidality, predictit, are reflective of biological predisposition, and arepotential drug targets) brings to the fore genes that suggestan inflammatory/accelerated aging component, which maybe a targetable common denominator.

Disclosure: MindX Sciences – Consultant, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.138

SA67. A NEURAL SIGNATURE OF MALLEABILITY: GEN-ERAL INTELLIGENCE CORRELATES WITH VENTRALSTRIATAL ACTIVATION AND EPIGENETIC MARKERS OFDOPAMINE NEUROTRANSMISSION

Swapnil Awasthin,1, Jakob Kaminski1, Michael Rapp2,

Florian Schlagenhauf1, Henrik Walter1, Barbara Ruggeri3,Stephan Ripke4, Gunter Schumann3, Andreas Heinz1

1Charité Universitätsmedizin2Social and Preventive Medicine, University of Potsdam3Institute of Psychiatry, Psychology and Neuroscience, King'sCollege London4Massachusetts General Hospital

Background: General intelligence has a substantialgenetic background in children, adolescents, and adults,but environmental factors also strongly correlate withcognitive performance as evidenced by a strong (up to oneSD) increase in average intelligence test results in the

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M. Barbu et al.38

second half of the previous century. This change occurred ina period apparently too short to accommodate radicalgenetic changes. It is highly suggestive that environmentalfactors interact with genotype by possible modification ofepigenetic factors that regulate gene expression and thuscontribute to individual malleability. This modificationmight as well be reflected in recent observations of anassociation between dopamine-dependent encoding ofreward prediction errors and cognitive capacity, which wasmodulated by adverse life events.Methods: In a cohort of 1475 young healthy human sub-jects of both sexes from the IMAGEN sample, general IQ wasestimated based on a principal component analysis of WISC-IV scores. As predictors we used functional brain activationelicited by temporarily surprising reward-predicting cues(BOLD-signal) during performance of the MID-task, a poly-genic score for intelligence based on previously reportedresults (Benyamin et al. 2014) and methylation count in cgrich islands relevant for dopaminergic neurotransmission.Results: Here we show that general IQ in adolescents ispositively associated with 1) functional activation elicitedby temporarily surprising reward-predicting cues, 2) apolygenic score for intelligence in children, and negativewith 3) epigenetic markers for dopamine neurotransmission.With respect to components of general IQ, fluid IQ wasassociated with striatal functional activation, and crystal-lized IQ more strongly correlated with the genetic score andepigenetic markers.Discussion: Our results demonstrate a neurobiologicalcorrelate of the malleability of general IQ and point tothe importance of epigenetic mechanisms influencing dopa-mine neurotransmission. Peripheral epigenetic markers arein need of confirmation in the central nervous system andshould be tested in longitudinal settings specifically asses-sing individual and social stress factors that can modifyepigenetic structure.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.139

SA68. INTER-INDIVIDUAL CORTICAL AND SUBCORTICALSIMILARITY IS ASSOCIATED WITH DIFFERENCES IN PSY-CHIATRIC, COGNITION AND SOCIO-ECONOMIC TRAITS

Baptiste Couvy-Duchesnen

, Lachlan Strike, Futao Zhang,Naomi Wray, Margaret Wright, Peter Visscher, Jian Yang

University of Queensland

Background: Many neuroimaging studies have attemptedto identify brain features associated with psychiatric traits,cognition or socio-economic status, however, few werelarge scale studies and even fewer replicated their results.If small samples might explain the lack of success ofassociation studies an important question is how muchvariation in neuropsychiatric phenotypes is associated withinformation held in brain image data, and whether this

limits our ability to detect brain markers.Methods: Here, we extend previous work by Sabuncuet al. (2016) and calculate Brain Relatedness Matrices(BRM) from vertex-wise cortical and subcortical measure-ment extracted from T1 MRI images (FreeSurfer processing).We used a new versatile mixed linear model software thataccommodates multiple types of data to construct related-ness matrices, allowing to estimate the variance associatedwith information held in brain images in a wide range oftraits collected as part of the Human Connectome Project(N=1,110, mean age 28, 54% females).Results: We showed that brain cortical and subcorticaldifferences could account for 66% of the variance in IQ(p=5.1E-6), 28% of depression score (p=0.016), 32% ofanxiety (p=3.1E-6), 36% of ADHD (p=9.8E-9), 45% of Child-hood conduct disorder score (p=1.6E-10) but also 27% of thevariance in number of illicit drug used (p=6.1E-6) and 33% inthe frequency of Marijuana use (p=1.4E-7). Furthermore,brain T1 individual similarities are associated with 94% ofvariation in age (po1e-16), 83% of BMI (po1E-16), 49% ofeducation years (p=2.6E-12) and 51% of the variance inincome level (p=9.0E-13). These results are all withinsample associations, with some replicating those publishedby Sabuncu et al. For the others, we sought replication in theQueensland Twin IMaging sample (N=1,040). Furthermore,our approach allows breaking down the variance accountedfor by the brain into compartments: subcortical, cortical, leftor right hemisphere, surface area or thickness, which canguide brain wide association studies.Discussion: We anticipate that the availability of largerimaging samples (HCP or UKB) will allow for more explora-tory analyses of brain markers and we introduce Brain WideAssociation Study (BWAS), as a strategy to test the associa-tion of each vertex with a trait of interest in a mixed modelframework. Such an approach does not require usinganatomical atlases and allows detecting localised markersof the trait or disease. Finally, we detail the consequencesof these results: prioritisation of brain modality or structurein association analysis as well as the calculation of brainscores for psychiatric or cognitive traits using Best LinearUnbiased Predictor (BLUP) estimates of the BWAS, whichmay be used to test new hypotheses.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.140

SA69. Poster Withdrawn: QUANTIFYING THE EFFECTS OF16P11.2 CNVs ON BRAIN STRUCTURE, A MULTI-SITE‘GENETIC-FIRST’MRI STUDY

Sandra Martin-Brevetn,1, Borja Rodriguez-Herreros2,

Jared A. Nielsen3, Clara Moreau4, Claudia Modenato1,Anne M. Maillard1, Wendy K. Chung5, Elliott H. Sherr6,John E. Spiro7, Jacques S. Beckmann8,Nouchine Hadjikhani9, Alexandre Reymond8,Randy L. Buckner3, Bogdan Draganski1,Sébastien Jacquemont2

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39PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

1CHUV2CHU Sainte Justine3Harvard University4University of Montreal5Columbia University6University of California7Simons Foundation8University of Lausanne9Harvard Medical School

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.141

SA70. SEX-STRATIFIED ANALYSIS OF OBSESSIVE-COM-PULSIVE DISORDER REVEALS MINOR DIFFERENCES INGENETIC ARCHITECTURE

Ekaterina Khramtsovan,1, Lea Davis2, Barbara Stranger1,

International Obsessive Compulsive Disorder FoundationGenetics Collaborative (IOCDF-GC), OCD CollaborativeGenetics Association Studies (OCGAS)

1University of Chicago2Vanderbilt University Medical Center

Background: Obsessive-Compulsive Disorder (OCD), aheritable neurobehavioral disorder, demonstrates sexualdimorphism in age of onset and clinical presentation,suggesting a possible sex difference in genetic architecture.Here, we present the first genome-wide assessment of sex-specific genetic architecture of OCD on currently the largestOCD cohort available from the Psychiatric Genomics Con-sortium (total cases and controls N=9,870 after qualitycontrol, 1:1.4 male/female ratio).Methods: First, we performed a sex-stratified meta-GWAS toidentify specific autosomal and sex chromosome genetic var-iants differentially associated to OCD risk in each of the sexes.Second, we assessed whether the most heterogeneous OCD riskalleles and top (po10-3) sex-specific genome-wide associationsare involved in gene regulation to elucidate the biologicalmechanisms by which those variants may impact dimorphism.Third, we used heritability analysis to (a) assess the proportionof overall OCD heritability explained by the X chromosome, and(b) to test for evidence of variable liability threshold for OCDbetween males and females. Lastly, we performed a sex-stratified genetic correlation analysis with other traits whichmay play a role in OCD development (e.g. brain volumes), showsexual dimorphisms (e.g. autism, Tourette's syndrome, etc.) orare known to be differential clinical symptoms in OCD (e.g.smoking, alcohol consumption, etc.).Results: There were no genome-wide significant associa-tions in either sex. Sex heterogenous SNPs (including andexcluding SNPs in the HLA region) were strongly enriched forimmune expression quantitative trait loci (po0.001). Topassociations were significantly enriched for brain eQTLs(p=0.003) in females and for immune eQTLs (p=0.003) inmales. Using DAPPLE, we identified 10 genes implicated byheterogeneous OCD risk brain eQTLs (FDRo0.05) that

showed significantly more network connectivity thanexpected by chance. There were no differences betweensexes in OCD heritability (h2male=0.23, se=0.08;h2female=0.24, se=0.06). The X chromosome contributed6.7% to total heritability which is not statistically differentfrom expectation. The genetic correlation between sexes ishigh: GCTA GREML (1.0, se=0.27). Although OCD demon-strated significant genetic correlation with many traits,there were no statistically significant differences betweensexes when corrected for multiple testing.Discussion: We present the first genome-wide assessmentof sex-specific genetic architecture of OCD. We identifiedminor sex differences in genetic architecture of OCD, andalthough the sex-stratified sample size is likely too small toidentify variants with small effect, we have developed arobust analytic pipeline for sex-stratified genetic analysiswhich will be applied in the near future to OCD as largercohorts become available. The pipeline will also be appliedto additional phenotypes where a sex bias in genetic effectsmay influence trait variation. This will enable a deeperunderstanding of how genetic variants may regulate biolo-gical processes influencing sex-biased phenotypes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.142

SA71. RARE AND DE NOVO VARIANTS IN OBSESSIVECOMPULSIVE DISORDER

Matt Halvorsenn,1, JF. Samuels2, Ying Wang2,

Gerald Nestadt3, David Goldstein4

1University of North Carolina at Chapel Hill2Johns Hopkins University School of Medicine3Johns Hopkins Hospital4Institute for Genomic Medicine, Columbia University Med-ical School, Columbia University Medical Center

Background: Obsessive Compulsive Disorder (OCD) is acomplex neuropsychiatric disorder that affects approxi-mately 1% of the population. It is likely that the geneticarchitecture underlying the disorder is complex, and thatfurthermore some subset of it involves rare and de novovariants of relatively large effect size.Methods: We have generated what to our knowledge isthe largest high throughput sequencing dataset for thisdisorder presently in existence. The data consist of over550 sporadic OCD trios and quartets selected for wholeexome sequencing, as well as 150 representative affectedmembers of multiplex families for OCD that were selectedfor whole genome sequencing. We have carried out ananalysis of rare and de novo coding variation within thiscohort in order to assess how much it contributes to OCDrisk, as well as if there are any single genes with exome-wide significant levels of damaging variant burden.Results: In assessing de novo mutation burden in trios,while we don’t observe a marked departure in mutationrate from what is expected, we do note an elevation of

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damaging de novo variant burden in cases relative tocontrols (odds ratio=1.3, p=0.097), as well as in individualswith an early age at onset (e.g., o7 years). We also noteseveral genes burdened with recurrent nonsynonymous denovo mutation, a portion of which are intolerant to geneticvariation. In gene-based collapsing analyses, while we failto identify any single genes that pass the exome-widesignificance threshold, we describe several promising trendsin regards to ultrarare damaging variant burden that shouldbe monitored as sample size increases.Discussion: In general, the sequence data we have gen-erated provides further support for a complex geneticarchitecture in OCD, as well as the need for a larger numberof samples for adequate resolution.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.143

SA72. GENE EXPRESSION IN BLOOD OF ADOLESCENTSWITH PSYCHIATRIC DISORDERS

Leticia Spindolan,1, Marcos Santoro1, Pedro Pan1,

Fernanda Talarico1, Gabriela Xavier1, Carolina Carvalho1,Ary Gadelha1, Giovanni Salum Junior2, EuripedesConstantino Miguel3, Luis Rohde4, Evelin Aline Zanardo3,Leslie Domenici Kulikowski3, Rodrigo Bressan1,Vanessa Ota1, Sintia Belangero1

1Federal University of Sao Paulo2Hospital de Clinicas de Posto Alegre3University of Sao Paulo4Federal University of Rio Grande do Sul

Background: Neuropsychiatric disorders represent a largepublic health and economic burden at a national and globallevel, and delineating the genetic architecture of mentaldisorders across molecular levels will aid in the develop-ment of novel treatment and prevention strategies.Whereas most psychiatric disorders are moderately to highlyheritable and there are evidences of shared genetic etiologyfor psychiatric disorders, we aimed to investigate geneexpression profiling in adolescents with psychiatric disordersfrom a large prospective community school-based study inBrazil, the High Risk Cohort (HRC) Study for PsychiatricDisorders.Methods: This is a cross-sectional study comprised ofadolescents from the HRC. Participants were assessed usingthe structured diagnostic interview Development and Well-Being Assessment (DAWBA) to evaluate psychiatric diagnosisaccording to the DSM-IV and psychopathology measureswere assessed using Child Behavior Checklist (CBCL). Tran-scriptome in blood was compared between 23 adolescentswith at least one psychiatric disorder (PD group) and 25healthy controls (HC group) with no previous psychiatricdisorder and low psychopathology symptoms. Blood geneexpression profiling was measured using HumanHT-12 v4.0Expression BeadChip (Illumina) and the 100 most associatedgenes list was brought forth to assess whether they were

enriched for any Gene Ontology (GO) Biological Processcategory or canonical pathway (by KEGG - Kyoto Encyclo-pedia of Genes and Genomes) using the Enrichr tool.Results: The most prevalent diagnosis in PD group wasanxiety disorders (44%), followed by major depression(28%), conduct disorders (28%) and attention deficit hyper-activity disorder (ADHD – 24%), knowing that some of thosediagnoses were overlapped. We have not found differen-tially expressed genes between the PD and HC groups aftermultiple comparisons correction. The 100 most associatedgenes were enriched with GO “proteasome-mediated ubi-quitin-dependent protein catabolic process” (p=0.0005)and “proteasomal protein catabolic process” (p=0.0007);and with the KEGG “proteasome Homo sapiens” (p=0.020)and “lysosome Homo sapiens” (p=0.023) canonicalpathways.Discussion: Although we have not found a significant geneexpression profiling, likely by the sample size, our cohort isa very well clinically characterized and unique sample ofadolescents with psychiatric disorders and healthy controlsfrom HRC Study. Degradation of proteins by the ubiquitin-proteasome system is an essential biological process in thedevelopment of eukaryotic organisms. The proteasomepathway has been associated with neurodevelopmentalsyndromes and early onset of some psychiatric disorder.Therefore, our results suggest that this pathway could beassociated with early onset psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.144

SA73. POLYGENIC BURDEN ANALYSIS OF LONGITUDI-NAL CLUSTERS OF QUALITY OF LIFE AND FUNCTIONINGIN PATIENTS WITH SEVERE MENTAL ILLNESS

Ashley Comesn,1, Fanny Aldinger2, Monika Budde2,

Urs Heilbronner2, Janos Kalman2, Nikola Müller3,Thomas G. Schulze4, Ivan Kondofersky5

1Institute of Psychiatric Phenomics and Genomics2Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich3Regulatory Networks, Institute of Computational Biology,Helmholtz Zentrum München4Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich5Institute of Computational Biology, Helmholtz ZentrumMunich

Background: Psychiatric illnesses such as bipolar disor-der, schizophrenia and schizoaffective disorder are severe,disabling disorders associated with decreased Quality OfLife (QOL) and functioning. Stigmatization, co-morbidities,adverse effects of medications and chronic symptoms due totreatment resistance are factors responsible for this asso-ciation. In this study, we aim to characterize patients withgood and poor outcomes according to QOL and functioningscores. Using cluster analysis, we sought to identify

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41PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

longitudinal trajectories and investigate whether levels ofQOL and functioning are associated with polygenic riskscores. Determining clusters of patients at higher risk ofpoorer outcomes is critical to provide early and effectiveinterventions.Methods: Longitudinal data was used from the ClinicalResearch Group 241 and PsyCourse studies in Germany.Participants were phenotyped using a comprehensive bat-tery which included data on socio-demographics, history ofillness, symptomatology, QOL and functioning. Data wascollected at four equidistant time points over 18 months.The Infinium Psycharray from Illumina was used to genotypepatients. The QOL and functioning domain was representedby 28 longitudinally measures items (WHOQOL-BREF; GAF;work status). Dimension reduction of the 28 items by meansof Factor Analysis for Mixed Data (FAMD) was applied. Thisallowed for the computation of abstract data dimensionswhich were used for calculation of longitudinal trajectories.These trajectories are a representation of the overall statusof patients and both the overall level as well as thelongitudinal change of this status were used as inputs fork-mean clustering of longitudinal data. This, in turn,resulted in the identification of three distinct subpopula-tions of patients. A multinomial regression of clustermembership on schizophrenia Polygenic Risk Scores (PRS)(11 p-value thresholds) was performed.Results: Individual trajectories across time on nine dimen-sions were used for cluster analysis. Together, these dimen-sions explained 27.13% of variance in the data. Thesedimensions were mainly driven by QOL items. In a sampleof 254 patients, three clusters were observed; cluster A(63%) consisted of participants with the highest averagescores for functioning, cluster B (33%) and cluster C (4%)consisting of participants with lower functioning over thecourse of the longitudinal study. A significantly higherproportion of individuals in cluster B were hospitalized atbaseline in comparison to cluster A. Furthermore, indivi-duals in cluster A had a significantly higher GAF score atbaseline than those individuals in cluster B. No significantdifferences were seen for age, center, diagnosis, sex, workstatus, or duration of illness between the clusters. Anominally significant effect of SZ-PRS on cluster member-ship was observed from the threshold 0.2 on, however thisdid not survive FDR correction. In terms of cluster member-ship, the highest polygenic risk loading was observed forcluster B and the lowest for cluster C.Discussion: Phenotypic data provides insight to targetsufferers of severe mental illness with worse outcomes.Further work is needed to improve methods to deal withmissing data and increase sample size. Associations withother biological data will be explored (e.g. microRNA;methylation data; proteomics; imaging data).

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.145

SA74. GENETIC UNDERPINNINGS OF SOCIAL WITHDRA-WAL IN THE GENERAL POPULATION

Cornelius Klemannn,1, Nina Roth Mota1, Janita Bralten1,

Tessel E Galesloot2, Lambertus ALM Kiemeney2,Barbara Franke1, Geert Poelmans1

1Radboud University Nijmegen Medical Centre2Radboud Institute for Health Sciences, Radboud UniversityNijmegen Medical Centre

Background: Social withdrawal is present as a trait in thegeneral population and is a common early symptom ofneuropsychiatric conditions such as Alzheimer's Disease(AD), Schizophrenia (SCZ) and Major Depressive Disorder(MDD). However, the underlying, biological causes of socialwithdrawal (as trait or disease state) are still poorly under-stood and may also differ between diseases. With this study,we aim to elucidate the genetics – and hence the biologicaletiology – of social withdrawal within the general populationand patients with AD, SCZ and MDD.Methods: We conducted a Genome-Wide AssociationStudy (GWAS) of social withdrawal in a Dutch generalpopulation sample, i.e. 2988 adult participants from theNijmegen Biomedical Study (NBS). For the GWAS, we usedthe total score on a social withdrawal measure that wasbased on the answers to 4 items from the extraversionsubscale of the Eysenck's Personality Questionnaire (EPQ)regarding social interaction avoidance, and 3 items from theAutism Spectrum Quotient (AQ) about (lack of) social skills.Based on the GWAS results, gene-wide analyses – i.e. takinginto account all SNPs within each gene – were performed.Further, a molecular landscape was built based on theproteins encoded by the genes associated with the mostsignificantly associated SNPs from the social withdrawalGWAS.Results: Our social withdrawal measure showed a Cron-bach's alpha of 0.693 within the NBS sample. The socialwithdrawal GWAS on the NBS sample did not result ingenome-wide significant SNPs. The top SNPs werers558196057 (P=1.43E-07) in an intron of AK8, andrs181663926 (P=8.11E-07) in an intron of TSC1. However,gene-wide analysis resulted in a significant association(P=2.30E-06) of the GIT1 gene with social withdrawal,which survived correction for the 17.876 genes tested.The molecular landscape provides some insights into themolecular interactions that are involved in social with-drawal in the general population.Discussion: The association of social withdrawal withGIT1 is promising, because it encodes a protein involved inneurite outgrowth and synapse formation. The molecularlandscape shows the interactions of GIT1 with other mole-cules linked to social withdrawal and as such provides cluesto the mechanisms underlying social withdrawal in thegeneral population. Future research will focus on analyzingsocial withdrawal in two other general population samples(i.e. the Leiden sample with 1241 subjects and the UK

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M. Barbu et al.42

Biobank sample with 500.000 subjects) and the findingsfrom these studies will be incorporated in the molecularlandscape of social withdrawal. Moreover, based on thesummary statistics from these GWASs, we will performpolygenic risk score-based analyses to determine the (puta-tive) genetic link(s) between social withdrawal as a generalpopulation trait and social withdrawal as a disease state inpatients with AD, SCZ and MDD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.146

SA75. ASSOCIATION OF SUICIDE MARKERS WITH COM-PULSIVE SYMPTOMS IN HEALTHY SUBJECTS

Tim Krause, Bettina Konte, Ina Giegling,Annette Hartmann

n

, Dan Rujescu

Martin Luther University Halle-Wittenberg

Background: Suicide is one of the leading causes of deathworldwide. A complex interplay between various risk factors isassumed to ultimately trigger a suicide attempt. Among those,genetic variations and personality traits seem to be the mostrelevant predictors. Results from a genome-wide associationstudy we participated in (Galfalvy et al. 2015) point to severalvariations associated with the condition. In order to elucidatetheir underlying function a closer look on the influence onpersonality traits as one of the main predictors seemedfeasible. Among others, stressful life events have been knownto increase the risk of suicidal behavior. Therefore, weinvestigated whether 23 susceptibility markers associated withsuicidal behavior also affect obsessive- compulsive behavior (asa personality trait prone to show a high risk of coping problemsunder stress) in healthy individuals.Methods: Unrelated healthy volunteers of German des-cent were screened for an absence of any psychiatricdisorder in themselves or their first degree relatives.Obsessive and compulsive symptoms were elevated usingthe Maudsley Obsessive Compulsive Inventory (MOCI).Finally, 2104 subjects (52% female) were enrolled in thestudy. Genotype data was obtained using chip technologyand imputation. After stringent quality controls 23 SingleNucleotide Polymorphisms (SNPs) were analyzed using anadditive linear regression model. Benjamini-Hochberg pro-cedure was used to correct for multiple testing.Results: In females, significant associations with the MOCItotal score were identified for two intergenic SNPs, localizednear BRINP3 (associated with coronary heart disease andaggressive periodontitis) and LOC647132 (a processed pseu-dogene which is associated with antibody response tosmallpox vaccine), both involved in inflammation processes.In males, significant associations could be detected for seven

SNPs localized in the TBX20 gene linked to migration anddevelopment of brainstem motor neurons, cardiac develop-ment and multiple cardiac functions and pathologies.Discussion: These results indicate a sex specific overlapof the genetic make-up between suicidality and obsessive-compulsive behavior, thereby emphasizing the relevance ofpersonality traits for suicidal behavior. Further researchapproaches are necessary in order to replicate these find-ings and also to identify the underlying functional relevanceof the associated variants.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.147

SA76. ABERRANT TELOMERE LENGTH AND MITOCHON-DRIAL DNA COPY NUMBER IN SUICIDE COMPLETERS

Ikuo Otsukan,1, Takeshi Izumi2, Naofumi Shimmyo1,

Shuken Boku1, Ichiro Sora1, Akitoyo Hishimoto1

1Kobe University2Hokkaido University

Background: Short Telomere Length (TL) and mitochon-drial DNA copy number (mtDNAcn) alterations in individualsunder psychological stress, and with various psychiatricdiseases. However, no study has examined whether aberrantTL or mtDNAcn occur in completed suicide, one of the mostserious outcomes of mental illnesses.Methods: TL and mtDNAcn in post-mortem samples from528 suicide completers without severe physical illness (508peripheral bloods; 20 brains) and 560 samples from controlsubjects (peripheral bloods from 535 healthy individuals; 25post-mortem brains) were analysed by PCR method.Results: Suicide completers had significantly shorter TLand higher mtDNAcn of peripheral bloods with sex/age-dependent differences (shorter TL was more remarkably infemale/young suicides; higher mtDNAcn more so in male/elderly suicides). The normal age-related decline of TL andmtDNAcn were significantly altered in suicide completers.Furthermore, shorter TL and lower mtDNAcn of post-mor-tem prefrontal cortex were seen in suicide completerscompared to controls.Discussion: Our results indicate that further research ontelomere shortening and mitochondrial dysfunction mayhelp elucidate the molecular underpinnings of suicide-related pathophysiology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.148

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43PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

SA77. MULTI-TISSUE TRANSCRIPTOME ANALYSISREVEALS GENETIC MECHANISMS OF NEUROPSYCHIATRICTRAITS

Eske Derksn,1, Eric Gamazon2, Aeilko Zwinderman3,

Nancy Cox4, Damiaan Denys3

1QIMR Berghofer2Vanderbilt Genetics Institute, Vanderbilt University3Academic Medical Center4Vanderbilt University Medical Center

Background: The genetic architecture of psychiatric dis-orders is characterized by a large number of small-effectvariants located primarily in non-coding regions, suggestingthat the underlying causal effects may influence disease riskby modulating gene expression.Methods: We provide comprehensive analyses using tran-scriptome data from an unprecedented collection of tissuesto gain pathophysiological insights into the role of the brain,neuroendocrine factors (adrenal gland) and gastrointestinalsystems (colon).Results: Among significant (FDRo0.05) expression Quantita-tive Trait Loci (eQTLs), we identified functional target genes forAttention Deficit Hyperactivity Disorder (Ngenes=4), BipolarDisorder (Ngenes=9), and Schizophrenia (Ngenes=874). Colon-expressed PLEK2 is a depression-associated gene; this wasreplicated in two independent datasets. In addition, we proposegene mechanisms for the well-known 108 schizophrenia loci3,including multiple replicated genes (beyond the ComplementComponent 4 A [C4A]) in the MHC region.Discussion: Our analyses highlight the importance ofmulti-tissue approaches as 70% of the genes were detectedonly in inaccessible tissues.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.149

SA78. GAPS: GENOMIC AGGREGATION PROJECTIN SWEDEN

Sarah Bergenn,1, Patrick Sullivan2

1Karolinska Institutet2University of North Carolina at Chapel Hill

Background: Since psychiatric disorders have geneticarchitectures dominated by common variants of smalleffects, psychiatric genetics necessitates large samplesizes. Collaboration and unconventional ascertainmentmethods are essential to fulfill this need. Electronic healthrecords have been increasingly recognized for their researchpotential, although they often pose substantial technical,legal and ethical challenges. Universal health care andnational-scale registers with comprehensive medical, devel-opmental, demographic, and geographic information makethe Nordic countries ideal for psychiatric genetic

epidemiology. Of all countries with these characteristics,Sweden has the largest population.Methods: The Genomic Aggregation Project in Sweden(GAPS) is gathering genetic data from subjects with andwithout complex genetic diseases in a single location forstandardized processing and use in a wide variety ofscientific investigations. Thirty-two groups with 4200 Kgenotyped samples have joined GAPS. Although GAPS isgeneral across medicine, many psychiatric disorders arerepresented within GAPS, and initial studies will focus onmajor depressive disorder.Results: Through in-depth genetic investigations, thegenes and pathways that will be identified can be leveragedfor predictive and drug-development purposes.Discussion: Instead of amassing studies with a commonphenotype across populations, a population-based consor-tium holds many advantages such as facilitating phenotypicharmonization across studies through national registers, agreater range of information for research, and reducedpossibility of population stratification. Sweden offers excep-tional possibilities for psychiatric genetics, and GAPS aimsto harness the wealth of available information for researchto improve human health.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.150

SA79. FUNCTIONAL CHARACTERIZATION OF HUMANCYP2C9 ALLELIC VARIANTS IN COS-7 CELLS

Shengying Qinn

Shanghai Jiao Tong University

Background: Variability in activity of CYP2C9, which isinvolved in the metabolism of approximately 15% of currenttherapeutic drugs, is an important contributor to interindi-vidual differences in drug response.Methods: To evaluate the functional alternations ofCYP2C9(n)2, CYP2C9(n)3, CYP2C9(n)8, CYP2C9(n)11 andCYP2C9(n)31, identified in our previous study in ChineseHan population, allelic variants as well as the wild-typeCYP2C9 were transiently expressed in COS-7 cells. Kineticparameters (Km, Vmax, and Clint) for S-warfarin 7-hydro-xylation by these recombinant CYP2C9s were determined.Results: Relative to CYP2C9.1, recombinant CYP2C9.3 andCYP2C9.11 exhibited significantly higher Km values, and allallelic variants showed significantly decreased Vmax andClint values. Among all allelic variants, catalytic activity ofCYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8%of Clint ratio, respectively; P o 0.001).Discussion: These findings should be useful for predictingthe phenotype profiles of CYP2C9 in Chinese Han popula-tion, comparing the functional results of these allelesaccurately, and finally optimizing pharmacotherapy of drugtreatment.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.151

SA80. ASSOCIATION OF CYP2D6 METABOLIZER STATUSWITH ANTIDEPRESSANT INDUCED MANIA

Lindsay Melhuish Beaupren

, Clement Zai, Arun Tiwari,Emanuela Mundo, Sajid Shaikh, Maria Tampakeras,Natalie Freeman, James L. Kennedy

Centre for Addiction and Mental Health

Background: Bipolar Disorder (BD) is a mood disordercharacterized by alternating periods of depression and mania/hypomania. It affects approximately 1% of the population and isconsidered one of the top 20 leading causes of disability.Although mood stabilizers are currently the frontline treatmentfor BD, antidepressants still play a valuable role in treating thedepressive symptoms. However, 20–40% of these individuals willexperience Antidepressant-Induced Mania (AIM). There areseveral clinical factors that have been suggested to contributeto this phenomenon, such as BD type I, age of onset, andnumber and severity of manic episodes prior to the start of theantidepressant. The serotonin transporter gene has also beenthoroughly studied in this context. Studies suggest that indivi-duals with the short allele of this gene have a greater risk ofexperiencing AIM. More recently, it's been suggested thatindividuals that are slow metabolizers of the CYP2D6 liverenzyme gene are also at a greater risk of experiencing AIMwhen given an antidepressant that acts on that enzyme. Wesought to extend these findings.Methods: Using a subset of the Toronto Bipolar sample(N=52), we investigated whether being a slow or inter-mediate metabolizers for any of five liver enzyme genes(CYP2D6, CYP2C9, CYP2C19, CYP1A2 and CYP3A4) wouldmake one more susceptible to experiencing AIM. Individualswho were part of this sample met the DSM-IV criteria for aBD diagnosis and were of European descent.Results: Our preliminary data (N=40) showed a trend ofassociation with CYP2D6 metabolizer status. Individuals thatwere either poor or intermediate metabolizers of this liverenzyme were more likely to have experienced AIM whengiven serotonergic antidepressants (x2=3.14, p=0.077).Discussion: Our findings provide preliminary support tothe earlier observation of association of poor and inter-mediate metabolizer status of CYP2D6 with AIM. This ispresumably because the drug has more time to build up inthe system of those who are poor or intermediate meta-bolizers than extensive metabolizers, who are able tobetter break down the drug. The data suggests that inaddition to the potential clinical factors, pharmacogeneticcomponents may need to be considered prior to prescribingantidepressants to individuals with BD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.152

SA81. UNRAVELING GENOMIC CONTRIBUTIONS TO VEN-LAFAXINE REMISSION IN OLDER ADULTS WITH LATE-LIFE DEPRESSION USING A GENOME-WIDE APPROACH

Victoria Marshen,1, Malgorzata Maciukiewicz1, Soham Rej2,

Arun Tiwari1, Etienne Sibille1, Daniel Blumberger1,Jordan Karp3, Eric J. Lenze4, Charles Reynolds3,James Kennedy1, Benoit Mulsant1, Daniel Mueller5

1Centre for Addiction and Mental Health2McGill University3University of Pittsburgh4Washington University5University of Toronto

Background: In geriatric depression, antidepressanttreatment response is often slow and incomplete; newbiomarkers for antidepressant response could lead to pre-cision medicine and uncover new mechanisms of illness.Therefore, we conducted a Genome-Wide Association Study(GWAS) in older adults treated with venlafaxine.Methods: Three-hundred and fifty participants (460years) of mixed ethnic ancestry, diagnosed with majordepression (MADRS415), were treated with venlafaxine(�12 weeks). Individuals were genotyped using the IlluminaPsychArray, and genetic data was imputed to 7.5 millionvariants per individual. Associations with remission status(MADRSr10) and change in MADRS score were conductedusing logistic/ linear regressions, adjusted for ancestry, sex,recruitment site, length in treatment, depressive episodeduration, and baseline depressive severity. We also con-ducted pathway enrichment analysis using DEPICT.Results: Our top hits in association with MADRS scorechange were with variants near MIR1246 and in ERBB4, aschizophrenia susceptibility gene. ERBB4 has been impli-cated in post-ketamine treatment down regulation of GABAand glutamate levels in the rat prefrontal cortex andhippocampus, resulting in an antidepressant effect. We alsoobserved a suggestive association between remission statusand a variant in phosphodiesterase gene PDE9A, suggestinga role in synaptic neurotransmitter signaling. Our top hitpathways included processes in the metabolic pathway ofamyloid precursor protein. However, no variants survivedcorrections for multiple testing (po5� 10-8).Discussion: Our findings suggest novel gene variant asso-ciations with measures of venlafaxine remission in olderadults, as well as interesting neuro-relevant genetic path-ways. A new, larger study of geriatric depression treatmentwill confirm these novel findings.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.153

SA82. HLA-DQB1 6672G4C INFLUENCES THE RISK OFCLOZAPINE-INDUCED AGRANULOCYTOSIS IN INDIVI-DUALS OF EUROPEAN ANCESTRY

Bettina Konten,1, James Walters2, Ina Giegling1,

Sophie Legge2, Dan Cohen3, Munir Pirmohamed4,Jari Tiihonen5, Annette Hartmann1, J.P. Bogers6,Jan van der Weide7, Karen van der Weide7, Anu Putkonen8,Eila Repo-Tiihonen9, T. Hallikainen8, E. Silva5,Oddur Ingimarsson10, Engilbert Sigurdsson11,James Kennedy12, Gerome Breen13, Patrick Sullivan14,Marcella Rietschel15, Hreinn Stefansson16, David Collier17,Michael O'Donovan2, Dan Rujescu1

1Martin Luther University Halle-Wittenberg2Cardiff University3Mental Health Care Organization North-Holland4The University of Liverpool5Karolinska Institutet6Mental Health Services Rivierduinen7St. Jansdal Hospital8University of Eastern Finland, Niuvanniemi Hospital9Niuvanniemi Hospital10University of Iceland, Landspitali University Hospital,Mental Health Services11Landspitali University Hospital12Centre for Addiction and Mental Health13King's College London14University of North Carolina at Chapel Hill15Central Institute of Mental Health16deCODE genetics17King's College London, Mental Health Care OrganizationNorth-Holland

Background: The atypical antipsychotic drug clozapine isthe only effective drug for treatment-resistant schizophre-nia, but also bears the risk of inducing severe adverse drugresponses including neutropenia and agranulocytosis. Agra-nulocytosis and neutropenia occurs in about 1% and 3% oftreated individuals. The aetiology is largely unknown, butthere is evidence for contributing genetic factors. Identify-ing biomarkers could decrease blood monitoring effort andenable a more widespread use of clozapine. Several studiesidentified HLA variants (e.g. Athanasiou et al. 2011) andespecially a polymorphism located in HLA-DBQ1 (6672 G4C,rs113332494) as associated with clozapine-induced agranu-locytosis or neutropenia. Our study was conducted toreplicate previous findings on HLA-DBQ1 6672 G4C.Methods: The sample was comprised of individuals fromsites of Finland, Germany, the Netherlands and the UK andwas collected in the course of the CRESTAR project, whichaimed at the development of pharmacogenetic biomarkersfor schizophrenia. We analysed the risk allele distribution ofrs113332494 in individuals of different ethnic backgroundincluding 180 clozapine-induced neutropenia cases of which

61 developed agranulocytosis and 1396 controls treatedwith clozapine but not affected by this severe adverse drugresponse. We also performed association analyses in sub-samples using logistic regression with an additive modelseeking replication of previous findings on rs113332494.

This CRESTAR project was funded by the EuropeanUnion's Seventh Framework Programme for research, tech-nological development and demonstration under grantagreement #279227.Results: rs113332494 was associated with neutropenia(OR=6.34, P=2.13E-06) and agranulocytosis (OR=9.59,P=1.11E-05) in individuals of European ancestry. The asso-ciation signal was mainly driven by agranulocytosis cases.Discussion: Our study gives further evidence of an impli-cation of HLA-DQB1 in agranulocytosis. We were able toreplicate previous findings. This implicates immune functionas contributing process to this severe adverse drug response.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.154

SA83. EFFECT OF PSYCHOGENOMIC TESTING ON MED-ICATION TRIALS AND RESPONSE IN CHILD AND ADOLES-CENT OUTPATIENT PSYCHIATRY

Rikinkumar Pateln

, Ahmed Elmaadawi, Suhayl Nasr,Shady Mashaly

Beacon Health System

Background: The significance of psychogenomic testingat clinical practice is still under investigations. Therefore,we thought to evaluate the role of psychogenomic testing inthe management of children and adolescents seeking men-tal health care in the outpatient Child and AdolescentPsychiatry (CAP) clinic.Methods: We selected patients who received psychoge-nomic testing and had regular follow-ups at the clinic for6 to 8 month period. Among 4 board certified childpsychiatrists at the clinic, 151 patients met the inclusioncriteria. We examined their psychiatric diagnoses, medica-tions history, and reviewed the CYP450 profile; including2D6, 2C9, 2C19, 3A4, also 5HT transporter (SLC6A4), 5HTreceptor (HTR2A), COMT, ADRA2A and MTHFR genes. Weevaluated how the results impacted the clinical care for ourpatients. We also assessed the number of medicationsadded, eliminated, switched or titrated and the time toachieve clinical improvement.Results: In our sample, the average age was 12.9 years,and it ranged from 5 to 19 years-old. 78 subjects were male(52%) vs. 73 female (48%). 25% of patients were diagnosedwith Major Depressive Disorder (MDD), 47% with ADHD, 26%with Anxiety disorder, and 2% with other diagnoses. Theaverage number of medications for each specific disorderbefore testing was 1.47 medications and after testing was1.83 medications. The total number of medication change inMDD was 0.22, & it made significant improvement in patientswith mean CGI response of 3.08 (p= 0.028, df= 1, 35).

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Whereas number of medication trial did not have significantimpact on the outcome of treatment of ADHD and Anxietywho had total number of medication change 0.07 and -0.25respectively, & mean CGI response of 2.79 & 2.38 respec-tively (p= 0.39). In MDD, the CYP2D6 status (normal vsabnormal metabolizer) significantly affected improvement(p= 0.025), whereas CYP2C19, COMT & MTHFR status did notaffect improvement. However, response to ADHD & Anxietytreatment was not related to psychogenomic testing status.In ADHD, the COMT status (normal vs abnormal metabolizer)did not significantly affect improvement (p= 0.7923).Discussion: In our study population, psychogenomic test-ing was an advantageous tool to decrease the number ofmedication change and improve the CGI response in MDD.Contrary to expectation the increased COMT activity wasnot associated with better response to treatment in ADHDpatients. So, the clinicians should carefully evaluate eachgene test result pertinent to the treating disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.155

SA84. PLEIOTROPIC GENES IN PSYCHIATRY: EFFECTSOF CALCIUM CHANNELS AND THE STRESS-RELATEDFKBP5 GENE ON ANTIDEPRESSANT RESPONSE ANDTREATMENT RESISTANCE

Chiara Fabbrin,1, Filippo Corponi1, Diego Albani2,

Gianluigi Forloni2, Siegfried Kasper3, Joseph Zohar4,Daniel Souery5, Stuart Montgomery6, Vilma Mantovani7,Julien Mendlewicz8, Alexander Kautzky3, Ilaria Raimondi2,Alessandro Serretti1

1University of Bologna2IRCCS Istituto di Ricerche Farmacologiche3Medical University Vienna4Sheba Medical Center, Tel Hashomer, Sackler School ofMedicine, Tel Aviv University5Laboratoire de Psychologie Médicale, Université Libre deBruxelles and Psy Pluriel - Centre Européen de PsychologieMédicale6Lmperial College School of Medicine7Center for Applied Biomedical Research (CRBA), St. OrsolaUniversity Hospital8Universite´ Libre de Bruxelles

Background: The substantial contribution of genetic var-iants to inter-individual variance in antidepressant responsemakes genetic polymorphisms a unique opportunity toprovide tailored antidepressant treatments. The presentstudy combined a candidate approach of variants withstrong previous evidence and a genome-wide approach inorder to investigate the role of eight genes that appearoptimal candidates for involvement in antidepressantresponse on the basis of their biological function andprevious literature suggesting a pleiotropic effect acrossseveral psychiatric traits.

Methods: Three samples of patients with major depres-sive disorder (n=357, 218 and 96) were genotyped for 44SNPs in genes involved in neurotransmission (CACNA1C,CACNB2, ANK3), neural differentiation, synaptic plasticity,adhesion processes, structural organization (GRM7, TCF4,ITIH3, SYNE1) and glucocorticoid signaling (FKBP5). Pheno-types were response/remission at week 4 and Treatment-Resistant Depression (TRD: non response/non remission to atleast two antidepressants). STARnD genome-wide data wereused to replicate findings for response/remission (Level 1,n=1409) and TRD (Level 2, n=620). Standard qualitycontrol and genotype imputation were performed and path-ways including the most promising candidate genes forinvolvement in TRD were investigated in STARnD Level 2.Top pathway(s) were investigated also using machine learn-ing (R cran Caret package). At SNP-level results withpo0.05 in at least two samples were considered significantsince the previous evidence supporting the role of thesegenes. For pathway analysis, 10.000 permutations werecarried out and 10 fold cross-validation, repeated 100times, was used for machine learning models.Results: Several FKBP5 SNPs (rs3800373, rs1360780,rs9470080) showed consistent associations with response,remission or TRD across at least two samples. Results involvingCACNA1C SNPs (rs2283326, rs10848635, rs1006737) had contra-dictory direction of association across samples. ANK3 rs1049862AA genotype showed a consistent association with a morefavorable outcome in two samples. In STARnD pathway analysisfor the top candidate genes did not identify significant resultsafter permutation. The best pathway associated with TRDincluded the CACNA1C gene (GO:0006942, regulation of striatedmuscle contraction, corrected p=0.15). Neural networks andgradient boosted machine showed that independent SNPs in thispathway predicted TRD with a mean accuracy of 0.73,sensitivity of 0.83 and specificity of 0.56.Discussion: According to the present results and previousliterature, FKBP5 polymorphisms should be considered forinclusion in pharmacogenetic tests for the prediction ofantidepressant response and TRD. The contribution ofCACNA1C polymorphisms was unclear, but further investiga-tion is supported by previous literature and interestingfindings for GO:0006942 pathway that includes severalgenes coding for ion channels that are expressed in thecentral nervous system as well as other genes relevant forexcitatory mechanisms.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.156

SA85. PHARMACOGENOMICS OF METHYLPHENIDATETREATMENT OF DANISH CHILDREN WITH ADHD

Majbritt Busk Madsenn,1, Kristine Kaalund-Brok2,

Pia Jeppesen2, Anne Katrine Pagsberg2, Tine Houmann2,Kerstin Plessen2, Wesley Thompson3, Haja N. Kadarmideen4,Henrik Rasmussen3

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47PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

1Institute of Biological Psychiatry, Mental Health CentreSct. Hans2Centre for Child and Adolescent Mental Health, MentalHealth Services of the Capital Region of Denmark3Institute of Biological Psychiatry, Mental Health CentreSct. Hans, Mental Health Services of the Capital Region ofDenmark4Technical University of Denmark

Background: The first choice drug for treatment ofAttention Deficit Hyperactivity Disorder (ADHD) in Denmarkand several other countries is Methylphenidate (MPH). Morethan 30% of the children treated with MPH have beenreported to switch to another drug due to lack of efficacyor adverse reactions. Most likely, a significant fraction ofthis individual variation in treatment outcome is caused bygenetic differences. Previous studies have not identifiedgenes or genetic variants conclusively implicated in theresponse to MPH.Methods: We performed a pharmacogenomics study of theefficacy and adverse reactions of MPH in a sample of 207Danish children with ADHD, who were drug-naïve at baselineand were monitored for 12 weeks. Each week the ADHDsymptom severity was scored on the ADHD-RS questionnaire,and any adverse reactions were recorded.

We divided the ADHD symptom scores into inattentionand hyperactivity/impulsive sub-scores, and performedGWAS on the outcome of MPH treatment defined as thedifference in symptom severity from baseline to end ofstudy. This was followed by calculation of pair wise epistaticinteraction coefficients on the top SNPs from the GWAS.

Moreover, we used functional principal component ana-lysis to derive proxies that describe the longitudinal natureof the data for both the efficacy measurements and theadverse reactions. Subsequently, we performed GWAS usingthe proxies as phenotypes for the MPH outcome across theentire treatment period.Results: None of the GWAS resulted in genome-wide asso-ciated hits. However, among the top SNPs for the inattentionsub-score were some that fell in: RAS guanyl releasing protein1 (RASGRP1), sodium/potassium transporting ATPase interact-ing 2 (NKAIN2) and tetratricopeptide repeat domain 12(TTC12). For the hyperactivity/impulsive sub-score one ofthe top SNPs is in the vicinity of gamma-aminobutyric acidtype A receptor gamma3 subunit (GABRG3).

In the interaction analysis we identified the SNPs with thelargest difference in connectivity between the inattention andhyperactivity/impulsive sub-scores and found that some ofthese were located in or near: myelin transcription factor 1 like(MYT1L), synaptotagmin 17 (SYT17), potassium voltage-gatedchannel subfamily Q member 5 (KCNQ5) and potassium voltage-gated channel modifier subfamily S member 3 (KCNS3).Discussion: Despite the lack of genome-wide significantSNPs, some of the top hits from the GWAS reside in or neargenes that could modulate the response to MPH. Some ofthese genes have previously been implicated in psychiatricdisorders (RASGRP1, NKAIN2 and MYT1L), are involved inneurotransmission (GABRG3, KCNQ5, KCNS3 and NKAIN2) orhas been implicated in substance abuse, e.g. TTC12 has beenimplicated in heroin dependence and SYT17 in alcoholism.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.157

SA86. WHOLE GENOME SEQUENCING OF SCHIZOPHRE-NIA FAMILIES WITH MULTIPLE AFFECTED INDIVIDUALS

Xiangning Chenn

, Jingchun Chen, Jain-Shin Wu, Travis Mize

University of Nevada, Las Vegas

Background: It has long been established that schizophre-nia is highly heritable and family history is a reliable predictorfor the disorder. However, both GWAS and exome sequencingstudies fail to answer the question what genetic variantsconstitute family history. While it is generally believed thatcases from families with multiple affected individuals havehigher genetic risk loading, it is not clear to what extent andwhere do these cases differ from sporadic cases where there isno apparent family history of mental disorders. Whole genomesequencing of cases from families with multiple affectedindividuals may help to answer this question.Methods: We selected 20 Chinese families with at least2 affected siblings and 1 unaffected sibling and conductedwhole genome sequencing. Of these families, 7 had bothparents. Some of the parents had schizophrenia or otherpsychiatric disorders. We used the GATK protocols to alignsequence reads, call and annotate variants. In the first passof analyses, we generated a list of variants for each familythat were found in affected individuals only. We matchedthe list across the families and generated a new list ofvariants that were shared for at least 2 families. Variants inthis second list were functionally annotated, and analyzedfor enrichment for biological pathways.Results: We found that there were 6 SNVs that were foundin the affected individuals in 6 families. Three of them werein the ADAD2 gene, a nuclear double stranded RNA bindingprotein. One of the 3 SNVs in ADAD2 was non-synonymous,rs11149631, changing Gly to Arg. The other 3 were inNUP205, HNF4G and MAGEC1 genes. In the analyses offunctional variants, we found that non-synonymous SNVsfound in at least two families (640 SNVs in 539 genes) wereenriched in EMC-receptor interaction pathway and cell-matrix adhesion process. When we tested whether thesegenes were enriched in any known diseases, we identifiedchildhood onset schizophrenia. Of the 16 genes involved inchildhood onset schizophrenia, 5 genes (SEZ6, PDZRN3,HSPG2, ARL16 and ITGA6) were in our list.Discussion: Our overrepresentation enrichment analyses fornon-synonymous SNVs found in affected individuals in two ormore families indicate that the EMC-receptor interaction andcell-matrix adhesion are involved in schizophrenia, consistentwith previous report from other GWAS and sequencing analyses.The same genes are also enriched for genes involved inchildhood onset schizophrenia, implying that there may be alink or similarity between childhood onset schizophrenia andcases from families with multiple affected individuals. To ourknowledge, this is the first report of such connection.

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Furthermore, our analyses also suggest that ADAD2 is a topcandidate and further validation is justified.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.158

SA87. POLYGENIC RISK SCORE ANALYSES OF SYMPTOMSAND TREATMENT RESPONSE IN A FIRST EPISODE SCHI-ZOPHRENIA COHORT

Marcos Santoro1, Vanessa Otan,1, Simone de Jong2,

Cristiano Noto1, Fernanda Talarico1, Leticia Spindola1,Eduardo Gouvea1, Ary Gadelha1, Quirino Cordeiro1,Rodrigo Bressan1, Sintia Belangero1, Gerome Breen2

1Federal University of Sao Paulo2King's College London

Background: Schizophrenia (SCZ) is a severe mental dis-order affecting �1% of the population and is characterizedby the presence of psychosis and other features, such asnegative (i.e., flattened affect and social withdrawal) anddisorganization symptoms (e. g. impaired cognitive func-tion, disorganized speech and behavior). Symptomatic andpsychosocial deterioration progress rapidly during the per-iod just after the onset of the disorder, termed the FirstEpisode of Schizophrenia (FES). In this study, we aimed totest if the SCZ Polygenic Risk Score (PRS) was associatedwith clinical symptoms at the FES, nine weeks after initia-tion of risperidone treatment (FES-9W) and with theresponse to risperidone.Methods: We performed a detailed clinical assessment of60 antipsychotic naïve patients in their FES and, again, afternine weeks of standardized treatment with Risperidone.After blood collection and DNA isolation, the samples weregenotyped using the Illumina PsychArrayChip and thenimputed. To calculate PRS we used the latest availableGWAS summary statistics from the Psychiatric GenomicsConsortium wave-2 SCZ group as a training set. We usedPoisson Regression to test association between PRS andclinical measurements correcting for the four principalcomponents (genotyping). We considered as significant ap-valueo0.05/36 (Bonferroni correction for multiplecomparisons).Results: The polygenic risk score was significantly differ-ent between cases and controls with a best p-threshold of0.0112 (NSNPs=21,622) and an explained variance of 0.19(Naegelkerk's pseudo-r2).

Within-cases, we found a positive association of the bestPRS score with the PANSS excitement factor (five-factormodel) (p-value=0.0003). The PRS was slightly positivelycorrelated with depressive symptoms at baseline (CDSStotal, p-value=0.003) but was negatively associated withdepressive symptoms after risperidone treatment (CDSStotal, p-value=0.001).

Looking at response to risperidone, we observed apositive association for ΔCDSS (p-value=0.0006). However,there was no correlation between Δtotal PANSS and PRS.

Discussion: We verified that the schizophrenia PRS wasalso able to distinguish cases from control in this south-eastern Brazilian sample, with a similar variance explained(�0.19, observed scale) to that seen in Northern Europeanpopulations. One strength of our study is that all patientswere antipsychotic-naïve at the baseline and received thesame antipsycotic treatment for relatively the same time. Itis well known that some patients may have an increase ofdepressive symptoms once the positive symptoms remit,however, there is no study so far that evaluated the relationbetween PRS and post-schizophrenia depression. Takentogether, these results suggest that FES patients whopresent with higher depressive and excitement symptomsand who show reduction in these dimensions after treat-ment with risperidone have a significantly higher geneticrisk for SCZ (as measured by PRS). These results highlightthe importance of studying schizophrenia, and other dis-orders, in the early stages to understand the relationshipbetween polygenic genetic risk and phenotypic features.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.159

SA88. PARANOID THINKING IN HEALTHY INDIVIDUALS –

ASSOCIATION WITH SCHIZOPHRENIA GENETICS?

Stefan Watzken,1, Sandra Buck1, Adam Kropidlowski2,

Bettina Konte3, Ina Giegling4, Annette Hartmann3,Dan Rujescu4

1Psychiatric University Hospital Halle (Saale) Germany2University of Dresden3Ludwig Maximilian University of Munich4University of Halle

Background: Paranoid thinking is a psychological phe-nomenon affecting a considerable part of the generalpopulation. According to Freeman and colleagues (2005)there is a “hierarchy of paranoia”, which ranks from socialworries and beliefs of persecution to paranoid delusionswhich are common in schizophrenic disorders. Therefore,the assumption of this continual approach leads to thehypothesis that subclinical paranoid thinking and persecu-tory delusions in context of schizophrenia share a commongenetic basis. Our primary aim was to verify this hypothesis.Methods: Associations of 128 genome–wide significantschizophrenia risk variants (Schizophrenia Working Groupof the Psychiatric Genomics Consortium, 2014) were inves-tigated on paranoid thinking. Individual paranoid thinkingwas measured with a newly composed subscale based on theMinnesota Multiphasic Personality Inventory (MMPI), in aGerman sample including 2635 healthy subjects. From thissample n=1174 individuals with either none (n=558) or high(n=616) scores of paranoid thinking were selected.Results: Using a logistic regression model controlling forage, sex and education, six markers showed significantassociations to paranoid thinking. Interestingly, these

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49PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

associations could indeed be shown in a comparison ofextreme groups, but only very restricted in the followingvariance analysis of continual associations.Discussion: Despite discrepant findings, this study sug-gests a genetic contribution to the complex development ofparanoid thoughts.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.160

SA89. SHARED IMMUNE/INFLAMMATION RELATED CO-EXPRESSION NETWORK FROM FRONTAL CORTEX INTHE NORMAL AGED BRAIN AND IN SCHIZOPHRENIA

Sanghyeon Kimn

, Maree Webster

Stanley Medical Research Institute

Background: Schizophrenia is a common and devastatingbrain disease. However, the exact causes of the diseaseremain unknown. Previous studies identify shared geneexpression profiles between schizophrenia and the normalaged brain and suggest that brain aging may be acceleratedin those with schizophrenia.Methods: We constructed co-expression networks usingRNA-Seq data from frontal cortex of 114 normal individualsranging in age from 29 to 106 years as well as RNA-Seq datafrom frontal cortex of 64 subjects with schizophrenia and 66unaffected controls ranging in age from 19 to 70. Wecompared co-expression modules significantly associatedwith schizophrenia to those whose expression levels weresignificantly correlated with aging in normal individuals.Results: We identified a significant overlap between nodesin the immune/inflammation module that were associatedwith schizophrenia and those in the immune/inflammationmodule correlated with aging in normal subjects (Po1e-06).Discussion: The results show that an activated immune/inflammation related co-expression network is associatedwith the normal aging brain as well as with schizophreniaand supports the hypothesis that there may be acceleratedbrain aging in schizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.161

SA90. LONGITUDINAL EPIGENETIC CHANGES DURINGTHE ONSET OF PSYCHOSIS

Boris Chaumetten,1, Oussama Kebir2, Marie-Odile Krebs3

1McGill University2INSERM3INSERM Paris Descartes University

Background: In the last 20 years, researchers and psy-chiatrists in the field of psychosis have moved from aconception of a chronic presentation to a more dynamicparadigm. Accordingly, psychotic disorders may progressfrom an at-risk presentation with subtle and non-specificsymptoms to a chronic psychosis. The biological processesthat underlie this progression remain largely unknown.Genetic and environmental factors are both necessary butinsufficient to explain the emergence of psychosis in the at-risk individuals. Current pathophysiological hypothesesfavor the gene x environment interactions that could bemediated by epigenetics. We have recently reported inMolecular Psychiatry the DNA methylation changes occur-ring during the onset of psychosis in genes involved in redoxmetabolism and axon guidance. We have completed thisstudy by a functional analysis and have conducted the firstlongitudinal transcriptomic analysis in blood samples beforeand after the emergence of psychosis.Methods: The transcriptomic analysis was conducted onperipheral blood samples from 31 at-risk individuals forpsychosis who later convert to psychosis (converters) and 63controls (non-converters) recruited in Ste Anne Hospital(Paris, France). Individuals were followed for one year andblood samples were collected at baseline and at the end ofthe follow-up. The design corresponds to an interactionbetween Group and Time, with individuals as their owncontrols. Differentially expressed gene between the twogroups were identified by RNA sequencing on an initialdiscovery sub-group (n=15 individuals; 30 samples) usingtwo different algorithms (edgeR and DESeq). Only concor-dant results from both algorithms were retained for furtheranalyses, after correction for cell heterogeneity. The mostpromising results were replicated by high-throughput real-time qPCR in the whole cohort (n=94 individuals; 188samples). We also explored the expression of 5 candidategenes from the previous methylomic study.Results: From the RNAseq analyses, we identified 4 brain-expressed genes with significant longitudinal changes in con-verters compared to non-converters. One of these genes(CPT1A) was replicated in the larger cohort. CPT1A is involvedin the fatty-acid metabolism, and represents a plausible targetfor the prevention of the onset of psychosis. Two candidategenes (NRP1 - axon guidance - and GSTM5 - redox metabolism)from the methylomic study were also confirmed. As expected,the observed hypermethylation during the onset of psychosiswas correlated with a decrease of gene expression. Post-hocanalyses demonstrate that these results are unlikely to be dueto psychotropic treatment modifications.Discussion: This study sheds light on the epigenetic mechan-isms that could explain the emergence of psychosis in adoles-cence. The results open new perspectives towards new phase-specific and disease-modifying therapeutic strategies for theprevention of psychosis. While peripheral investigations inpsychiatric disease contain several limits, even in an intra-subject design, they could help to identify peripheral stagingbiomarkers for clinical practice. We will also discuss theimportance of an integrative approach in the omics field.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.162

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SA91. INCREASED PREDICTED C4A EXPRESSION IS ASSO-CIATED WITH COGNITIVE DEFICIT IN BOTH SCHIZOPHRE-NIA AND ALZHEIMER'S DISEASE

Nina McCarthyn,1, Simon M. Laws2, Tenielle Porter2,

Samantha C. Burnham3, Eric K. Moses1, Assen Jablensky1

1University of Western Australia2Edith Cowan University3CSIRO Health and Biosecurity

Background: Recently, Sekar et al. (Nature, 2016)reported that the top GWAS hit for schizophrenia in theMajor Histocompatibility Complex (MHC) locus implicatedstructural variants in the C4 gene which are associated withC4A expression and may affect synaptic pruning. Synapse lossis associated with cognitive decline in a number of disorders,including Alzheimer's disease and schizophrenia. We hypothe-sised that C4A expression predicted from C4 structural allelesis associated with cognition. We tested this in the WesternAustralian Family Study of Schizophrenia (WAFSS) (n=770,including 402 schizophrenia cases and 368 controls), and theAustralian Imaging, Biomarkers and Lifestyle Study (AIBL)(n=1,112, including 211 Alzheimer's disease cases, 133 withmild cognitive impairment and 768 controls).Methods: Sekar et al. showed that C4 structural allelescould be imputed from GWAS data with an accuracy of�70%. We used 222 reference haplotypes with C4 structuralalleles measured by Sekar et al. to impute C4 alleles in allindividuals using Beagle. C4A expression was predicted foreach individual using the regression coefficients calculatedby Sekar et al. Composite measures of cognition wereavailable for both WAFSS and AIBL (Hallmeyer et al., Am JHum Genet. 2005; Burnham et al., J Alzheimers Dis. 2015).Linear regression was used to assess their relationship withpredicted C4A expression. P values for these relationshipswere calculated using linear mixed models to account forthe relatedness between some WAFSS participants, andrepeated measurements in the AIBL dataset. All analyseswere adjusted for case status, age, sex, and education.Results: Although mean C4A expression was not signifi-cantly different between schizophrenia cases and controlsin the WAFSS (P=0.7), cases were overrepresented in thosewith the highest C4A expression levels. There was a smallbut consistent association between increased cognitivedeficit and increased levels of C4A in both the WAFSS andthe AIBL samples (Po0.05) which was particularly pro-nounced in cases.Discussion: These data suggest that C4 structural variantspreviously shown to be associated with schizophrenia mayspecifically implicate the cognitive deficit which is a corefeature of schizophrenia. Further, our finding that a similarrelationship between C4A levels and cognition exists inpatients with schizophrenia and Alzheimer's disease sug-gests that the locus may be pleiotropic and have implica-tions for a range of neuropsychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.163

SA92. BIOINFORMATICS ANALYSIS OF RARE AMINO ACIDSUBSTITUTIONS IN THE DISC1 INTERACTOME IMPLI-CATED IN SCHIZOPHRENIA

Shaolei Tengn

Howard University

Background: Disrupted In Schizophrenia 1 (DISC1) gene is awell-researched target for developing psychiatric disordersincluding schizophrenia, bipolar disorder and major depression.DISC1 protein directly interacts with a large set of proteins, so-called DISC1 Interactome, that are involved in brain develop-ment and neuronal signaling. Recent exome sequencing pro-jects showed that coding variants with low allele frequencyhave large effects on the risk for developing schizophrenia,which indicates that rare mutations account for much of themissing heritability in the development of schizophrenia.Methods: In the presented study, we applied bioinformaticsapproaches to analyse the effects of rare amino acid substitu-tions in the DISC1 Interactome on protein structure and functionfrom public databases. We applied sequence-based machinelearning methods to predict the effects of the rare disease-causing mutations on protein function, protein stability and posttranslational modification. In addition, we carried out structure-based modelling methods to analyse the effects of raremutations on protein stability and protein-protein interaction.Results: We collected 6,254 non-synonymous codingmutations reported in the 1000 Genomes Project locatedin 104 DISC1 Interactome genes from dbNSFP. Of the 6,254variants, 5,929 coding mutations (95%) are rare amino acidsubstitutions with a minor allele frequency less than 1%. Weobserved that the distributions of damaging mutations arefound to be higher in rare mutations than those in commonmutations in the DISC1 Interactome. Some amino acidsubstitutions may be involved in post translational modifica-tions such as phosphorylation and sumoylation. We showedthat the rare missense mutations could significantly affectthe protein structures, which result in the changes onprotein stability and protein-protein interaction.Discussion: The bioinformatics analysis improves ourunderstanding of the roles of rare amino acid substitutionsin the DISC1 interactome genes in susceptibility to schizo-phrenia. The findings can provide useful information toestimate the functional effects of rare DISC1 Interactomemutations on protein function and structure, which offerthe targets for developing more precise treatments andmedications for schizophrenia patients.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.164

SA93. IMAGING GENETICS TOWARDS A NEW DIAGNOSISOF SCHIZOPHRENIA

Wenhao Jiangn

, Jessica Turner

Georgia State University

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51PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

Background: Current diagnoses of Schizophrenia (SZ) andrelated psychiatric disorders are catalogued by phenomen-ological principles and clinical descriptions. Complicatedgene and environmental factor interactions likely play animportant role in the onset of SZ and induce great hetero-geneity. This unclear etiology and heterogeneity preventthe establishing of accurate subgroups within SZ throughclinical observation alone; simultaneously, the boundariesamong psychiatric disorders previously drawn by phenom-enological findings are merging because there is greatoverlap, especially in genetic variations and brain imagingfindings. By characterizing and quantifying brain regionsaffected in psychiatric disorders, imaging genetics is avaluable research method to fulfill a new diagnostic system.We review contributions of imaging genetics to SZ diagnosis,limitations, and possible future directions.Methods: Among numerous imaging genetic studies, wereviewed recent studies with relatively clear and consistentfindings. They were either done in task-phase imaging toindicate certain cognitive impairments of SZ, or the genesincluded were highlighted in SZ itself or an importantcognitive domain related to SZ.Results: Some pioneering studies contribute to subtypesand disorder boundaries. The clustering study from Arnedoet al. formed correlations between disjoined networks ofsymptom groups and Single Nucleotide Polymorphism (SNP)sets, and it may be promising for future SZ subtypes.Bipolar-SZ Network on Intermediate Phenotypes studiescombining various clinical biomarkers and brain imagingdivided SZ, bipolar disorder and schizoaffective disorderinto three different “biotypes” regardless original diag-noses, and it provided meaningful insight into the disorderboundaries. For imaging genetics research, large numbers ofassociations between functional imaging intermediate phe-notypes and genes have been found in working memory,episodic memory, emotion, attention, cognitive control,and theory of mind in SZ or healthy risk allele carriers.Such associations were difficult to identify while usingstructural brains measures.Discussion: Imaging genetics will continue to shape thediagnosis of SZ and related disorders. However, there arestill problems to solve. Most importantly, the logicbehind imaging genetics has been questioned. Frankeet al. reminds us the structural brain deficits believed tobe important pathological alterations of SZ may reflectprenatal and later development environmental effectsnot specific to SZ, or the diagnostic category of SZ maynot be uniformly organized. The following aspects needfuture effort. Firstly, more brain measures need to beintroduced, and the criteria of intermediate phenotypesshould be carefully checked. The specificity of brainalterations will need careful examination in clinicalsettings. Secondly, more genetic factors need to becollected. Polygenic risk scores, parallel independentcomponent analysis and other clustering method may bepromising. Factors other than SNPs, such as copy numbervariations and regulatory factors will need to beincluded. Finally, imaging genetics will need compatiblephenomenological assessment scales which need notdistinguish current diagnoses but provide a comprehen-sive scan of clinical features.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.165

SA94. A DIRECT REGULATORY LINK BETWEEN MICRO-RNA MIR-137 AND SHANK2 WITH IMPLICATIONS FORNEUROPSYCHIATRIC DISORDERS

Simone Berkeln

, Ana de Sena Cortabitarte,Flavia-Bianca Cristian, Christine Fischer, Gudrun Rappold

Institute of Human Genetics Heidelberg

Background: The SHANK gene family encodes for post-synaptic scaffolding proteins with an important role atglutamatergic synapses in the brain and has been linked toa spectrum of neurodevelopmental disorders. The schizo-phrenia associated microRNA miR-137 and the SHANK genesconverge on several levels, (a) both are expressed at thesynapse, (b) both influence neuronal development, and(c) both have a strong link to neurodevelopmental andneuropsychiatric disorders like intellectual disability, autismand schizophrenia. This compiled evidence raised the ques-tion if the SHANKs might be targets of miR-137.Methods: The in silico analysis of all three SHANK genesidentified a single, highly conserved binding site for miR-137 inthe 3´UTR of SHANK2. Luciferase assays were carried out in aneuroblastoma cell line (SH-SY5Y) and in mouse primaryhippocampal neurons to validate the putative binding site.MiR-137 was overexpressed or inhibited in hippocampal neuronsand Shank2 expression was analyzed by qPCR and Western blot.In addition, we analyzed expression levels of experimentallyvalidated miR-137 target genes in the dorsolateral prefrontalcortex (DLPFC) of schizophrenia and control individuals usingthe RNA-seq data from the CommonMind Consortium.Results: We can show that miR-137 targets the 3´UTR ofSHANK2 in a site-specific manner. Overexpression of miR-137 significantly lowered endogenous Shank2 protein levelswithout detectable influence on mRNA level; conversely,the inhibition of miR-137 resulted in the increase of Shank2protein in neuronal cells. To further support the linkbetween miR-137 and schizophrenia, we compared theexpression of mir-137 precursor and miR-137 target genes(including SHANK2) in the DLPFC of schizophrenia andcontrol individuals. Almost one third (18/63; 29%) ofvalidated miR-137 target genes showed significant expres-sion differences in the DLPFC of schizophrenia individualscompared to controls and we propose that further targets(like SHANK2) may be regulated on protein level.Discussion: In this study we identified SHANK2 as a noveldirect target of miR-137. We discovered that physiologicallevels of miR-137 regulate SHANK2 expression and that themost likely mechanism of microRNA-mediated regulation isby repressing SHANK2 protein translation rather than mRNAdegradation. Our study provides first evidence of a directregulatory link between miR-137 and SHANK2 and supportsthe finding that miR-137 signaling is altered in schizophrenia.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.166

SA95. INDEPENDENT GENETIC EVIDENCE LINKS STRIA-TAL-ENRICHED PROTEIN TYROSINE PHOSPHATASE(STEP) TO HUMAN ATTENTION AND SCHIZOPHRENIA-RELATED TRAITS

Dimitrios Avramopoulosn,1, Alexandros Chatzimanolis2,

John McGrath1, Paula Wolyniec1, Nikolaos Smyrnis2,Ann Pulver1, Nikolaos Stefanis2

1Johns Hopkins University2National University of Athens, Medical School

Background: Genetic association and protein expressionfindings in humans and observations in animal models, haveimplicated the STriatal-Enriched protein tyrosine Phospha-tase (STEP) in cognitive functioning and schizophrenia.Methods: Here, we aimed to confirm the associationbetween common genetic polymorphisms within PTPN5encoding STEP, and sustained attention performanceassessed with the Continuous Performance Test-IdenticalPairs (CPT-IP) among healthy young males (n=1814) andindividuals diagnosed with Schizophrenia (SZ; n=341) orBipolar Disorder (BP; n=239). Moreover, self-rated schizo-typal traits and subclinical Psychotic Experiences (PEs) wereexamined in healthy males, as well as symptom dimensionsin an extended SZ data set (n=647).Results: We observed that rs10766504, previously asso-ciated with increased CPT-IP omission errors among healthyfemales, predicted greater CPT-IP target detectability inboth healthy males and SZ/BP patients (po0.05), whenomission and commission errors were jointly considered (d'sensitivity index). We also identified an independent geneticlocus (rs873670) downstream of the PTPN5 showing astronger association with CPT-IP d' index, regardless ofdiagnostic status (po0.001). In addition, healthy malescarrying the rs873670 allele, which was found advantageousfor attentional capacity, reported significantly higher para-noid schizotypy and PEs. Gene expression analysis did notprovide evidence for rs873670 genotype correlation withPTPN5 mRNA levels in prefrontal cortex and temporal lobehuman brain postmortem samples (n=250).Discussion: These findings underscore PTPN5 as a highlypromising candidate gene for sustained attention thatmerits further genetic and functional investigation. Thisstudy also suggests that PTPN5 exerts pleiotropic effects onattention performance and behavioral expressions, whichhave been linked to altered striatum activity.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.167

SA96. ASSOCIATION STUDY POLYMORPHISMS OF THENEUREGULIN 1 (NRG1) GENE WITH SCHIZOPHRENIA

John Nin,1, Junzhe Xu2

1University of California, Berkeley2SUNY at Buffalo

Background: The dysfunction of Neuregulin 1 (NRG1) isone of the plausible hypotheses for the pathogenesis ofschizophrenia. The Neuregulin 1 (NRG1) is located on chro-mosome 8p, as suggested by multiple linkage studies. Theaim of this study is to clarify the contribution of polymorph-isms of the Neuregulin 1 (NRG1) with schizophrenia.Methods: After informed consent was obtained, 100 schi-zophrenia patients and 100 control subjects were enrolledin this study. All subjects were administered the DiagnosticInterview for Genetic Studies (DIGS) (National Institute ofMental Health-Molecular Genetics Initiative, 1992; Nurnber-ger et al., 1994) by a research assistant with extensivetraining in this interview. Blood samples were collected inanonymously identified 10-ml Vacutainer tubes (BectonDickinson). DNA was prepared by a modified SDS/ProteinaseK procedure (Gusells et al., 1979). We genotyped poly-morphism Neuregulin 1 (NRG1) with the PCR-RFLP methods.The PCR products were digested by restricted enzyme.Results: We observed a significant association betweenthe polymorphism neuregulin 1 (NRG1) and the schizophre-nia (Chi-Square Test P= 0.0449).Discussion: The NRG1 gene was originally identified as asusceptibility gene for schizophrenia by using a combination ofa linkage and association approaches based on microsatellitemarkers and then using SNPs after microsatellite at riskhaplotypes were identified. We found there is the frequencyof the polymorphism of Neuregulin 1 (NRG1) was significantlyincreased in schizophrenia patients. This allelic associationsuggests that the functional polymorphism Neuregulin 1(NRG1) may play a role in susceptibility to schizophrenia.Further study with larger sample sizes is required.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.168

SA97. CHANGES OF OPEN CHROMATIN REGIONS REVEALSTAGE-SPECIFIC TRANSCRIPTIONAL NETWORKDYNAMICS IN HUMAN IPSC-DERIVED NEURONS

Siwei Zhangn,1, Winton Moy1, Hanwen Zhang1,

Heather McGowan2, Jianxin Shi3, Catherine Leites1,Alan R. Sanders1, Zhiping Pang4, Pablo V. Gejman5,Jubao Duan5

1NorthShore University HealthSystem2Rutgers University

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53PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

3National Cancer Institute4University of Chicago5Center for Psychiatric Genetics, NorthShore UniversityHealthSystem

Background: The application of human induced Pluripo-tent Stem Cells (iPSCs)-differentiated neurons has served as apromising model for gaining insights into the molecular andcellular mechanisms of genetic risk for mental disorders.Multiple factors determine the fate and trajectory of neuro-nal cell differentiation, of which transcriptional regulationplays a major role. Chromatin accessibility (openness) toTranscription Factors (TF) strongly influences gene transcrip-tion and cell differentiation. However, the dynamic changesof open chromatin and the TF networks during neuronaldifferentiation from iPSCs are poorly understood.Methods: Here, we performed a global mapping of OpenChromatin Regions (OCRs) using the Assay for Transposase-Accessible Chromatin with high throughput sequencing(ATAC-Seq) at different cell stages of glutamatergic neuronaldifferentiation, examined the correlation of changes of openchromatin and mRNA abundances (assayed by RNA-Seq), andconstructed the neuronal stage-specific TF networks througha genome-wide inference of TF-binding footprints in OCRs.Results: We found that OCRs were highly dynamic duringneuronal differentiation, and more importantly that OCRaccessibility at core promoter regions was positively corre-lated with mRNA abundances at their respective cell stages.Furthermore, we found that the dynamic changes of OCRsduring neuronal differentiation were accompanied by thebinding events of cell stage-specific TFs. As expected,binding footprints of OCT4 and NANOG, genes that encodepluripotent stem cell-specific markers, are most enriched iniPSCs. Intriguingly, binding footprints of NEUROD1 and NEU-ROG2, the two TFs that have been reported to rapidly inducehigh efficient conversion of iPSCs to excitatory neurons, areamong those most enriched in the relatively mature neurons.Discussion: Further TF network analysis based on theinferred TF binding footprints in OCRs successfully identifiedcore TF networks and their master regulators for differentneuronal stages. Interestingly, both NEUROD1 and NEUROG2are in the same core TF network specific to more matureneurons, suggesting their pivotal role in epigenetic controlof neuronal differentiation and maturation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.169

SA98. RNAseq TRANSCRIPTOME STUDY OF SCHIZO-PHRENIA IN THE MGS AFRICAN AMERICAN SAMPLE

Alan Sandersn,1, Jubao Duan1, Eugene Drigalenko2,

Harald Goring3, Pablo Gejman1

1NorthShore University HealthSystem, University of Chicago2Texas Biomedical Research Institute3South Texas Diabetes and Obesity Institute

Background: GWAS on predominantly European Ancestry(EA) samples have implicated over 100 loci as beingassociated at genome-wide significant levels with risk forSchizophrenia (SZ). Some of these risk loci are shared acrossancestral groups, including within variably admixed AfricanAmerican (AA) samples. Regulation of mRNA expression maybe involved in the etiology for some of these loci, thussuggesting utility of a transcriptomic profiling approach. Inboth of two previous large transcriptomic profiling studieson lymphoblastoid cell lines (LCLs) from non-overlapping EASZ case-control samples, using arrays (N=714; Sanderset al., 2013) and RNAseq (N=1,189; Sanders et al., 2017),we found genes differentially expressed by affection statusto be enriched for immune-related genes, consistent withhypothesized immune contributions to SZ risk.Methods: The single largest reported SZ GWAS on an AAsample is on the Molecular Genetics of SZ (MGS) dataset (Shiet al., 2009), from which we derived the current transcrip-tomic (RNAseq) sample. After various sample quality controlsteps including identity verification ensuring concordancebetween known sex (i.e., dosages of X and Y chromosomes)and RNAseq expression levels of sex-dimorphic expressedgenes on chromosomes X and Y, and RNAseq-derived geno-type concordance versus previous GWAS genotypes, wemoved samples with at least 8 M read depth from 378 SZcases and 386 controls to analyses.Results: To adjust for known or potentially confoundingeffects, we collected data on measured (EBV load, growthrate, and energy status), RNAseq batch, ancestry (top twogenotypic principal components from GWAS), and otherdemographic (sex, age) covariates to include in the regres-sion analysis to identify genes differentially expressed byaffection status.Discussion: We will present and discuss results in severalmain areas: (1) degree of replication of AA transcriptomicresults for previous EA findings, (2) pathway and networkanalyses of differentially expressed genes, (3) gene setenrichment analyses, especially for immune related genes,(4) differences compared to findings for previous EA tran-scriptomic work, and (5) combined analyses of the currentAA and previous EA transcriptomic datasets. This work wassupported NIH grant R01MH098059 using samples from theMGS collaboration.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.170

SA99. TARGETED SEQUENCING OF 187 PUTATIVE SCHI-ZOPHRENIA RISK GENES IN 5,207 CASES AND 4,991CONTROLS

Elliott Reesn,1, Noa Carrera2, Joanne Morgan2,

Andrew Pocklington2, Valentina Escott-Price2,George Kirov2, Peter Holmans2, James T.R. Walters2,Michael Owen2, Michael O'Donovan2

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1Medical Research Council Centre for NeuropsychiatricGenetics and Genomics, Institute of Psychological Medicineand Clinical Neurosciences, Cardiff University2Medical Research Council Centre for NeuropsychiatricGenetics and Genomics, Cardiff University

Background: Recent sequencing studies have shown asmall fraction of SZ risk comes from rare mutations. Theyhave also advanced our understanding of SZ pathophysiol-ogy, with multiple studies implicating post-synaptic pro-teins, including the activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor(NMDAR) complexes. Thus far, only one gene, SETD1A, hasbeen associated with SZ at genome-wide levels of signifi-cance. We aimed to identify novel SZ genes by sequencing187 genes in 5,207 cases and 4,991 controls. Included amongthese genes are members of ARC and NMDAR complexes, aswell as Voltage-Gated Sodium (VGSC) and Calcium Channels(VGCC), all of which have been previously implicated in SZ.Methods: A total of 5,724 cases, 5,769 controls wereselected for Ion Torrent sequencing of 187 candidate SZgenes. None of these samples have been included inprevious SZ sequencing studies. After stringent qualitycontrol (low sequence quality, relatedness and ancestry),our sample consisted 5,207 cases and 4,991 controls. Gene-set and single-gene association statistics were generatedusing a Firth's penalised-likelihood logistic regression model.Results: Cases had a significant excess of Loss-of-Function(LoF) mutations (o 0.1%) in all 187 genes after correctionfor multiple testing (P=0.0023, OR=1.33). No other class ofmutation was enriched in cases after correction for multipletesting. For gene-sets previously implicated in SZ, cases hadhigher rates of LoF mutations in ARC (P=0.047, OR=2.7),NMDAR (P=0.024, OR=1.7), and VGSCs (P=0.015,OR=1.98). No support was found for association with VGCCs(P=0.22, OR=0.72). We observed strong enrichment of LoFalleles in genes previously associated with DevelopmentalDisorders (DD) (P=0.0025, OR=8.21). No single gene wassignificantly associated with SZ after correction for multipletesting.Discussion: In a new, independent sequencing study ofSZ, we found an excess of LoF alleles in cases in all 187targeted genes, and provide independent support for theinvolvement of ARC and NMDAR post-synaptic protein com-plexes, and voltage-gated sodium channels, in SZ pathogen-esis. We also provide further evidence for a shared geneticrisk between SZ and DD. However, our study was under-powered to identify specific risk genes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.171

SA100. GABRB2 IS FUNCTIONALLY CONSERVED INMOUSE AND MAN FOR ESSENTIAL NEURO-PSYCHOMO-TOR ACTIVITIES

Hong Xuen,1, Rigil Kent Yeung1, Shui Ying Tsang1,

Zhenghua Xiang2, Pak-Chung Sham3, Gerald Stoeber4

1Hong Kong University of Science and Technology2Second Military Medical University3University of Hong Kong4University of Wuerzburg

Background: The type A γ-aminobutyric acid (GABAA)receptor β2 subunit gene (GABRB2) has been associated withvarious neuropsychiatric disorders including Schizophrenia(SCZ). However, limited examination of the phenotypicalchanges in GABRB2-knockout mice have been conducted.Methods: Herein, GABRB2 homozygous (KO) and Hetero-zygous (Het) knockouts were compared with Wild-Type (WT)mice for neuropsychiatric and neurochemical alterations.Results: KO exhibited increased acoustic startle, prepulseinhibition deficits, locomotor hyperactivity, behavioralstereotypy, spatial-working memory deficit and sociabilityimpairments, establishing GABRB2-KO as SCZ-like. More-over, reduced anxiety and depression was observed in KO,and 8-week male KO displayed compromised fertility. Hetmice partially exhibited these symptoms, and the atypicalantipsychotic, risperidone, partially restored these pheno-types, especially hyper-motor activity, but not sociability.Parent-of-origin effects on spontaneous motor activitieswere also detected. Audiogenic epilepsy was observed inKO and latency to pentylenetetrazol-induced seizure wassignificantly shortened, with shorter latency in female thanmale in both tests. The oxidation and inflammation mar-kers, malondialdehyde, TNFα and IL6, were elevated in KObrains, and immunostaining indicated less GFAP-expressingastrocytes and DCX-expressing new-born neurons in KOhippocampus, suggesting possible involvement of oxidativestress-induced neurogenesis inhibition.Discussion: Our results highlight GABRB2 being evolutio-narily adapted to maintain fundamental neuro-psychomotoractivities, and its dysfunction is attributable to a range ofpsychiatric and neurological symptoms, often comorbid inhuman.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.172

SA101. ARE COMT, MIR137, MTHFR AND DNMT3B POLY-MORPHIC ALLELES ASSOCIATED WITH SCHIZOPHRENIASYMPTOMS SEVERITY IN MEN AND WOMEN?

Hanna Kandratsenkan,1, Anastasiya Nestsiarovich2,

Inna Goloenko1, Nina Danilenko1, Anna Makarevich1,Victor Obyedkov2, Oleg Davydenko1

1Institute of Genetics and Cytology of the National Acad-emy of Sciences of Belarus2Republican Research and Practice Center for Mental Health

Background: The mechanisms that determine the devel-opment of schizophrenia, progress notes or clinical mani-festation can be different in males and females. The aim ofthe study was to analyze the association of some key genes

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with symptoms severity in men and women suffering fromschizophrenia.Methods: 150 Belarusian schizophrenia patients weregenotyped using RFLP and TaqMan assays. PANSS was usedto evaluate the symptom severity. Patient inclusion criteriawere: ICD-10 schizophrenia diagnosis, age 24–65(46,879,44) years.Results: There was an association of COMT rs4680 withtotal score of negative items in combined sample with theeffect much stronger for males than for females. Patientswith G-allele had a higher degree of negative symptoms. ForMIR137 rs1625579 a significant impact on the negativesymptomsis observed only for females. COMT rs4680 andMIR137 rs1625579 were associated with total score ofgeneral psychopathology symptoms in combined sample,but the effect of COMTwas stronger for males, and MIR137 -for females. Moreover, DNMT3b rs2424913 has a significantinfluence on such symptoms only for females. Carriers ofMIR137 TT-genotype, COMT G-allele and DNMT3b T-alleledemonstrated higher level of the symptoms. MTHFRrs1801133and MIR137 rs1625579 were associated with totalscore of positive symptoms in combined sample, but thisassociation in females and males separately doesn’t reachstatistically proved level.The highest degree of the symp-toms had patients with MTHFR T- and MIR137 TT-alleles.Discussion: These results indicate that genes investigatedhave gender-specific impacts on symptoms and confirm thedifferent mechanisms of schizophrenia pathogenesis betweenmales and females.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.173

SA102. A COGNITIVE AND MOLECULAR ANALYSIS OFSDCCAG8, A SCHIZOPHRENIA RISK GENE THAT FUNC-TIONS IN THE CENTROSOME

Mairead Flynnn,1, Laura Whitton2, Aiden Corvin3,

Denise Harold3, Micheal Gill3, Gary Donohoe2,Ciaran Morrison4, Derek Morris2

1Neuroimaging and Cognitive Genomics (NICOG), School ofBiochemistry, National University of Ireland Galway2Cognitive Genetics and Cognitive Therapy Group, Neuroi-maging and Cognitive Genomics (NICOG) Centre, School ofPsychology, National University of Ireland Galway3Neuropsychiatric Genetics Research Group, Institute ofMolecular Medicine, Trinity College Dublin4Centre for Chromosome Biology, National University ofIreland Galway

Background: Schizophrenia affects 1% of adults and is amajor global health problem. Although aetiology is com-plex, genetics represents a vital tool for probing theneurobiology of the disorder in the absence of biomarkers.We undertook an interdisciplinary project investigating therole of centrosome genes in schizophrenia. The centrosome,an organelle within cells, plays a crucial role in brain

development where it directs cell shape, polarity andmotility. The centrosome also seeds the growth ofantenna-like signalling structures called primary cilia. Raremutations in centrosome genes cause disorders that presentwith severe cognitive deficits and variable neuropsychiatricphenotypes.Methods: We mined online databases to generate a list ofgenes encoding proteins with centrosome function. Thesewere cross-referenced with schizophrenia risk genes identi-fied in the 2014 PGC GWAS. Neurocognitive analysis: priori-tised candidate genes were taken forward to analysis in asample of Irish psychosis patients and controls (n=1,200).Participants were grouped by genotype at genome-widesignificant SNPs and linear regression was used to test ifgenotype at schizophrenia risk SNPs was significantly asso-ciated with different domains of cognitive function. Mole-cular analysis: CRISPR-Cas9 genome editing technology wasused to generate SDCCAG8 knockout cell lines in hTERT-RPE1 epithelial cells and in SH-SY5Y cells, a neuronal cellline. After serum starvation, cilia and centrosome markerswere used to perform ciliation counts by immunofluores-cence. Centrosome amplification was induced by exposingcells to 5 Gy ionising radiation and the number of centro-somes was counted after 72 hours by immunofluorescence.Results: We identified 7 schizophrenia risk genes thathave centrosomal functions: SDCCAG8, NEK4, MPHOSPH9,MAD1L1, PRKD1, MAPK3 and GIGYF2. Neurocognitive analy-sis of schizophrenia risk SNPs within these seven genesidentified nominally significant associations with at leastone domain of cognition for 5 of these 7 genes. Most of thesignificant associations were identified for social cognition,with the effect of SDCCAG8 on this domain being the mostsignificant finding (p=0.001). SDCCAG8 is also associatedwith educational attainment and the genome-wide signifi-cant SNPs for the two phenotypes are in high linkagedisequilibrium indicating a pleiotropic effect. We success-fully generated SDCCAG8 knockout in RPE1 cells and in SH-SY5Y cells. Preliminary data shows that SDCCAG8 knockoutclones, while viable in a p53 wildtype background, haveslower proliferation rates. The capacity of the clones tociliate is also reduced, by 50% in RPE1 clones and 75% in SH-SY5Y clones. In response to DNA damage there was anincrease in centrosome amplification in RPE1 knockoutclones when compared to wildtype cells.Discussion: SDCCAG8 is a schizophrenia risk gene that wefind is also associated with social cognition and educationalattainment. Our data suggest that loss of SDCCAG8 impairscells’ ability to make primary cilia and that their capacity torepair genome damage may be reduced. Further work willaddress whether SDCCAG8 affects activities that may con-tribute to schizophrenia, including cell migration and cellsignalling. This could identify molecular mechanisms bywhich SDCCAG8 mutations contribute to schizophrenia riskand cognition, and help uncover the biological processesthat implicate centrosome genes in various neurodevelop-mental phenotypes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.174

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SA103. GENETIC RISK BETWEEN THE CACNA1I GENEAND SCHIZOPHRENIA IN CHINESE VIGHUR POPULATION

Lin Hen,1, Wei Xu2

1Bio-X Institutes, Shanghai Jiao Tong Universtiy2School of Life Science, Anhui Medical University

Background: Schizophrenia (SCZ) is a common mentaldisorder with high heritability, and genetic factors play amajor role in the pathogenesis. Recent researches indicatedthat the CACNA1I involved in calcium channels probablyaffect the potential pathogenesis of SCZ.Methods: In this study, we attempt to investigate whetherthe CACNA1I gene contributes the risk to SCZ in the UighurChinese population, and performed a case-control studyinvolving 985 patient samples and 1218 normal controls toanalyze nine SNPs within the CACNA1I gene.Results: Among the sites, six SNPs were significantlyassociated with SCZ in the allele distribution: rs132575(adjusted Pallele=0.039, OR=1.159), rs713860 (adjustedPallele=0.039, OR=0.792), rs738168 (adjusted Pal-lele=0.039, OR=0.785), rs136805 (adjusted Pallele=0.014,OR=1.212), rs5757760 (adjusted Pallele=0.042, OR=0.873)and rs5750871 (adjusted Pallele=0.039, OR=0.859). Inaddition, two SNPs turned to be risk factors for SCZ notonly in the allele distribution, but also in the genotypedistribution: rs132575 (adjusted Pgenotype=0.037) andrs136805 (adjusted Pgenotype=0.037).Discussion: Overall, the present study provided evidencethat significant association exists between the CACNA1Igene and SCZ in the Uighur Chinese population, subsequentvalidation of functional analysis and genetic associationstudies are needed to further extend this study.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.175

SA104. LINE-1 HYPOMETHYLATION MIGHT BE RELATEDTO A POOR RESPONSE TO TREATMENT

Diogo Marquesn,1, Vanessa Ota1, Marcos Santoro1,

Fernanda Talarico1, Leticia Spindola1, Gabriela Xavier1,Ary Gadelha1, Eduardo Gouvea1, Cristiano Noto1,Quirino Cordeiro1, Rodrigo Bressan1, Patricia Moretti2,Sintia Belangero1

1Federal University of Sao Paulo2University of Brasilia

Background: The study of antipsychotic-naïve First-Epi-sode of Psychosis (FEP) patients allows comparisons withhealthy controls to determine changes in the DNA methyla-tion related to the psychosis without interfering with

confounding factors such as disease time and treatmenteffect. A second assessment, after starting treatment, canprovide information about the antipsychotic action andtreatment response predictors. We aim to investigate themethylation profile over long interspersed nuclear element1 (LINE-1) regions, which are retrotransposon that repre-sents 17% of human genome, in FEP patients before andafter risperidone treatment and Healthy Controls (HC). Wehypothesized that there is hypomethylation in those regionsin antipsychotic-naïve FEP patients when compared to HCand that risperidone could recover the methylation patternof LINE-1 methylation patients that responded to thetreatment.Methods: Antipsychotic-naïve FEP patients (N=22) wereassessed in two time points: at baseline and after twomonths of risperidone treatment. The patients were eval-uated using PANSS (Positive and Negative Syndrome Scale)and treatment response was defined as a reduction of 50% inPANSS total scores and then, we categorized patients inresponders (N=16) and non-responders (N=6). The healthycontrol group (N=24) were age-and-gender-matched volun-teers. Blood samples were collected, DNA isolated and afterthat, the bisulfite conversion performed. LINE-1 fragmentscontaining three CpGs are amplified by PCR and submittedto pyrosequencing and the methylation levels were com-pared among groups.Results: We did not find significant differences regardingmethylation of LINE-1 between HC and antipsychotic-naïveFEP or FEP after treatment. Using paired analyses, we alsodid not identify any association before and after treatment.Nevertheless, considering response to risperidone, weobserved a difference of LINE-1 methylation comparingresponders, non-responders and controls (p=0.030). TheBonferroni post-hoc indicated this difference is due toresponders vs non-responders, evidencing hypomethylationin non-responders, suggesting there may be higher genomicinstability or even there is a methylation increase alonggenome in individuals which do not respond to treatment.We already enlarged the sample size to have 80 patients (40responders and 40 non-responders) and 80 controls, but weare still doing the pyrosequencing and the results analysis.Discussion: Despite the small sample size, our prelimin-ary findings are original considering this the first study tocorrelate global methylation to exclusive-risperidone treat-ment response in an antipsychotic-naïve FEP cohort. Inter-estingly, Reynolds and Fachim (2016) proposed methylationwould affect the response to treatment independently ofother factors. Although we could not state what would bethe cause or consequence, in a future, it would still bepossible to consider LINE-1 methylation might be a predictorof treatment response. As a perspective, we are enlargingconsiderably the sample size and, perhaps, our findingscould point LINE-1 methylation as useful tool treatmentmanagement.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.176

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SA105. IDENTIFICATION OF PHENOTYPIC PREDICTORSOF PATHOGENIC COPY NUMBER VARIANTS IN APSYCHOSIS POPULATION

Claire Foleyn,1, Eleisa Heron1, James Walters2,

Louise Gallagher1, Aiden Corvin1

1Trinity College Dublin2Cardiff University

Background: Copy Number Variants (CNVs) significantlyimpact one's risk of developing a NeurodevelopmentalDisorder (NDD). Eleven CNVs are robustly implicated inSchizophrenia (SCZ), increasing risk by 2 to 60-fold. Carriersare also at substantially higher risk of developing otherNDDs (penetrance for autism/developmental delay/conge-nital malformations= 8–88%). Genetic testing is a standardof care for people with Autism Spectrum Disorder (ASD); 10–20% carry CNVs that may have implications for clinicalmanagement and genetic counselling. As o5% of SCZpatients carry pathogenic CNVs, a clinical screening toolto identify SCZ patients most at risk would inform guidelinesfor testing in SCZ.

The aim of this study was 1) to investigate clinicallyidentifiable phenotypic features for association with putativelypathogenic CNVs, in a psychosis population, and 2) to investi-gate whether associated phenotypic features were predictive ofCNV carrier status in patients with psychosis. Putativelypredictive phenotypic characteristics may aid the identificationof patients who would benefit from clinical genetic testing.Methods: The primary analysis was carried out on a dataset derived from an Irish SCZ research cohort with extensiveclinical phenotype information and Genome-Wide AssociationStudy (GWAS) data. Literature review identified neurodeve-lopmentally related phenotype variables for correlationanalyses in a group of carriers of CNVs at 15 SCZ-associatedloci, compared to a group without the CNVs. Phenotypevariables identified included: early onset of symptoms,history of learning difficulties, specific learning disorder,remedial school support, low educational attainment, historyof developmental delay, comorbid neurodevelopmental diag-nosis (ASD, intellectual disability, epilepsy, ADHD), familyhistory of NDD. The probability of pathogenic CNV carrier-status was analysed using logistic regression. A subsequentanalysis was undertaken in a second psychosis data set(Cardiff) with similar neurodevelopmental phenotype andgenetic data.Results: In the Irish data set, nineteen individuals (1.6%)carried risk CNVs from a total sample of 1,215 cases.‘Specific learning disorder’ (OR=9.0 (95% CI 1.38–39.98,p=0.03)); ‘History of learning difficulties’ (OR=4.0 (95% CI1.55- 10.30, p=0.005)); ‘History of developmental delay’(OR=5.8 (95% CI 1.91 - 16.44, p=0.005)) and ‘co-morbidNDD’ (OR=4.9 (95% CI 1.18 - 16.73, p=0.034)) weresignificantly associated with carrier status. ‘History oflearning difficulties’ was significantly correlated with theother three variables. Logistic regression odds ratios forprobability of a pathogenic CNV were 9.2, 5.3, 6.4 respec-tively in the presence of positive history of specific LD,history of developmental delay or co-morbid NDD.

Analyses in the Cardiff data set (n=479) were supportive

of a significant correlation between the CNV carrier groupand presence of co-morbid NDD (p=0.0012). Correlationwith history of developmental delay did not reach signifi-cance (p=0.13).

Broad confidence intervals were observed in analyses inboth data sets, indicating need for replication in largerdatasets.Discussion: These preliminary analyses indicate thatsymptoms of early developmental compromise, similar tosymptoms observed in ASD and developmental delay mayhave clinical utility in screening for SCZ patients atincreased risk of carrying pathogenic CNVs. The findingrequires replication in larger datasets which is currentlybeing pursued.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.177

SA106. HERITABILITY AND FAMILIALITY OF NEO PER-SONALITY DIMENSIONS IN THE KOREAN FAMILIES WITHSCHIZOPHRENIA

GiOk Kimn

, Byung Dae Lee

Pusan National University Hospital

Background: Categorical syndrome such as schizophreniacould be the complex of many continuous mental structurephenotypes including several personality development/degeneration dimensions. Previous many models suggestthat personality dimensions are heritable and influencethe genetic loading of schizophrenia. The psychobiologicalmodel of personality suggests an individual's temperament isheritable and regulated by neurotransmission linked to thepathophysiology of schizophrenia. Recently, evidence hasappeared that dimensions of character are also heritableand may influence the risk for schizotypy. This is the studyto search heritability and familiality of personality dimen-sions in the Korean schizophrenic LD (Linkage Disequili-brium) families.Methods: We have recruited 179 probands (with schizo-phrenia) with their parents and siblings whenever possible.We have used NEO questionnaires for measuring personalityand symptomatic dimensions. Heritabilities of personalitydimensions in total 472 family members were estimatedusing Sequential Oligogenic Linkage Analysis Routines(SOLAR). Personality dimensions in total family memberswere compared with those in 336 healthy unrelated controlsfor measuring the familialities using ANOVA analysis.Genetic/environmental correlations with symptomaticdimensions for significant personality dimensions aggre-gated in families were also investigated using SOLAR.Results: Heritability: Four of the 5 NEO variables weresignificantly heritable and were included in the subsequentanalyses. Familial aggregation: The three groups (control,unaffected 1st degree relative, case) were found to besignificantly different and with the expected order of averagegroup scores for all heritable dimensions. Low Extroversion and

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low Conscientiousness could differentiate the cases from the1st degree relatives and controls qualitatively. Genetic/envir-onmental correlation: genetic/environmental correlations withschizophrenic phenotype was suggested.Discussion: Our results show that the aberrations in sev-eral personality dimensions could form the complexity ofschizophrenic syndrome as a result of genetic-environmentcoactions or interactions in spite of some limitations(recruited family, phenotyping). Four of the five NEO vari-ables (Extroversion, Conscientiousness, Neuroticism, Open-ness) were significantly heritable and were included in thesubsequent analyses. Two endophenotypes (low Extroversionand low Conscientiousness) could differentiate the casesfrom the 1st degree relatives and controls qualitatively.The control, unaffected 1st degree relative, and case groupswere significantly different and with the expected order ofaverage group scores for two endophenotypes. (Neuroticismand Openness) Based on these results genetic and environ-mental correlations with schizophrenic phenotype was sug-gested. Finally, future genome-wide linkage and associationstudies with much more complete pedigrees are expected.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.178

SA107. ELEVATED PERIPHERAL EXPRESSION OF NEUR-EGULIN-1 (NRG1) MRNA ISOFORMS IN PATIENTS WITHTREATMENT-RESISTANT SCHIZOPHRENIA

Md Shaki Mostaidn,1, Ting Ting Lee1, Gursharan Chana1,

Suresh Sundram2, Cynthia Shannon Weickert3,Christos Pantelis1, Ian Paul Everall1, Chad Bousman1

1University of Melbourne2Monash University3Neuroscience Research Australia

Background: Differential expression of Neuregulin-1(NRG1) mRNA isoforms and proteins has been reported inschizophrenia, primarily in post-mortem brain tissue. In thisstudy, we examined 12 NRG1 SNPs, eight NRG1 mRNAisoforms (type I, type I(Ig2), type II, type III, type IV, EGFα,EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein inserum of clozapine-treated schizophrenia patients (N=71)and healthy controls (N=57). In addition, using culturedPeripheral Blood Mononuclear Cells (PBMC) from 15 healthyindividuals, we examined the effect of clozapine on NRG1mRNA isoform and protein expression.Methods: RT-PCR was used to measure gene expressionlevel of different NRG1 isoforms in the whole blood of theschizophrenia patients and healthy controls in the clinicalcohort as well as from the total RNA extracted from the In-Vitro clozapine exposure study. ELISA was used to measureNRG1-β1 protein level in serum in the clinical cohort andalso in the total protein extracted from the in vitroclozapine exposure study.Results: We found elevated levels of NRG1 mRNA, speci-fically the EGFα (P=0.0175), EGFβ (P=0.002) and typeI(Ig2)

(P=0.023) containing transcripts, but lower NRG1-β1 serumprotein levels (p=0.019) in schizophrenia patients com-pared to healthy controls. However, adjusting for smokingstatus attenuated the difference in NRG1-β1 serum levels(p=0.050). Examination of clinical factors showed NRG1EGFα (p=0.02) and EGFβ (p=0.02) isoform expression wasnegatively correlated with age of onset. However, we foundlimited evidence that NRG1 mRNA isoform or proteinexpression was associated with current chlorpromazineequivalent dose or clozapine plasma levels, the lattercorroborated by our PBMC clozapine exposure experiment.Our SNP analysis found no robust expression quantitativetrait loci.Discussion: Our results represent the first comprehensiveinvestigation of NRG1 isoforms and protein expression in theblood of clozapine-treated schizophrenia patients and sug-gest NRG1 transcription is up-regulated in those withschizophrenia and perhaps more specifically in treatment-resistant schizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.179

SA108. THE IMMUNE 8: IMPAIRED COGNITION IN SCHI-ZOPHRENIA RELATED TO GENETIC, ENVIRONMENTAL,AND IMMUNE INTERACTIONS IN IRISH AND UK COHORTS

Jessica Hollandn,1, Derek Morris1, Donna Cosgrove1,

Denise Harold2, Omar David Mothershill1, Aiden Corvin2,Gary Donohoe1

1National University of Ireland Galway2Trinity College Dublin

Background: The aim of this study is to characterise theeffects of 8 already identified genetic risk variants on socialcognitive deficits in schizophrenia. Although the aetiologyof schizophrenia is largely unknown, it is increasingly clearthat genetic and environmental interactions contribute tocognitive deficits associated with this disorder. The ‘ImmuneHypothesis’ suggests that schizophrenia is often predictedby early environmentally-driven immune challenges, andgenetically driven sub-optimal immune responsiveness. Inthe largest genetic study of schizophrenia to date, recentGenome-Wide Association Studies (GWAS) have establishedthe strongest association with schizophrenia was found at aregion of the genome that is synonymous with immunefunction- the major histocompatibility complex, or MHC.Social cognitive deficits are core features of Schizophrenia,which relate to genetic risk. The current study analyses theeffects of immune challenge (genetic and environmental)on social cognition, examining a set of genes related toimmune function and schizophrenia risk, as well as environ-mental factors that may contribute to cognitive deficit.Methods: To test if genetic variants related to immunefunction impair cognition, 8 genes were selected by crossreferencing “Immunology” Gene Ontology lists with themost recent list of genes implicated in GWAS for

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schizophrenia. 1013 participants were genotyped and cog-nitively assessed in an Irish population of schizophreniasufferers and healthy controls, and this cohort was used forprimary analysis of a gene-cognition relationship. A sepa-rate cohort of already collected data was also examinedfrom the Avon Longitudinal Study of Parents and Children(ALSPAC) for replication of results and mediation analysis,consisting of �5000 participants. Block regression analysisusing SPSS statistical software was performed, testing arelationship between genetic risk levels and cognitivedeficits. In a second element to the study, environmentalfactors were examined as possible mediators of the rela-tionship between genetic risk variants and cognitive impair-ment (PROCESS mediation, SPSS) in the ALSPAC sample.Results: Regression analysis suggests that 7 of 8 geneticvariants selected contribute to impairments in cognitionacross an Irish sample, and these findings were replicated inthe ALSPAC sample. Cognitive deficits overlapped for themajority of genes examined, across domains of socialcognition, IQ and episodic memory. In examining ALSPACas a replication sample, many of the same genetic variantsalso showed negative effects on social cognition, as well asmore generalized effects of these genes on various cognitivedomains. In mediation analysis, environmental factors suchas childhood abuse were also found to impact on this gene-cognition relationship.Discussion: The "Immune 8" may serve as significant riskmarkers for schizophrenia, and further elucidate aetiologyof this disorder. Future studies on neurobiology of socialcognition, and greater knowledge of genetic risk mayestablish targets for interventions. Childhood abuse wasalso found to be significantly related to cognitive deficit.The role of environmental stressors contributing to geneticrisk and immune function is an interesting avenue for futureresearch in schizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.180

SA109. CROSS-SPECIES ANALYSIS OF ALCOHOL-REGU-LATED AND DEPENDENCE-ASSOCIATED GENE NET-WORKS IN THE VENTRAL TEGMENTAL AREA

Kristin Mignognan,1, Brien Riley1, Silviu Bacanu2,

Aaron Wolen1, Mike Miles1

1Virginia Commonwealth University2Virginia Institute for Psychiatric and Behavioral Genetics

Background: Despite studies suggesting that AlcoholDependence (AD) is moderately heritable, Genome-WideAssociation Studies (GWAS) on AD lack power for detectingthe small contribution of individual genes to risk, and theability to determine their mechanistic role in this complexdisorder. Gene co-expression networks provide informationabout the mechanistic framework through which geneticvariants take their effects on AD. Studying gene expression

in human brains can be problematic. However, studies haveidentified significantly ethanol-associated gene networks inmice. Direct integration of human GWAS and Protein-ProteinInteraction (PPI) data with mouse gene expression data hasthe potential to identify novel associated loci and themechanistic frameworks through which they function. Wetherefore believe that this co-analysis will identify such lociand networks, and that these networks will reflect results ofother GWAS's.Methods: The present analysis used Edge-Weighted densemodule searching for Genome-Wide Association Studies (EW-dmGWAS) to co-analyze GWAS data from the Irish AffectedSib-Pair Study of Alcohol Dependence, human PPI data, andacute-ethanol-exposed mouse gene expression data, toidentify and prioritize ethanol-regulated gene networks(i.e. modules) with respect to AD risk contribution. Expres-sion data was obtained from the Ventral Tegmental Area(VTA), due to its role in reward pathways, and previousfindings of significantly ethanol-regulated networks in thisregion. To validate our results, we tested modules foroverrepresentation of genes with nominal GWAS p-valuesfrom an alternative GWAS dataset (Avon Longitudinal Studyof Parents and Children; ALSPAC). To determine the func-tional relatedness of genes within significantly overrepre-sented modules, we analyzed their functional enrichmentusing ToppGene. Finally, to specifically assess the prioritiza-tion of modules, we examined the association of modulescores with ALSPAC p-values.Results: Of the 276 significantly alcohol-associated mod-ules, 25 of them contained at least one gene with nominalsignificance in ALSPAC. One of these modules showedsignificant overrepresentation of these genes, after correc-tion for multiple testing (p=0.006). This module showedfunctional enrichment for genes associated with ubiquitina-tion, abnormal glial and muscle cell morphology, and neurondegeneration. Finally, module scores was significantly,negatively associated with ALSPAC p-value (β=-2.05,p=0.003) (meaning higher module scores indicated smallerp-values).Discussion: The results indicate that integration of mousegene expression data and human genetic data via EW-dmGWAS allows identification of novel alcohol-associatedgene networks in the VTA, and that the resulting scoressuccessfully prioritize these modules with respect to asso-ciation with risk for AD. This suggests that these modulesare bridging the gap between the disparate results ofindependent GWAS's, and that some of the relevant mechan-isms involve dopaminergic reward pathways relevant to theearly stages of AD development. One of these modules wassignificantly overrepresented with nominally significantgenes from that dataset, indicating that it is of particularimportance. The functional enrichment of its constituentgenes suggests that the Ventral Tegmental Area is associatedwith AD by way of alcohol-regulated pathways involvingneuron degeneration via ubiquitination.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.181

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SA110. SHARED POLYGENIC RISK ANALYSIS OF ALCO-HOLISM AND 5 MAJOR PSYCHIATRIC DISORDERS

Xaquín Gurriarán Basn,1, Julio Rodríguez-López2,

César Pereiro3, José Manuel Fernández4, Emilio Fariñas5,Mario Páramo6, Raquel Calvo1, Manuel Arrojo7,Gerardo Flórez8, Javier Costas2

1Santiago de Compostela University2Instituto de Investigación Sanitaria (IDIS) de Santiago deCompostela; Servizo Galego de Saúde (SERGAS)3Unidade Asistencial de Drogodependencias, Servizo Galegode Saúde (SERGAS)4Unidade Asistencial de Drogodependencias5Unidad Municipal de Atención a Drogodependientes(UMAD), Santiago de Compostela6Instituto de Investigación Sanitaria (IDIS) de Santiago deCompostela, Complexo Hospitalario Universitario de San-tiago de Compostela (CHUS), Servizo Galego de Saúde(SERGAS)7Servizo de Psiquiatría, Complexo Hospitalario Universi-tario de Santiago de Compostela8Unidad de Conductas Adictivas, Servizo de Psiquiatría,Complexo Hospitalario Universitario de Ourense (CHUO)

Background: Alcohol is the most commonly used andabused substance. Addictions to alcohol and other legal/illicit drugs are heritable disorders influenced by a largenumber of variants of small effect, frequently being acomorbidity of other psychiatric disorders. This comorbiditybetween a mental illness and a Substance Use Disorder(SUD) is consistently contributing to an increased disabilityin individuals. In spite of this evidence of importantcomorbidity, shared genetic factors remain partially under-studied. Previous GWAS of SUD showed evidence of geneticoverlap with schizophrenia, bipolar disorder and majordepressive disorder. We tested individual associations usingPolygenic Risk Scores (PRS) from the Psychiatric GenomicsConsortium's Cross-Disorder meta-analysis as discoverysamples, and each of the five psychiatric disorders includedin the study (ADHD, AUT, BIP, MDD, and SCZ), including 2014PGC schizophrenia mega-analysis results, and, as targetsample, a 1144 individuals case/control sample of alcoholabuse/dependence from Galicia, northwest Spain.Methods: A total of 572 substance dependent patientswere included. Inclusion criteria were: age between 18 and65, born in Galicia and follow DSM-IV criteria for depen-dence of at least one substance and abuse/dependence ofother substance. The substances registered in the studywere: alcohol, tobacco, cannabis, cocaine, opiates, hypno-tics, stimulants, hallucinogens and solvents. Most patients(N=540) were diagnosed with alcohol abuse/dependence. Atotal number of 604 controls from Galicia were included(mean age at recruitment: 40.26, SD: 10.70). DNA wasextracted from blood samples and genotyping was per-formed using Illumina Infinium PsychArray. Variant imputa-tion was executed with SHAPEIT and IMPUTE2, and PRSmodels were derived from the summary statistics of the PGCcross-disorder meta-analysis (CROSS) and 2014 PGC schizo-phrenia mega-analysis (SCZ2). Extensive data cleaning andQuality Control (QC) was employed. SNPs within the

extended MHC region were excluded from part of theanalysis. Associations between every PRS model and ourdata were tested using logistics regression.Results: After QC and imputation, a total number of 503alcohol cases and 587 controls remained (728 males and 362females) and genotypic data remained in a total number of6294324 SNPs. Covariates were included in regressionanalysis for correction (missing genotyping rate, significantMDS dimensions, sex and age). General CROSS-disorder PRSs(5 disorders included) showed a strong association withalcohol dependence (P=7.39e-06, ΔR=2%). After analyzingeach disease separately, significant results were found inbipolar disorder (P=0.0064, ΔR=0.7%) and schizophrenia(P=7.06e-05, ΔR=1.5%). A consistent result was achievedusing the greater sample of SCZ2 were obtained a consistent(P=4.49e-10, ΔR=4.1%). SCZ2 and general CROSS-disordersresults are robust after Bonferroni multiple test correction(7 thresholds and 7 pathologies employed).Discussion: The use of a greater sample in SCZ2 improvesresults in schizophrenia, showing the consistency of these inthis pathology. Moreover, the variability percent explainedis high considering previous data of shared genetic suscept-ibility between schizophrenia and other psychiatric disor-ders. Despite the fact that the sample used in majordepression disorder was bigger than the one in bipolardisorder, these results were not significant. It is necessaryto consider that a fraction of PGC individuals show comor-bidity with SUDs. As evidenced in this study, an increase inthe number of PGC discovery individuals sample willimprove the ability to detect this shared geneticsusceptibility.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.182

SA111. FURTHER EVIDENCE FOR THE ASSOCIATIONBETWEEN SYT1-RS2251214 AND USE OF STIMULANTS:CRACK COCAINE ADDICTION SUSCEPTIBILITY ANDSEVERITY

Renata Basso Cupertinon,1, Bruna Santos da Silva1,

Djenifer B. Kappel1, Jaqueline Bohrer Schuch1, BrenoSanvicente Vieira2, Lisia von Diemen3, Anderson Stolf3,Felix Henrique Paim Kessler3, Eugênio Horácio Grevet1,Flávio Pechansky3, Rodrigo Grassi-Oliveira2,Claiton Henrique Dotto Bau1, Diego Luiz Rovaris1

1Universidade Federal do Rio Grande do Sul2Pontifical Catholic University of Rio Grande do Sul3HCPA/UFRGS

Background: Synaptotagmin 1 is expressed in synapticvesicles and plays an important role on neuroexocytosis. Avariant in its encoding gene (SYT1-rs2251214) has beenassociated with ADHD susceptibility and with other exter-nalizing behaviors and comorbidities. Recently, it was alsoshown to influence response variability to Methylphenidate(MPH) in adults with ADHD, being associated with both short

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and long term treatment response and persistence, as wellas other outcomes. Although the stimulant effects of MPHand cocaine are similar and seem to be mediated byinhibition of dopamine reuptake, additional mechanismsrelated to increases in the release of neurotransmittersmight also be involved in the action of these stimulants.This study aims to investigate if this genetic variation in theexocytosis-related gene SYT1 would also have an influencein crack cocaine addiction susceptibility and its severity. Apathway study evaluating genes related to neurotransmitterrelease have already described a nominal association ofother SYT1 variant with cocaine dependence.Methods: Three hundred and fifteen crack cocaine users(47.6% are women) and seven hundred and sixty-nine controls(43.4% are women) were enrolled in this study. All partici-pants are white Brazilians of European descent. Diagnosesand clinical assessments were performed according to theDSM-IV criteria. The Addiction Severity Index 6th version wasused to assess the severity of dependence. Logistic regressionmodels, general linear models and generalized estimatingequations were used to evaluate the effects of the SYT1-rs2251214 SNP on the outcomes investigated.Results: A significant effect of the SYT1-rs2251214 SNP oncrack cocaine addiction susceptibility was found (P=0.011),where the GG genotype confers risk to crack cocaineaddiction. Effects were analyzed separately according tosex, where it was associated in women (P=0.022), but notin men (P=0.177). Crack cocaine addicted women present-ing this genotype had significantly lower scores on severityindexes regarding family/social problems (P=0.016) andpsychiatric problems (P=0.042). Furthermore, these womenseem to have experimented crack cocaine earlier than thosecarrying the A-allele (P=0.024).Discussion: The findings that women with SYT1-rs2251214GG genotype have increased susceptibility to crack cocaineaddiction and experiment this substance earlier are inaccordance with a previous report showing a more externa-lizing profile associated with this genotype. On the otherhand, the A-allele related higher severity scores mightreflect a “stronger response” to crack cocaine use, parallel-ing the A-allele reported better response to MPH treatment.That is, the presence of the A-allele might be related to thepharmacodynamics of different stimulants, even if withopposite effects in relation to the susceptibility to bothADHD and crack cocaine addiction. These SYT1-rs2251214SNP effects reinforce the importance of this gene inpsychiatric genetics, and further suggest that the presentresults should be replicated in independent samples.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.183

SA112. AN ALCOHOL DEPENDENCE GWAS ON 2,650CASES AND 47,000 CONTROLS FROM THE UNITEDKINGDOM

Johan Hilge Thygesen1, Niamh O'Brien1,Gregory John Lydall1, Franziska Degenhardt2,

Stefanie Heilmann-Heimbach2, Nicholas Bass1,Marsha. Y Morgan1, Andrew McQuillin

n,1

1University College London2Institute of Human Genetics, University of Bonn

Background: In 2012 over three million deaths wereattributed to alcohol consumption world-wide, correspond-ing to one in every twenty deaths. Excess consumption ofalcohol is associated with a wide-range of problems relatingto both physical and mental health. Mental disorders areoften comorbid with alcohol dependence; mental disorderswith comorbid alcohol dependence have worse outcome andincur substantially increased costs. Meta analyses of twinand adoption studies has provided a best-fit estimate for theheritability of alcohol used disorders of 0.49 [95% CI 0.43–0.53]. GWAS studies to date have found associations withseveral genes responsible for alcohol metabolism, e.g.ALDH2, ADH1B and ADH1C. Notably these association find-ings are “protective” for risk of alcohol dependence.Several other associations have been reported but theseawait replication.Methods: We will report a meta-analysis of GWAS datafrom UK alcohol dependent subjects that have been ana-lysed on three different SNP arrays. Control data was fromour own laboratory and from the Welcome Trust CaseControl Consortium.Results: Early results from analysis of Psych Chip datafrom 1,750 cases and 1,100 healthy control subjects pro-vides genome wide significant support for a SNP at the ADHlocus on chromosome 4 and suggestive evidence for a SNP onchromosome 11 near the SYT13 and PRDM11 genes. SYT13encodes synaptotagmin XIII which is a brain expressedmembrane trafficking protein. Little is known about thefunction of SYT13 but other members of the synaptotagminfamily of proteins act as Ca2+ sensors for exocytosis at thesynapse and elsewhere.Discussion: An improved understanding of the geneticarchitecture will help elucidate the neurobiology of ADSand its sequelae. Therefore, there is the potential toidentify novel disease mechanisms and novel therapeutictargets not only for alcohol dependence itself but for manyrelated phenotypes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.184

SA113. POSTMORTEM STUDY OF MESSENGER RNAEXPRESSION IN THE DORSOLATERAL PREFRONTAL COR-TEX OF SUBJECTS WITH CONSUMMATE SUICIDE ANDSUBSTANCE ABUSE

Brenda Cabreran,1, Mirna Morales1, Nancy Monroy2,

AL Romero-Pimente1, RC Mendoza-Morales3, EE González-Sáenz4, F García-Dolores3, A Mendoza-Larios3, E Díaz-Otañes3, Consuelo Walss-Bass5, Claudia Rangel1,Humberto Nicolini1

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1National Institute of Genomic Medicine2National Institute of Neurology and Neurosurgery3Instituto de Ciencias Forenses (INCIFO), Tribunal Superiorde Justicia de la CDMX4Hospital Psiquiátrico Fray Bernardino Álvarez5University of Texas Health Science Center at San Antonio

Background: It is estimated that subjects with alcoholabuse are almost 10 times more likely to commit suicide andthose with substance abuse about 14 times more.

The prefrontal cortex is the cerebral area responsible fordecision making, inhibition and short-term memory, func-tions that have been altered in subjects with suicidalbehavior. In addition, structural and functional changes inindividuals with suicidal behavior have been identified inthis area. Cognitive abilities associated with the prefrontalarea, specifically the dorsolateral prefrontal cortex, havebeen identified in subjects with substance abuse.

Therefore, it is of special interest to evaluate geneexpression in this cerebral area in order to identify genesexpressed in suicide subjects with substance use comparedwith suicide death without this comorbidity to have a betterunderstanding of the pathology of suicide and that could beused in the future as biomarkers of suicidal behavior insubjects with substance abuse and implement adequateprevention measures for this sector of the population.Methods: We collected samples from the dorsolateralprefrontal cortex of subjects who committed suicide andof subjects with death other than suicide. RNA isolation wasperformed using the Qiagen RNAeasy, after RNA extractionthe purity of RNA extracted by means of spectrophotometry(NanoDrop1000 Spectrophotometer from Thermo Fisher)and its integrity with 1% agarose gel electrophoresis wasevaluated.

The expression of messenger RNA from 67 samples (43Subjects with consummate suicide and 24 subjects withdeath other than suicide) through the HumanHT-12 v4BeadChip microarray containing 47, 231 probes was eval-uated. The analysis of the data obtained from the micro-array will be performed comparing the expression ofmessenger RNA between the group with consummate sui-cide and the group with death other than suicide with apaired t-test for each probe evaluated in the microarray.Subsequently, a statistical model of ANOVA will be appliedto assess whether the diagnosis of substance abuse duringthe lifetime and toxicology at the time of death had anyeffect on the expression of messenger RNA. The genes thatare differentially expressed will be validated by real-timePCR.Results: The final sample consisted of 67 brain samplesdivided into the group of "individuals who consumed suicide"(n=43) and the group of "controls" or subjects with a causeof death other than suicide (n=24). There were no sig-nificant differences in gender and age between both groups.

The analysis of microarray data will be performed in thenext weeks.Discussion: Subjects with substance abuse are atincreased risk for suicidal behavior, most studies of expres-sion have excluded this group of patients and little is knownabout the molecular basis of the association betweensubstance abuse and suicidal behavior.

We hypothesize that subjects with death by self-harmand substance abuse have different expression profiles ofthe messenger RNA in the dorsolateral prefrontal cortexcompared to suicide victims without substance abuse andcontrols who had a death from other causes.

I believe that after conducting the analysis of the resultsof the microarray (which will take only a few weeks) we willbe able to extend the discussion by commenting on thedifferences between the study groups.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.185

SA114. GENETIC ETIOLOGY OF SELF-RATING OF THEEFFECTS OF ALCOHOL (SRE) SCORES IN YOUNG ADULTS

Alexis Edwardsn,1, Jon Heron2, Bradley Webb1,

Chris Chatzinakos1, Silviu Bacanu1, Kenneth Kendler1,Danielle Dick3, Marc Schuckit4

1Virginia Institute for Psychiatric and Behavioral Genetics2School of Social and Community Medicine, University ofBristol3Virginia Commonwealth University4University of California, San Diego

Background: Alcohol misuse is a significant public healthconcern with social, medical, and economic consequences.Previous studies suggest that initial sensitivity to alcoholmay impact use of the substance: those with low sensitivitymay drink more, potentially establishing unhealthy drinkinghabits that persist into adulthood. The Self-Rating of theEffects of Alcohol (SRE) scale was developed to quantifyinitial sensitivity to alcohol, and SRE scores have beenpositively associated with concurrent and later drinkingbehaviors. Furthermore, evidence suggests that SRE scoresare influenced by familial factors, raising the possibility thatgenetic liability to low alcohol sensitivity may increase riskof later alcohol misuse. We sought to clarify the role ofgenetic factors on SRE scores in two samples of youngadults.Methods: We derived SRE scores in two population-basedcohort studies. ALSPAC participants were born between1991–1992 in the southwest region of England and havebeen assessed at least once per year since birth. SRE scoreswere derived based on assessments at ages 15.5, 16.5, and17.5. S4S participants were students at a large, public,urban university in the southeastern US, enrolled during thefall or spring of their freshman year (2011–2013), andassessed each subsequent spring. Participants were ofdiverse ancestry and were 18+ years of age at initialenrollment. The first available SRE score was used forsubsequent analyses. Phenotypic and genotypic data meet-ing all quality control filters were available for a total ofN=7339 participants. We conducted Genome-Wide Associa-tion Studies (GWAS) within each sample/ancestry group,using ancestry-informative principal components, sex, andage at first available SRE assessment as covariates. Initial

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GWAS results were meta-analyzed in METAL. SNP-basedheritabilities for each sample/ancestry group were esti-mated in GCTA. Additional secondary analyses were con-ducted in VEGAS and JEPEGMIX2.Results: A total of 15,642,250 markers were analyzed inat least one group. No individual marker met genome-widesignificance criteria. The top marker, rs146298733(p=3.16e-07), mapped to an intron in DLGAP1, variants inwhich have been previously associated with psychiatricoutcomes including major depression and obsessive-compul-sive disorder. Meta-analysis of GCTA results indicated thatSRE is modestly heritable (h2SNP=0.19, SE=0.10), thoughthis was driven primarily by the ALSPAC sample, for whichassessments were prospective. Pathway analyses implicatedthe GABAergic system and genes related to thromboxanesignaling, both of which have been associated with alcohol-related phenotypes.Discussion: We present evidence consistent with priorreports that initial sensitivity to alcohol is influenced bygenetic factors. Preliminary analyses implicate systemsknown to influence other alcohol phenotypes and providenovel targets for future analysis. Implicated loci andaggregate genetic risk should be confirmed in independentsamples. Heterogeneity across samples suggests that assess-ment methods are important to SRE measurement, whichmay have implications for genetic analyses. Further char-acterization of genetic influences may elucidate mechan-isms underlying the pathway from initial sensitivity toalcohol problems.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.186

SA115. EVALUATION OF GENE EXPRESSION IN EARLYSUBSTANCE ABUSE

Fernanda Talaricon,1, Marcos Santoro1, Leticia Spindola1,

Vanessa Ota1, Evelin Aline Zanardo2,Leslie Domenici Kulikowski2, Renata Pellegrino3, Pedro Pan1,Ary Gadelha1, Giovanni Salum Junior4, Hakon Hakonarson5,Rodrigo Bressan1, Sintia Belangero1

1Federal University of Sao Paulo2University of Sao Paulo3Center for Applied Genomics, Children's Hospital ofPhiladelphia4Hospital De Clinicas De Posto Alegre5Children's Hospital of Philadelphia

Background: Psychiatric disorders cause an enormous bur-den of suffering, high morbidity and mortality rates. They arecomplex diseases characterized by alterations in multiplegenes, combined with environmental factors, such as sub-stance abuse. At the time these disorders are diagnosed, mostpatients need care and treatment for the rest of their livesand few remit completely. Therefore, it is very important to

understand the genetic and environmental factors responsibleto the transition to a disorder. Thus, longitudinal studies fromchildhood to adulthood may be very useful to understand thetriggers before the transition to psychiatric disorders. The aimof this study is to compare gene expression profiles in alongitudinal cohort of early adolescents with and withoutsubstance abuse (alcohol, tobacco, marijuana and others).Methods: In this study, we used a subsample of a BrazilianHigh Risk Cohort (HRC) for Psychiatric Disorders, consisting of110 adolescents selected from 750 individuals. To evaluatewhether the participants have any disorder (such as ADHD,anxiety), interviewers applied the DAWBA (Development andWell-Being Assessment) in all participants. Their parentsanswered a drug abuse questionnaire. For the transcriptome,we used the HumanHT-12 v4 Expression BeadChip, comparingsubstance abusers (N= 98) and non-substance abusers (N=12). Using methylumi and limma R packages we used the listof the top 100 differentially expressed genes to create anetwork based in co-expression genes by Cytoscape softwareand to identify enriched pathways (Reactome base data) andBiological Process (GO base data).Results: We found an association between substanceabuse and emotional disorder (X-squared=5.01, p=0.025),where among 110 participants, 17 have the disorder, being5 of them substance abusers, whereas among the remaining93 (with no disorder), 7 were substance abusers. On theother hand, participants who have any type of hyperactivityhad never used drugs. Using the most differentiallyexpressed genes (top 100), we found a total of 18 pathwaysand 2 biological process significantly associated with sub-stance use and psychiatric disorder. Among them, the mostassociated were related to immune system and rRNAprocessing (p-values o 0.001). Besides, within the top 15differentially expressed genes, most of them were pre-viously associated with mental illness, substance abuse anddependence (for example, CCR3, and CHST7).Discussion: Although, we found an association betweenemotional disorders and substance abuse, we cannot saywhether this is a cause or consequence. The understanding ofthe biological alterations that trigger the psychiatric disordersand their association with substance abuse, might help todevelop prevention strategies to psychiatric disorders and avoidsubstance abuse. Furthermore, we found no substance abuserswith ADHD which may be related with their age (very youngindividuals). Although we have found no significant co-expres-sion network, we identified 18 pathways as well as 2 biologicalprocesses related to immune system, rRNA processing, amongothers. Therefore, our results suggest that these pathwayscould be associated with substance abuse in adolescents. It isalso worth to mention that our cohort is a very well clinicallycharacterized and unique sample of adolescents with psychia-tric disorders and healthy controls, and we are running nextyear the 3rd year follow up which may increase the sample sizeof substance abuser and individuals with psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.187

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SA116. A NOVEL APPROACH TO COMBINE GWAS, PGRSAND GENE-GENE INTERACTIONS IN PSYCHIATRY

Joeri Meijsenn,1, Alexandros Rammos2, Riccardo Marioni1,

Kristin Nicodemus1

1University of Edinburgh2Trinity College Dublin

Background: Studies in psychiatric genetics have focusedalmost solely on single-loci and polygenic associations andhave not included possible interactions. Nicodemus et al.(2014, JAMA Psychiatry) introduced a novel statistical modelthat incorporates single marker, polygenic and epistaticcomponents to assess the association between SNPs in theZNF804A pathway and cognitive performance in psychosis.Two-SNP interaction modelling was conducted to test forepistasis. This resulted in a regression model that containedthe polygenic score and two two-SNP interaction terms,where the epistatic component explained more variation incognition than the polygenic score. This model is stillrelatively simplistic in modelling the genetic architectureof complex traits; in particular, the epistatic component, asthe model only allowed for pairwise interactions betweenSNPs. We sought to implement a more flexible specificationof the epistatic component by the use of non-parametricrule sets via the algorithm C5.0.Methods: As a proof-of-principle we simulated multiplephenotypes using SNPs located on chromosome 19 explain-ing A) 30% polygenic variation B) 30% epistatic variationusing 2-SNP models not included in the polygenic set, not inLD and under weak (β=0.09), intermediate (β=0.15) andstrong (β=0.24) interaction strength and C) a combinationcontaining both a polygenic and epistatic component. Fivehundred replicates were simulated per condition. Weapplied C5.0 in an effort to detect these epistatic interac-tions. C5.0 is a non-parametric algorithm to generatedecision tree-based rulesets. Because of its decision treebasis C5.0 only allows for the Boolean operator OR but doesallow for non-binary predictors. Each possible combinationfrom the top node to bottom node in the tree is a so-calledruleset and can be used as a predictor in a regression model.Results: We found C5.0 is highly capable of detecting bothepistatic SNPs in 100% of the 500 simulations of the stronginteraction, 99.2% of the intermediate interaction and 19.2%of the weak interaction models. For the intermediate andweak interactions C5.0 detected only one of the two epistaticSNPs in 0.8% and 41.2% of the replicates. C5.0 was immune todetecting polygenic additivity at the single SNP level. In thepolygenic setting of 30% variation explained by an additiveeffect, C5.0 detected in 11.4% simulations at least one rulesetwith no SNP being included more than 13 timesDiscussion: These results show that C5.0 is able to detectepistasis even in the presence of a phenotype containingstrong-single loci and polygenic components. Further workincludes creating an R package that embeds these differentcomponents through a penalised regression framework tocombine all three types of genetic variation (single loci,polygenic components, epistatic components) to betterreflect the underlying biology, and to apply this method tocognitive performance in Major Depressive Disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.188

SA117. ATTITUDE OF INDIAN RESEARCH PARTICIPANTSTOWARDS PRIVACY AND CONFIDENTIALITY

Triptish Bhatian,1, Nagendra N. Mishra2,

Vishwajit L. Nimgaonkar3, Smita N. Deshpande4,Lisa S. Parker3

1Indo-US Projects, PGIMER, Dr. R.M.L. Hospital2L.S. College, Muzaffarpur B.R.A. Bihar University3University of Pittsburgh4PGIMER, Dr. R.M.L. Hospital

Background: The right to privacy—and the related pro-fessional duty of confidentiality—allows participants to limitothers’ access to information about themselves while stillbenefiting from healthcare or benefiting others in research.Like the right to give informed consent, the right to privacyand the confidentiality of health information promote well-being and protect autonomy or self-determination. Thispaper reports the first empirical study in India of the beliefsand expectations of patients/participants, their relatives,and IEC members regarding privacy/confidentiality.Methods: The first goal of this qualitative study was toevaluate how IEC/IRB members understand privacy-relatedobligations, how their institutions protect patient/participantprivacy, as well as what IEC/IRB members believe patients/participants think. The second goal was to use thematicanalysis to learn about the privacy-related views and valuespatients/participants hold. After informed consent, membersof IEC/IRB (n=19) in New Delhi, patients or research partici-pants (n=29) in a psychiatric clinical setting, and relativesaccompanying those patients/participants (n=30) were inter-viewed based on interview guides. Interviews were tran-scribed, translated and thematic analyses were carried out.Results: Data collection and analysis were integrated,with the interview guides being continually revised toexplore newly emerging concepts and themes. Four themeswere extracted: IEC/IRB members’ understanding of priv-acy-related obligations, regulations, and guidelines; mea-sures to protect patient and research participant privacyand barriers to their implementation; differences betweenIEC/IRB members’ estimation of the value people placed onprivacy protection and people's actual views.Discussion: Analysis of semi-structured interviewsrevealed that IEC/IRB members sometimes underestimatethe value patients/participants and relatives place onprivacy protection. The recurrent themes identified in thestudy data indicate that it is mistaken to think that Indianpatients and the public do not value privacy. Themesdemonstrate that they make strategic choices about whatsort of health information to share and with whom.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.189

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65PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

Sunday, October 15, 2017

Poster Session II11:15 a.m. - 1:15 p.m.

SU1. EXPLORING GENETIC VARIATION THAT INFLU-ENCES BRAIN METHYLATION IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

Laura Pineda-Cirera1, Anu Shivalikanjli1, Judit Cabana-Domínguez1, The Lundbeck Foundation Initiative for Integra-tive Psychiatric Research (iPSYCH)2, Psychiatric GenomicsConsortium (PGC) ADHD Working Group, Ditte Demontis3,Anders D. Børglum3, Benjamin Neale4,Stephen V. Faraone5, Bru Cormand6,Noèlia Fernàndez-Castillo

n,1

1University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER), Insti-tuto de Salud Carlos III, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat2Aarhus University3Aarhus University, iPSYCH-The Lundbeck Foundation Initia-tive for Integrative Psychiatric Research4Stanley Center for Psychiatric Genetics, Broad Institute ofMassachusetts Institute of Technology, Massachusetts Gen-eral Hospital and Harvard Medical School, Harvard University5SUNY Upstate Medical University6University of Barcelona, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat

Background: Allele-Specific Methylation (ASM) is a com-mon epigenetic mechanism that involves SNPs correlatingwith differential levels of methylation at CpG sites. Epige-netic changes play a crucial role in driving lasting changes ingene expression in several tissues, including the brain. Asalteration of DNA methylation levels has recently beenlinked to ADHD symptoms, our aim is to explore thecontribution of ASM to ADHD through a case-control associa-tion study using different GWAS datasets.Methods: We performed a primary SNP selection based ontwo previous studies that identified ASM variants in differ-ent brain regions of post-mortem human samples. Subse-quently, from those variants we selected a total of 3,896SNPs following these criteria: associations in cis betweenthe SNP and methylation at a CpG site, correlation ofmethylation levels with gene expression (R2) Z 0.2,tagSNPs for each CpG site (LD; r2Z0.85). These candidateswere inspected in summary statistics data from the firstGWAS meta-analysis of adult and childhood ADHD, per-formed by iPSYCH and the Psychiatric Genomics Consortium(PGC) in 20,183 cases and 35,191 controls.

We applied False Discovery Rate (FDR) correction formultiple testing (5% FDR, corrected Pr 6.78e-05) todetermine the top hits. These signals were followed-up toretrieve (i) SNPs located within the same CpG site andthereafter (ii) SNPs in high linkage disequilibrium with the

associated SNPs (using the same FDR threshold). Impact ofthe variants on gene expression levels were furtherexplored in the GTEx database.Results: The case-control association study identifiedeight tagSNPs surviving FDR, which correlate with differ-ential methylation of six CpG sites. Top hits were followed-up to retrieve other SNPs that correlate with methylation ofthe same CpG sites, making a total of 39 candidate SNPs.The six CpG sites are located in the promoter regions of fivegenes, not previously related to ADHD. Notably, the riskSNPs associated with three of the genes are eQTLs for thosegenes in various brain tissues, including the cerebellarhemisphere and the cerebellum.Discussion: We have directed existing knowledge of ASMto evaluate its possible contribution to ADHD both atgenetic and epigenetic levels. We followed a systematicapproach by employing cis-acting ASM variants to pinpointcandidate genes for ADHD. Interestingly, several of theidentified variants are eQTLs for genes that are expressedin brain. Our aim is now to further investigate the role ofthese genes in the development of the ADHD phenotype.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.190

SU2. CORRELATION ANALYSIS OF miRNA AND mRNAEXPRESSION PROFILES IN PERIPHERAL BLOOD MONO-NUCLEAR CELLS FROM ADHD PATIENTS AND CONTROLS

Cristina Sanchez-Mora2, Iris Garcia-Martínez3,Mireia Pagerols4, María Soler5, Paula Rovira

n,1, Eva Calvo4,Natalia Padilla6, Vanessa Richarte7, Montse Corrales7,Barbara Franke8, Xavier de la Cruz6, Miguel Casas7,Bru Cormand9, JA Ramos-Quiroga7,Alejandro Arias-Vásquez8, Marta Ribases7

1Psychiatric Genetics Unit, Vall d’Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona, Mental HealthHospital Universitari Vall d’Hebron2Institut de Recerca Hospital University Vall d'HebronResearch Institute3Psychiatric Genetics Unit, Vall d’Hebron Research Institute(VHIR)4Psychiatric Genetics Unit, Vall d'Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona5Psychiatric Genetics Unit Group of Psychiatry, MentalHealth and Addiction Vall d'Hebron Research Institute(VHIR), CIBERSAM6Vall d’Hebron Institute of Research (VHIR)7Hospital Universitari Vall d’Hebron8Radboud University Nijmegen Medical Centre9University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER), Insti-tuto de Salud Carlos III, Spain, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat

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M. Barbu et al.66

Background: Attention Deficit Hyperactivity Disorders(ADHD) is a neurodevelopmental disorder characterized byimpairment in sustaining attention and inability to controlimpulses and modulate activity level. The aetiology of ADHDis complex, involving genetic and environmental factors,with an estimated heritability of 70–80%. Nevertheless,inconsistencies in the results of the genetic studies on ADHDmay be explained, in part, by epigenetic mechanisms suchas microRNAs (miRNAs) which play important roles in thecontrol of gene expression by pairing to target mRNAs.Under the hypothesis that alterations in the processing ortarget binding of miRNAs may result in differential mRNAexpression profiles predisposing to ADHD, we performedmRNA and miRNA expression profiling in Peripheral BloodMononuclear Cells (PBMCs) of 103 persistent ADHD indivi-duals and 115 controls.Methods: miRNA and mRNA expression profiling in PBMCsof 103 ADHD patients and 115 controls were assessed byhigh-throughput deep sequencing (HiSeq. 2000, Illumina)and the Human Gene 1,1 ST microarray (Affymetrix),respectively. The analyses of differential expression formiRNA and mRNA were carried out separately applyingLinear Model Fit using the Limma R package. ROC curveswere used to evaluate the accuracy of the differentiallyexpressed miRNAs in discriminating patients with ADHD fromcontrols in an independent sample of 46 cases and 46controls. In order to build miRNA-mRNA interaction net-works that may be relevant to ADHD, including positive andnegative relationships, we integrated the expression data ofmiRNAs and mRNAs differentially expressed in ADHD(adjusted p-valueso0.05) and ran Pearson Correlation Testsusing the Hmisc and corrplot R packages in a total sample of81 subjects with ADHD.Results: After quality control, normalization and back-ground correction, a total of 573 miRNAs and 19,784 tran-scripts were included in the analysis. We identified a total of79 miRNAs and 1,592 transcripts differentially expressed inADHD when compared to controls. Of them, miR-191-5p andmiR-23a-5p showed values of AUC 4 0.70 in the test sample;they were selected for the subsequent correlation analysis.Evidence for 126 miRNA-mRNA pairs was found (po0.05). Ofthem, the miR-23a-5p and OCIAD2 gene pair was experimen-tally validated according to miRTarBase 2016.Discussion: In conclusion, our findings provide for the firsttime tentative evidence for the contribution of miR-23a-5p -OCIAD2 correlated network to ADHD etiology through acomprehensive differentially expression analysis of miRNAand mRNA in PMBCs.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.191

SU3. THE ROLE OF A NEURONAL DIFFERENTIATIONGENE-SET IN ADHD SUSCEPTIBILITY

Djenifer B. Kappeln,1, Diego L. Rovaris1, Bruna S. da Silva1,

Renata B. Cupertino1, Diana Müller1, Cibele E. Bandeira1,Alana C. Panzenhagen1, Vitor C.T. Breda2, Gregory Zeni2,Nina R. Mota3, Eugenio H. Grevet2, Claiton H. Bau1

1Universidade Federal do Rio Grande do Sul2Hospital de Clínicas de Porto Alegre3Radboud University Nijmegen Medical Centre

Background: ADHD is a common neuropsychiatric disor-der, it is highly heritable and polygenic, with a great numberof combinations of variants, each with small effects,involved in its underlying molecular processes. However,the identification of the specific genetic factors associatedto ADHD is still a great challenge, and genome-widesignificant findings are just starting to appear. On the otherhand, gene-set and pathway based methods using GWASdata are helping to elucidate ADHD's pathophysiologicalmechanisms, having already implicated processes relatedto the development of the central nervous system in itsunderpinnings, particularly, axon guidance and neurite out-growth. In this sense, there is evidence suggesting that oneof the mechanisms by which methylphenidate, can improvesymptomatology and overall quality of life in patients is byaffecting neuronal differentiation. Thus, we attempted toverify, through a gene-set analysis, if a biological hypothesissuggesting the involvement of genes related to neuronaldifferentiation in the central nervous system can play a rolein ADHD susceptibility in adults.Methods: PsychChip genotype data for 45 M high-qualitySNPs was obtained after QC and imputation procedures for407 adults with ADHD (53.1% males, mean age of 33.6 years)and 463 unrelated controls (47.9% males, mean age of 29.4years) of European ancestry. Annotation from human gen-ome build 37 (hg19) with a flanking region of 2 kb upstreamand 1 kb downstream was considered for each gene. Com-petitive gene-set analysis was conducted using MAGMAsoftware, with a multi=mean model for gene-based ana-lyses. Sex, age, and the 10 first principal components wereincluded as covariates in this step. Gene-set analysis wasperformed with gene set enrichment for GWAS using datafrom Gene Ontology (GO). A GO annotated gene-set repre-senting 156 genes known to be involved in central nervoussystem neuron differentiation (GO: 0021953) specific path-ways was selected to be tested in a case-control associationstudy.Results: No single marker or gene analyzed reachedgenome-wide significance. In the gene-set analysis, wefound evidence that the group of genes represented bythe GO: 0021953 set was significantly associated with ADHD

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67PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

susceptibility in adults (p=0.037), when compared to theother genes in the genome. Within this gene-set, the top hitgenes were GIGYF2 (p=0.003), ABT1 (p=0.007), LHX4(p=0.019), OLIG2 (p=0.033), PAFAH1B1 (p=0.036).Discussion: Our results provide insight into the geneticsof ADHD and preliminary evidence suggesting that a mole-cular pathway involved in nervous system development andessential to neuronal differentiation could be informativeand contribute to the disorder's susceptibility. The use ofbiologically meaningful gene-sets, such as the regulatorymechanism involved in neuronal differentiation, containinggenes previously associated with neuropsychiatric disorders,can help to understand the specific molecular pathwaysassociated with ADHD. Interestingly, neurite outgrowth, aprocess previously implicated in ADHD susceptibility isclosely related to neuron differentiation since it marks thebeginning of the neuronal maturation stage and subsequentneuronal growth and function. The overall evidence, andthe results presented here suggesting that neuronal differ-entiation could be related to ADHD susceptibility, supportalterations of neuronal connectivity, synapse formation andsynaptic plasticity in the mechanisms playing a role inADHD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.192

SU4. GENOME-WIDE EXAMINATION OF PARENT-OF-ORI-GIN EFFECTS IN CHILDREN WITH ATTENTION DEFICITHYPERACTIVITY DISORDER

Dinka Smajlagicn,1, Siobhan Connolly2, Hakon Hakonarson3,

Irwin Waldman4, Josephine Elia3, Elizabeth Heron2,Jan Haavik1, Stefan Johansson1, Tetyana Zayats1

1University of Bergen2Trinity College Dublin3The Children's Hospital of Philadelphia4Emory University

Background: Attention Deficit Hyperactivity Disorder(ADHD) is one of the most common and most heritablechildhood-onset neuropsychiatric disorders, characterizedby multifaceted genetics. To date, genetic studies of ADHDfocused on additive effects only, explaining just a fractionof its heritability. Thus, we aimed at examining parent oforigin effects (POE) together with maternal and additiveeffects, providing novel insight into the complex geneticarchitecture of ADHD.Methods: We compiled parent-offspring data collectedthrough the Psychiatric Genomics Consortium and the Norwe-gian Mother and Child Cohort, consisting of 2060 trios and 328duos. Additional parent-offspring data is being added. ADHDwas diagnosed based on DSM-IV, ICD-10 and child behaviorchecklist. POE, maternal and additive genetic effects are beingevaluated using multinomial modelling implemented in EMIMsoftware. We explored our signals in the light of knownimprinted genes (POE) and the largest ADHD Genome-Wide

Association Study (GWAS) in children (N=17666). Gene basedanalyses are being performed using MAGMA software. Herit-ability estimates and genetic correlations of the examinedeffects are being calculated using LD score regression.Results: Our preliminary results indicate the presence ofnon-additive genetic effects in the development of ADHD.Our preliminary strongest imprinting signal is located inCALD1 locus (rs11980823, effect=0.77, SE=0.14, P=1.21E-07). This gene also revealed strong association signal in thepreviously reported large-scale childhood ADHD GWAS(rs79846815, P=2.03E-06). CALD1 plays essential an role innerve regeneration, a function previously implicated in anumber of neuropsychiatric disorders. Our preliminary gene-based analyses of the known imprinted genes revealed strongassociation with TP73 locus (P=0.0034), encoding a tran-scription factor implicated in disorders of nervous system(e.g. neuroblastoma). Additional hits were noted in the non-coding RNA genes, adding to the recent observations inneuropsychiatric genetics of gene regulation playing a pivotalrole in the development of disorders of mental health.Discussion: In conclusion, this is the first and the largestgenome-wide parent-offspring study in ADHD, exploring itsnon-additive genetic effects by detecting and distinguishingbetween POE (imprinting), maternal and child effects. Aswe increase our sample size, we will provide estimates ofsuch effects as well as those of their heritability and geneticcorrelations.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.193

SU5. IDENTIFICATION OF POLYGENIC ADAPTATION INATTENTION-DEFICIT/HYPERACTIVITY DISORDER USINGGWAS DATA

Paula Esteller-Cucala2, Iago Maceda2, The Lundbeck Foun-dation Initiative for Integrative Psychiatric Research(iPSYCH)3, Psychiatric Genomics Consortium (PGC) ADHDWorking Group, Ditte Demontis4, Anders D. Børglum4,Benjamin Neale5, Stephen V. Faraone6, Bru Cormand

n,1,Oscar Lao2

1University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER), Insti-tuto de Salud Carlos III, Spain, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Catalonia, Spain, Institutde Recerca Sant Joan de Déu (IR-SJD), Esplugues deLlobregat, Catalonia, Spain2Centre Nacional d'Anàlisi Genòmica (CNAG), Centre forGenomic Regulation (CRG), Barcelona Institute of Scienceand Technology (BIST)3Aarhus University4Aarhus University, iPSYCH-The Lundbeck Foundation Initia-tive for Integrative Psychiatric Research5Stanley Center for Psychiatric Genetics, Broad Institute ofMassachusetts Institute of Technology, Analytic and Transla-tion Genetics Unit, Massachusetts General Hospital andHarvard Medical School, Harvard University

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M. Barbu et al.68

6SUNY Upstate Medical University

Background: During the human Diaspora out of Africa,Anatomically Modern Humans (AMH) adapted to the newenvironments they encountered. On top, adaptation processcould have been fueled by interbreeding with homo archaicspecies -such as Neanderthal and Denisovan- present at thattime in Eurasia. In this context of natural adaptation,Attention-Deficit/Hyperactivity Disorder (ADHD) poses aninteresting evolutionary paradox: despite being associatedwith significant impairment, morbidity and increased ratesof mortality, it is a highly prevalent phenotype. Being ahighly heritable trait, several selective hypotheses havebeen proposed to explain the prevalence of this phenotype.

In the present study, we have analysed the signatures ofrecent polygenic selection and the effect of archaicinbreeding in ADHD.Methods: Databases:i) The effect size estimates of millions of SNPs reported at a

GWAS meta-analysis on ADHD conducted by the LundbeckFoundation Initiative for Integrative Psychiatric Research(iPSYCH) and the Psychiatric Genomics Consortium (PGC) onapproximately 20 K patients and 35 K controls.ii) The SDS statistic for detecting recent selection estimatedin the UK10K dataset.iii) Genotypes reported at archaic European anatomicallymodern humans individuals (ranging from �2 kilo years ago(kya) to �45 kya.iv) The sequenced Altai Neanderthal genome.v) Map of Neanderthal introgression haplotypes in currenthumans.

Analyses: The presence of signatures of recent polygenicadaptation of ADHD in UK10K samples was estimated bymeans of the SDS statistic. For ancestral human samples,regression analysis was conducted between the time of eachsample and the average ADHD genetic score (GS) by SNP. Forthe Altai Neanderthal sample, average ADHD GS wascompared with the one observed with ancestral humansamples. The map of introgressed Neanderthal alleles wasused for estimating the effect of introgressed Neanderthalalleles in ADHD in current humans.Results: Our results suggest that current North Europeanpopulations show signatures of recent (o2,000 years ago)polygenic adaptation in the alleles that are protective forADHD at a genomic level. Furthermore, analysis of ancientAMH European samples shows that the mean number ofADHD risk alleles per SNP linearly correlates with thesampling time more than expected under the hypothesisof neutrality. The analysis of the genetic variation of AltaiNeanderthal suggests that this sample carries more ADHDrisk alleles than current and ancient AMH samples. More-over, we observed that introgressed Neanderthal allelesinfluence ADHD susceptibility in current populations.Discussion: Overall, our results are compatible with athrifty-gene-like hypothesis such as the hunter-farmer the-ory, where some phenotypes related to ADHD (e.g. hyper-activity, impulsivity) may have been beneficial in the past ashunters but the change of lifestyle during the last 45 kyatowards farmers would have provided them as detrimentalin the new environment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.194

SU6. SYNERGISTIC EFFECT OF COMT AND KIAA0319GENES IN MODULATING ADHD BEHAVIORS

Weam Fageeran,1, Sarojini Sengupta1, Natalie Grizenko2,

Ridha Joober2

1McGill University2Douglas Institute, McGill University

Background: ADHD and Learning Disorder (LD) are com-plex disorders with genetic and environmental determi-nants. Twenty to 30% of the children with ADHD have anassociated LD. These problems usually persist into adoles-cence and are associated with chronic academic under-achievement and failure to complete school.Hypothesis: Given the evidence for overlapping heritabilitybetween ADHD and LD, we hypothesize KIAA0319, a geneassociated with LD, may interact with genes that haveshown to be implicated in ADHD. As proof of concept, wehave selected the COMT gene because of the well-docu-mented role of its Val/Met polymorphism in modulatingdopamine transmission in the frontal cortex. We alsoanticipated that the interaction betweenthese two genes would be more evident in the schoolenvironment.Methods: 400 children with ADHD (9–12 years old) wereincluded in a double-blind placebo controlled study withmethylphenidate. Teachers and parents were asked toevaluate the child's behavior at baseline, placebo, andMPH weeks using the appropriate version of Conners’ scale.The association between genotypes and ADHD behaviorswere tested using repeated measure ANOVA, the two geneswere the between-subject factors and the behaviors underthe three experimental conditions (EC), were the within-subject factor.Results: A highly significant 3-way interaction (KIAA0319n

COMTnEC) was revealed in two SNPs of the KIAA0319 gene(rs4504469 p= 0.006 and rs7766230 p= 0.004) only accord-ing to teachers. By stratifying the children according totheir COMT genotypes, we found that within the Met/Metgenotype group, there were no significant differences inConner's-T scores at baseline and on Placebo. However,significantly different patterns of response to MPH betweenKIAA0319 genotype groups were observed.Discussion: This is the first study identifying an interac-tion between a gene involved in LD and a gene implicated inADHD. This might help to individualize treatments forchildren with comorbid ADHD and learning disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.195

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69PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

SU7. BEYOND THE TRANSLOCATION: WHOLE GENOMESEQUENCING ANALYSIS OF THE SCOTTISH T(1;11)FAMILY

Niamh Ryan2, Jayon Lihm3, Melissa Kramer3,Shane McCarthy3, Kathryn Evans2, Elena Ghiban3,J. Kirsty Millar2, Generation Scotland2, Andrew McIntosh4,Douglas Blackwood4, Stephen Lawrie4, David Porteous2,W. Richard McCombie3, Pippa Thomson

n,1

1Institute of Genetics and Molecular Medicine2MRC Institute of Genetic and Molecular Medicine, Universityof Edinburgh3Stanley Institute for Cognitive Genomics, Cold SpringHarbor Laboratory4University of Edinburgh

Background: Psychiatric illnesses are a group of geneti-cally-related disorders with highly polygenic architectureand a significant environmental component. Even withinfamilies, these conditions show the attributes of manycomplex traits: reduced penetrance and phenotypic hetero-geneity. An extended pedigree design has several advan-tages: it avoids population stratification and reducesgenetic heterogeneity, narrowing the search for rare andfunctional variants that segregate with a phenotype. Wehave analysed a multigenerational pedigree where majormental illness segregates with a balanced translocationbetween chromosomes 1 and 11.Methods: Whole genome sequencing was performed on 49family members (20 carriers, 29 non-carriers of the translo-cation). Polygenic risk scores were calculated using summarystatistics from the PGC MDD 2011 and used to predictdiagnosis. Multipoint linkage analyses were performed usingthe variance components method implemented in SOLAR.Multiple phenotypic classes were used constructed to reflectthe multiple phenotypes within the family. Fine-mapping wasperformed using two-point linkage analyses across the linkedregions and association analyses performed in a Scottishcohort with measures of mental health, cognitive andpersonality traits (N= 6,555; 2,060 cases and 4,495 controls).Results: Two genome-wide significant peaks with LOD 45.5 were detected on the translocated chromosomes 1 and11 with maximum linkage to schizophrenia, bipolar disorder,recurrent major depression and cyclothymia; as previouslynoted for the translocation itself. In addition, two furtherpeaks, a second on chromosome 1 and a peak on chromo-some 5, showed genome-wide significant linkage to affec-tive disorder (bipolar disorder, and major depressivedisorder). Polygenic risk scores of schizophrenia and bipolardisorder, but not major depressive disorder significantlypredict mental illness in the family. Functional annotationof the whole genome sequence, and case-control associa-tion for affective disorder in the Scottish population,support a role for GRM5, CNTN5 and PDE4D in the pheno-typic heterogeneity seen in the family.Discussion: These results suggest that the high density ofpsychiatric illness in the t(1;11) family may be a combina-tion of: direct effects of the translocation on the geneslocated at the breakpoint (DISC1, DISC2, DISC1FP), “locking

together” of additional familial risk factors and the accu-mulation of common risk variants. We have identifiedadditional modifying loci that may explain the variance indisease expression. Our findings suggest that pleiotropy mayplay a significant role and that this is now tractable bywhole genome sequencing in families.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.196

SU8. MICROBIOTA FEATURES IN PARTICIPANTS WITHCHILDHOOD TRAUMA AMONG THE MAJOR DEPRESSIVEDISORDER AND HEALTHY CONTROLS

Li-Chung Chuangn,1, Yu-Chu Ella Chung2, Hsi-Chung Chen3,

Hsiang-Chin Lori Chou2, Meei-Shyuan Lee4, Yen-Hsuan Ni3,Wei-Liang Shih2, Po-Hsiu Kuo5

1Cardinal Tien Junior College of Health2College of Public Health, National Taiwan University3National Taiwan University Hospital4School of Public Health, National Defense Medical Center5National Taiwan University

Background: Early life stress is a significant environmen-tal factor for Major Depressive Disorder (MDD). Recentanimal studies have shown that the long-term effect ofearly life stress might influence the combination of intest-inal microbiota in the adult. The present study examinedthe association between early life stress and the microbiotafeatures in the fecal sample of adult participants.Methods: We recruited 7 MDD patients and 11 healthycontrols, and the Childhood Trauma Questionnaire was usedto examine the status of each dimension of childhoodmaltreatment. The fecal samples were examined by Illu-mina Miniseq or Miseq platform for 16 s rRNA sequencing ofmicrobiota features. Linear discriminant analysis effect size(LEfSe) was applied to test associations between early lifestress and microbiota.Results: We used the average score of sexual abuse by allparticipants as a cut-off point.

The abundance of Phascolarctobacterium, Deltaproteo-bacteria, Bilophila, Thiothrix, Thiotrichaceae, and Thiotri-chales significantly increased in the adult participants withchildhood trauma of sexual abuse. After adjusted for MDDstatus, the groups of microbiota still significantly increasedin abundance of Bilophila, Thiothrix, Thiotrichaceae, andThiotrichales.Discussion: The replication data with 15 MDD patientsand 25 healthy controls is underway. Our study revealed theassociation between the early life stress and the microbiotafeatures.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.197

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SU9. IDENTIFICATION OF GENES IN CHILD GENETIC RISKFOR ATTENTION DEFICIT/HYPERACTIVITY DISORDERTHAT INTERACT WITH MATERNAL DEPRESSIVE SYMP-TOMS IN PREDICTION OF INTERNALIZING PROBLEMS

Lawrence Chenn,1, Andrée-Anne Bouvette-Turcot1,

Elika Garg2, Thi Thu Thao Nguyen2, Patricia Silveira1,Josie Diorio2, Michael S. Kobor3, Kieran O'Donnell1,Michael Meaney1

1McGill University2Douglas Mental Health University Institute3University of British Columbia

Background: Maternal antenatal depression is associatedwith offspring socio-emotional problems. However, theimpact varies across the population such that some indivi-duals seem resilient. Genetic factors may define vulner-ability/resilience to the environment, effects that likelyspan many molecular pathways. Despite moderate successin candidate gene approaches, genome-wide approaches ingene-environment interactions (GxE) have been underexploited. We sought to identify genes and biological path-ways that moderate the relationship between MaternalAntenatal Depressive Symptoms (MADS) and child socio-emotional outcomes.Methods: Our sample included 190 mother-child dyadsfrom a Canadian longitudinal birth cohort. MADS wasmeasured with the Center for Epidemiologic Studies –

Depression Scale. Child socio-emotional outcomes weremother-reported at 5 years with the Child Behavior Check-list. We constructed Genomic Profile Risk Scores (GPRS)from the children's SNPs genome-wide that account forpolygenic risk for Attention Deficit/Hyperactivity Disorder(ADHD) based on risk information from the genome-wideassociations with ADHD by the Psychiatric Genomics Con-sortium and applied them in our GxE model. GPRS with thesmallest p-value in the GxE model was defined as the best-fit GPRS. SNPs constituting the best-fit GPRS were used in agenome-wide by environment association analysis follow-up. We used MetaCore to examine the enriched geneontology in a subset of SNPs in the GxE model with p-valuesless than .01.Results: GPRS moderated the relationship between MADSand child internalizing problems (po.05). A positive associationbetween MADS and internalizing problems was found only inchildren with high GPRS. Among the SNPs that were includedin the best-fit GPRS, 44 SNPs significantly interacted with MADSin predicting child internalizing problems after corrected formultiple testing (Benjamini & Hochberg FDR at 5%), includingrs2239032 in CACNA1C (p=2.11e-5), which is shared risk factorin major psychiatric disorders. The top genes underlying themoderating effect of the GPRS were enriched in processes suchas “neuron development” (p=1.56e-7) and “synapse organiza-tion” (p=5.58e-7), in molecular functions such as “inositol1,4,5-trisphosphate-sensitive calcium-release channel activity”(p=3.66e-4) and “retinoic acid receptor binding” (p=4.49e-4),and in pathway networks such as “synaptic contact”(p=1.12e-4), “synaptogenesis” (p=2.90e-4), “axonal guidance”(p=1.11e-3), “attractive and repulsive receptors” (p=3.80e-3),and “transmission of nerve impulse” (p=1.60e-3).

Discussion: We used the GPRS for ADHD to facilitate ourgenome-wide approach in examining GxE and identifiedgenes that have a moderating effect on the relationshipbetween MADS and internalizing problems in children. Theenriched biological pathways are implicated in axon devel-opment and synaptic functions, critically important in fetalneurodevelopment. These findings suggest that specificgenes involved in the biological framework for antenatalneurodevelopment can confer sensitivity or resilience to theinfluences of MADS on mental health.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.198

SU10. PHARMACOGENETIC TESTING HELPS TO REDUCEBENZODIAZEPINE AND SLEEP MEDICATION USE INPATIENTS WITH ANXIETY

Gwyneth Zai2, Clement Zai1, Arun Tiwari1, Sheraz Cheema1,Nicole King1, James L. Kennedy

n,1

1Centre for Addiction and Mental Health2Centre for Addiction and Mental Health, University of Toronto

Background: Despite evidence of public health concernsfor overuse of benzodiazepines and sleep medications in thepsychiatric population, reliable data on these prescribedmedication use remain unavailable. Prescription rates forsleep aids and benzodiazepines have grown significantlymore rapidly in the past decade than insomnia diagnoses(Moloney et al., 2011). Anxiety disorders were amongst themost frequent reason these medications were given becausebenzodiazepines can quickly relieve anxiousness and anxietyoften causes sleep disturbance where sleep medicationsmay be helpful to treat. The purpose of the study was todetermine whether psychiatric pharmacogenomic testingwill help reduce benzodiazepine and/or sleep medicationuse in patients who have an anxiety disorder.Methods: To evaluate whether the pharmacogenomictesting reduces the amount of prescribed benzodiazepineand/or sleep medication(s) used, we analyzed data from astudy. Individualized Medicine: Pharmacogenetic Assess-ment and Clinical Treatment (IMPACT) and identified 597participants with an anxiety disorder who have medicationsand follow-up data on symptom severity using the GAD-7questionnaire. We performed the analysis of variancerepeated measures test for a change in the GAD-7 symptomseverity scores and the McNemar's Test to compare the totalnumber of medication use.Results: The analyses showed that the pharmacogenetictesting resulted in significant improvement of anxietysymptoms (F=56.914, Po0.001) and significantly less ben-zodiazepine use (z=-4.632, Po0.001) but not sleep medi-cation use (z=-1.788, P=0.074).Discussion: Although the pharmacogenetic testing in thisstudy does not include guidance for benzodiazepines and sleepmedications, the use of the test can lead to more effective

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treatment of the underlying anxiety symptoms and may lead toa reduction in benzodiazepine and sleep medication use.

Disclosure: Assurex Health – Advisory Board, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.199

SU11. GENETICALLY PREDICTED GENE EXPRESSION INTHE BRAIN AND PERIPHERAL TISSUES ASSOCIATES WITHPTSD

Laura Huckinsn,1, Kiran Girdhar1, Amanda Dobbyn1,

Tanja Jovanovic2, Caroline Nievergelt3, Gabriel Hoffman1,Adam Maihofer3, Murray Stein3, Pamela Sklar4,Kerry Ressler5, Joseph Buxbaum1, Eli Stahl1,Nikolaos Daskalakis1, The CommonMind Consortium (CMC)6,PGC PTSD Working Group

1Icahn School of Medicine at Mount Sinai2Emory University School of Medicine3University of California, San Diego4Institute of Genomics and Multiscale Biology, Icahn Schoolof Medicine at Mount Sinai5McLean Hospital6The CommonMind Consortium

Background: Post-Traumatic Stress Disorder (PTSD) is adebilitating psychiatric disorder occurring in individualsexposed to trauma. To date, little is known about thegenetic aetiology of the disorder, although the latest GWAS(carried out by the PGC-PTSD working group) demonstratesthat genetic heritability is in line with other psychiatricdisorders. PTSD development involves multi-systemic dysre-gulation in multiple brain regions and diverse peripheraltissues. Some peripheral systems are particularly interestingsince epidemiologic evidence suggests that PTSD patientscommonly have cardiovascular, metabolic and immunedysregulation.Methods: Transcriptomic Imputation approaches usemachine-learning methods to impute gene expression fromlarge genotype data using curated eQTL reference panels.These offer an exciting opportunity to compare geneassociations across neurological and peripheral tissues.Here, we apply CommonMind Consortium (CMC) and Geno-type-Tissue Expression (GTEx) derived gene expressionprediction models to the PGC-PTSD data (9,245 cases/24,285 controls). Models included 12 brain regions, fivecardiovascular tissues, 2 endocrine tissues, the tibial nerve,adipose tissue and whole blood.Results: We identified 24 significant gene-tissue associa-tions, of which 5 were in peripheral tissues (adrenal gland,heart atrial appendage, tibial artery, tibial nerve). Westratified analyses according to trauma type (civilian vs.combat trauma), sex, and self-defined ancestry. Our threestrongest associations were identified in military cohortsonly, which supports the hypothesis that there is substantialgenetic heterogeneity between civilian and combat PTSDrisk.

We used the PsychENCODE neuronal and non-neuronal

reference map for two histone marks associated withtranscription and open chromatin (3-trimethyl-lysine 4(H3K4me3) and H3-acetyl-lysine 27 (H3K27ac) to understandpatterns of histone modification among our PTSD-associatedgenes. Preliminary analyses indicate a significant correla-tion between PTSD-association statistics and the presenceof both histone marks (correlation with neuronal H3K4me3,Pearson R=0.87, p=3.99� 10-5). We intend to expand thisanalysis to include a wider range of histone modificationmarks.Discussion: We will further expand these analyses toidentify tissue specific gene clusters and enriched pathwaysacross tissues or in specific tissues. Finally, we will useneuroimaging data and physiological cardiovascular data tofunctionally validate our results.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.200

SU12. HIGH-THROUGHPUT CHROMOSOMAL MICROAR-RAY ANALYSIS (CMA) IN A COLOMBIAN COHORT WITHAUTISM SPECTRUM DISORDERS

Claudia Lattign,1, Diana Nuñez1, Camilo Ospina2,

Francisco Paredes2, Andrea Lopez3

1Universidad de los Andes2Liga Colombiana de Autismo3Hospital Universitario Fundacion Santa Fe de Bogota

Background: Autism Spectrum Disorders (ASD) are neuro-developmental disorders that share difficulties in commu-nication, social interactions and stereotyped behaviors. ASDhas a heritability of 64 – 91% and near 10% of ASD patientshave large chromosomal rearrangements. Copy NumberVariations (CNVs), a type of chromosomal rearrangementscontributes to genomic disorders by disrupting functionalgenes, promoting loss of heterozygosity, disturbing imprint-ing regulation and changing gene expression by inherited,de novo and post-zygotic ways. Chromosomal MicroarrayAnalysis (CMA) is the standard genetic assessment used toevaluated intellectual disabilities and developmentaldelays, however careful interpretation of these results isessential for a correct genetic diagnosis.Methods: We analyzed 22 DNA samples by SNP 6.0 micro-array of Affymetrix, and .CEL files were calling withPennCNV software. To identify disrupted genes probablyassociated with ASD; we used 115 .CEL data files ofColombian population from public resources as 1000 Gen-omes Project. Careful consultation of public databases suchas UCSC genome Browser, DECIPHER and DGV was performedto determine if our results had been previously linked toneurodevelopmental disorders.Results: These analysis strategies led us to identify CNVs thatdisrupt known functional genes previously associated with ASDin 15 of 22 (68%) patients diagnosed with ASD. Among theseprobably pathogenic CNVs we found deletions and duplicationsfrom 50Kb – 5 Mb that disrupted 1 or more genes

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simultaneously. The main affected functions by disrupted genespresent in our patients were: DNA replication and reparation(CSNK1E), early development (NOTCH3), transcription regula-tion (MYT1L), vesicle transport (VPS13B), neuronal connections(SHANK3), metabolic process (GMPPA and PITPNA), cell-cellcontact (DLG5), and neurotransmitter transporter (SLC6A3),among others.Discussion: These results demonstrate the importance ofstudying these developmental disorders with high-through-put techniques and enrichment public databases to advancein the etiology knowledge of these disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.201

SU13. BIOTYPES IN AUTISTIC SPECTRUM DISORDERS:EXOME ANALYSIS IN 250 SPANISH TRIOS AND ITS RELA-TION WITH BIOMARKERS, CLINICAL MANIFESTATIONSAND NEUROPSYCHOLOGICAL VARIABLES

Javier Gonzalez-Peñasn,1, Alicia García-Alcón2,

Leticia Boada2, María Luisa Dorado2,Sandra Recio Lamparero2, María José Penzol2,Emiliano González-Vioque3, Javier Costas Costas4,Mara Parellada5

1Instituto de Investigación Sanitaria Gregorio Marañón2Hospital General Universitario Gregorio Marañón, Institutode Investigación Sanitaria Gregorio Marañón3Hospital Universitario Puerta de Hierro-Majadahonda,IDIPHIM4Instituto de Investigación Sanitaria (IDIS) de Santiago deCompostela, Complexo Hospitalario Universitario de San-tiago de Compostela (CHUS), Servizo Galego de Saúde(SERGAS), Santiago de Compostela5Hospital General Universitario Gregorio Marañón, Institutode Investigación Sanitaria Gregorio Marañón, UniversidadComplutense de Madrid

Background: Autism Spectrum Disorders (ASD) comprise aheterogeneous group of highly heritable (50%) neurodeve-lopmental disorders with a multi-factorial origin. Diagnosesof ASD is mainly based on i) deficiencies in social interactionand communication and ii) restrictive and repetitive beha-vioral patterns, interests or activities, including sensorialalterations. However, the diagnostic criteria has limited usein research field, as different subtypes have been identifiedwithin ASD.

In addition to important polygenic component, a greatvariety of single-gene disorders and chromosomal abnorm-alities have been described across latest genetic studies.Proper biological pathways and/or specific physiopathologi-cal mechanisms involved such as chromatin remodeling,glutamate/GABA balance or transcription processes havebeen identified as candidate gene sets enriched in deleter-ious rare, inherited and de novo variation.

Here we present phenotypic clusters identified from asample of well-characterized ASD trios. We describe

distinctive biological pathways involved and described typesof functional variation related with mentioned clusters.Methods: Our sample has 250 Spanish ASD trios recruitedat Hospital Universitario Gregorio Marañón. Demographic,clinical and neuropsychological variables were collectedfrom trio samples to perform cluster analysis with acombination of hierarchical and k-mean methodology. Gen-eral linear model was used to study association betweengenetic and phenotypic variables collected.

Exome from blood DNA was sequenced as part of theAutism Sequencing Consortium (ASC) dataset. ANNOVAR wasused for variant annotation from vcf files to filter rare (MAFo 0.1) and deleterious variation. We made use of a myriadof existent and recently published algorithms to describedfunctional, brain-expressed and intolerant variation.Results: ASD sample was exhaustively characterized, andclusters were defined according to several variables asIntellectual Disability (ID), developmental regression, psy-chiatric comorbility, gastrointestinal pathology or pro-infla-matory status. Distinctive patterns of protein-truncating,damaging missense, de novo, inherited ultrarrare or intoler-ant variation across identified phenotypic clusters werefound, affecting previously implicated gene sets as chromatinremodeling, synapse and immune-related pathways. Inter-estingly, in preliminary results we found a clear connectionbetween immune-affected cluster (defined by phenotype andbiomarkers) and intestinal membrane adhesion genes.Discussion: Through the study here presented, wedemonstrated enrichment of functional genetic rare varia-tion of distinctive nature across identified phenotypicclusters in our dataset, deepening previous findings inrelation with different entities within ASD.

We claim the usefulness of differentiate biologicalclusters with diagnosable attributes as this aim will notonly allow the establishment of stratification criteria forclinical purposes, but also improve decision making aboutpharmacological treatment choice and strengthen theimportance of early intervention therapies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.202

SU14. TRANSCRIPTOME ANALYSIS OF WNT7A-MEDIATEDGENE EXPRESSION IN HUMAN NEURAL PROGENITORCELLS DERIVED FROM CONTROL AND CHD8 HAPLOIN-SUFFICIENT INDUCED PLURIPOTENT STEM CELLS

Ping Wang, Ryan Mokhtari, Erika Pedrosa, Deyou Zheng,Herb Lachman

n

Albert Einstein College of Medicine

Background: CHD8 (Chromodomain Helicase DNA BindingProtein 8) codes for a member of the CHD family ofchromatin-remodeling factors and is one of the mostcommonly mutated genes in Autism Spectrum Disorders(ASD) identified in exome-sequencing studies. Loss of

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function mutations in the gene have also been found inSchizophrenia (SZ) and intellectual disabilities. We pre-viously reported RNA-seq analyses carried out on NeuralProgenitor Cells (NPCs), monolayer neurons and cerebralorganoids derived from control induced Pluripotent Stem(iPS) cells that were made haploinsufficient for CHD8 (CHD8+/-) using CRISPR-Cas9 gene editing. Several hundredDifferentially Expressed Genes (DEGs) were found in com-parisons between the CHD8+/- and isogenic controls (CHD8+/+), including a significant number of ASD and SZcandidate genes, such as the SZ and Bipolar Disorder (BD)candidate gene TCF4. Pathway analysis of DEGs showedenrichment for genes involved in Wnt-signaling. A number ofWnt receptors (members of the FZD family) and Wnt ligandswere differentially expressed, such as Wnt7A and itsreceptor FZD7, which were down-regulated in CHD8+/-NPCs.Methods: We tested the hypothesis that Wnt7A-mediatedgene expression is deficient in CHD8+/- NPCs by carryingout RNA-seq on two CHD8+/- lines and two controls,including the isogenic control sample. The NPCs weretreated with vehicle (control) or Wnt7A (1 microgram/ml)for 24 hours. Biological duplicates were prepared for eachsample. RNA was extracted and converted to cDNA forpaired-end sequencing. The RNA-seq reads were aligned tothe human genes annotated in the GENCODE database (v18).Gene expression levels were determined as transcripts permillion (TPM). Of the 12,898 expressed genes, with anaverage TPM 41 in either controls or CHD8+/� samples,DESeq. 2 was used to identify differentially expressed genes(DEGs) at false discovery rate [FDR] o 0.05. Functionenrichments for the DEGs were analyzed by the softwareDAVID (v6.8 Beta) and ingenuity pathway analysis (IPA).Results: We obtained 892 DEGs in the isogenic controlNPCs, from a comparison of the Wnt7A treated samples andcontrols, but only 410 among the CHD8+/- samples, sug-gesting a potential reduction in Wnt7A signaling in the CHD8+/- samples. Among the DEGs affected by Wnt7A in theisogenic controls, but not in CHD8+/- samples was TCF4.Pathway analysis showed that DEGs from the isogeniccontrols were enriched for Wnt-beta catenin signaling path-way and acute phase response signaling. In CHD8+/- NPCs,there was less enrichment of both. RNA-seq findings wereconfirmed for selected genes by quantitative real time PCR.Discussion: These preliminary findings suggest that CHD8haploinsufficiency can attenuate Wnt7A signaling. Wnt/β-catenin signaling plays a key role in brain development andin post-mitotic brain functions. Thus, the attenuation ofWnt7A-inducible genes in CHD8 haploinsufficient NPCs couldbe mediating some of the effects CHD8 loss-of-functionmutations have on brain structures and patient behaviors.Understanding the role of Wnt-signaling on neurodevelop-mental and neuropsychiatric disorders is important becauseof the insight provided on pathogenesis and from thetherapeutic perspective; canonical Wnt-signaling is a targetof lithium salts, for example. These preliminary studies arecurrently being expanded to include three additional con-trol and CHD8+/- NPC lines, and whether gene expressionchanges are affected by lithium.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.203

SU15. INTEGRATED WHOLE EXOME SEQUENCING ANDHOMOZYGOSITY MAPPING IDENTIFIES VARIANTS INKNOWN AND NOVEL AUTISM GENES INVOLVED IN NEU-RONAL MIGRATION AND ADHESION PATHWAYS

Swati Agarwalan,1, K.C. Shyamala2, Prakash Padakannaya1,

Nallur Ramachandra1

1University of Mysore2All India Institute of Speech and Hearing

Background: Genetic heterogeneity of autism makes itchallenging to identify the causal genes responsible for itspathogenesis. Although many genes are reported to beassociated with autism, recent studies report only a handfulof high confidence genes for autism. No disease genesaturation level is attained. There is a need to identifydamaging genomic variants which predispose an individualtowards autism manifestation.Methods: Whole Exome Sequencing (WES) is a reliabletechnique to identify DNA variants in the coding region ofthe genome. Based on stringent inclusion-exclusion criteria,the study recruited 50 autism subjects of Indian origin, ofwhich 13 were used for WES. PCR based Fragile X screeningwas performed to avoid the subjects with autism features.Results: Several damaging stop gain/loss mutationsencompassing autism genes CDH5, DDX23, CLDN5, andDPP3) were identified with protein truncations ranging from20–70%. These loss of function mutations disrupted impor-tant protein domains involved in various autism relatedpathways such as neuronal migration, synaptic pruning,synaptogenesis, and neuronal adhesion. Homozygosity map-ping analysis to identify risk homozygous haplotypes inprobands showed evidence of recessive polymorphisms inGIGYF1, SERPINE1, and EPHB6. These recessive alleles wereidentified across all the samples while polymorphisms inFOLH1, BCKDK, CDH11, and CTCF were specific to fewsamples. Mutations in language-specific genes, GCFC1 andMRPL19 were found associated with delayed speech lan-guage phenotype of autism. Several autism candidate genesWBP11, JMJD6, RBM8A, TRMT2A were identified.Discussion: A novel autism candidate gene CLDN5 thatphysically interacts with genes involved in various autismpathways was identified contributing to the phenotype.CLDN5 was found belonging to the leukocyte transendothe-lial migration pathway and elevated in autism cortex,impairing the blood brain barrier leading to compensatorygene expression and protein accumulation. This on-goingstudy identified several mutations specific for autism inIndian population, adding to the growing body of mutationalspectrum. The implications of these findings will be pre-sented and discussed.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.204

SU16. THE IMPACT OF CNVs ON ASD/ADHD RISK INMULTIPLEX FAMILIES

Sonja LaBiancan,1, Marcelo Bartalan1, Jette LaBianca2,

Thomas Werge1

1Research Institute of Biological Psychiatry, Mental HealthCentre Sct. Hans2Psychiatric Specialist Clinic, Lyngby

Background: Autism Spectrum Disorder (ASD) and Atten-tion-Deficit/Hyperactivity Disorder (ADHD) often co-occurwithin the same individual and/or family. High rates ofheritability are characteristic of both ASD (90%) and ADHD(76%), indicating a strong genetic component. Family studiesin clinical samples suggest 50–70% shared genetic risk factorsamong them. To date few large and rare Copy NumberVariants (CNVs) have been associated with ASD and impli-cated in ADHD. Several overlapping findings indicate pleio-tropic genes and shared biological pathways. In particularfamily studies are ideal for identification of segregatinggenetic variants such as CNVs and study their effect uponinherited traits. The aim of the study is to assess the impactof CNVs on ASD /ADHD risk in multiplex families.Methods: ASD/ADHD patients, affected and unaffectedrelatives were recruited from a Psychiatric Outpatient Clinic(POC) in Denmark. For all participants psychiatric data wasretrieved from the Danish National Health Registers anddiagnostic data of ASD/ADHD patients was collected fromthe medical journals at POC. Blood or saliva sample wascollected from all participants. Genotyping was performedon the ‘HumanOmniExpress-12v1-H’ microarray and OmniEx-press-24 v1.2 BeadChip at deCODE Genetics (Reykjavik,Iceland) and at the Infinium PsychChip v1.0 array at StatensSerum Institute (Copenhagen, Denmark). CNVs weredetected by the means of iPsychCNV and PennCNV.Results: In total 39 families were recruited including 277participants, among them 55 ASD/ADHD patients, 116affected relatives and 99 unaffected relatives. The geneticanalysis is ongoing. From the preliminary results, weobserve a higher burden of large and rare CNVs in ASD/ADHD patients than affected relatives and unaffectedrelatives. Among patients CNVs are more frequent in ASDand co-morbid ASD+ADHD patients than in ADHD patients.Previous ASD and ADHD risk loci were identified, several ofthem segregating among affected and unaffected relatives.Discussion: Our findings are consistent with others in thedemonstration that large and rare CNVs are more likely tooccur in patients, than unaffected relatives and in generalshow a stronger association to ASD than to ADHD. Further-more, our findings support the fact that other geneticfactors contribute to the inherited risk of ASD/ADHD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.205

SU17. ALTERED BRAIN CONNECTIVITY IN PATIENTSWITH 16P11.2

Clara Moreaun,1, Sebastian Urchs2, Simons Variation in

Individuals Project Consortium3, Alan Evans2,John D. Lewis2, Pierre Bellec1, Sébastien Jacquemont1

1University of Montreal2McGill University3Simons Foundation

Background: Copy Number Variants (CNVs) at the 16p11.2BP4-BP5 locus are among the most common genetic riskfactors associated with neurodevelopmental disorders [1].Deletion (DEL) have been associated with Autism SpectrumDisorder (ASD) and Duplication (DUP) with Schizophreniaand ASD. Voxel-based morphometry studies have revealed arobust association between the number of 16p11.2 genomiccopies and global brain volume, as well as regional struc-tural changes in key areas of the reward system, languagecircuitry and social cognition [2].

Our goal is to examine the effect of 16p11.2 CNVs onfunctional brain organization and its relationship withalterations in brain structure.Methods: This study was conducted in a cohort of 2016p11.2 DEL carriers, 19 DUP carriers and 74 controls (CON)[3]. Mean age was 23.8 yrs714.9. Resting-state fMRI andstructural scans were acquired at two sites on Siemens 3 TTIM Trio scanners using the same sequences (EPI: TR=3000;TE=30; scan time=06:12, flip angle=90). fMRI data werecorrected for slice timing and subject motion and registeredto MNI space [4] using the NIAK pipeline [5]. Timepoints withexcessive head-motion (4 0.5mm) were removed [6].Subjects with low time points (o 40), poor T1 quality orpoor T1/EPI coregistration were excluded. Nuisance covari-ates were regressed and data were smoothed (6mm FWHM).

Pairwise functional connectivity was estimated as thecorrelation between the average time series of 64 brainregions [7]. We then fitted a linear model to each connec-tion with the CNV status, subject motion, sex and recordingsite as explanatory factors. Differences between CNV statusgroups were then tested by post-hoc contrasts. Each con-trast was controlled for false discovery rate (FDR) across allconnections at q o 5% [8,9]. We report regions for whichmore than 2 connections survived FDR.Results: Connectivity of regions in the basal ganglia,medial temporal gyrus and precuneus showed significantdifferences for the DEL vs CON, and DEL vs DUP contrasts.

Specifically, connections among basal ganglia regions(caudate, thalamus, putamen) and between basal gangliaregions and superior and inferior temporal gyri showedsignificant overconnectivity in DEL group compared to both

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CON and DUP. Finally, connections between the caudate,superior frontal gyrus and inferior parietal lobule werefound to be stronger in DEL than DUP. No significantdifferences of functional connectivity were found for theDUP vs CON contrast. We examined in a larger normativedataset whether changes in global brain volumes maymediate these changes but found no relationship betweenbrain volume and connections altered in deletion carriers.Discussion: Our results are concordant with previousfindings of structural brain alterations in 16p11.2 DELcarriers. Striato-striatal and striato-cortical over-connectiv-ity in the DEL carriers is consistent with previous reports ofaberrant functional connectivity in ASD [10].

As previously observed the effect size of the duplicationon brain structure and cognitive traits is smaller than theeffects of the deletion. A larger sample size is likelyrequired to observe the changes in connectivity associatedwith the duplication.

1. 10.1038/nature13908

2. 10.1038/mp.2014.145

3. 10.1016/j.neuron.2012.02.014

4. 10.1016/j.neuroimage.2010.07.033

5. niak.simexp-lab.org

6. 10.1016/j.neuroimage.2011.10.018

7. 10.6084/m9.figshare.1285615

8. www.jstor.org/stable/2346101

9. 10.1016/j.neuroimage.2015.07.071

0. 10.1016/j.biopsych.2010.10.029

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.206

SU18. INVESTIGATING SHRINKAGE METHODS TOIMPROVE ACCURACY OF GWAS AND PRS EFFECT SIZEESTIMATES

Yunfeng Ruann,1, Shing Wan Choi2, Paul O'Reilly1

1King's College London2The University of Hong Kong

Background: As the scale and power of GWAS haveincreased to detect the small genetic effect sizes involvedin complex polygenic traits, the results of GWAS, especiallySNP effect size estimates, are increasingly utilised forprediction. A popular approach is the application of Poly-genic Risk Scores (PRS). However, the effect size estimatesare inherently prone to overfit the specific samples on which

the GWAS were performed (e.g. “the Winner's Curse”). Theinflation of effect size estimation reduces the out-of-sampleaccuracy of prediction based on GWAS results. Many shrink-age methods have been developed to correct for suchinflation. As GWAS results and large individual genotypedata sets become widely available, there is greater oppor-tunity to accurately evaluate effect size inflation andcompare the performance of different shrinkage methods.Methods: We develop a novel permutation-based shrink-age method and compare its performance with previouslydeveloped methods based on local false discovery rate andthe LASSO. We evaluate the performance of the methodsacross a wide range of phenotypes and investigate differentfactors (e.g. phenotype heritability) that influence theirimpact on the predictive power of polygenic risk scores.Results: Using large-scale real genotype data, we showthat SNP effect sizes are markedly overfit even in relativelylarge samples, but that our permutation-based shrinkageapproach can improve PRS prediction dramatically.Discussion: Our results suggest that GWAS results can beadjusted using an efficient empirical approach to providemore accurate effect size estimates and thus greaterdownstream predictive power. This approach could beapplied to a wide variety of big data settings.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.207

SU19. FROM FUNCTIONAL TO CAUSAL GENOMICS - ONTHE DIRECTED INTERACTIONS IN A GENE CO-EXPRES-SION NETWORK UNDERLYING OBSESSIVE COMPULSIVEDISORDER

Natalia Bielczykn

, Joanna Widomska, Jan Buitelaar,Jeffrey Glennon, Geert Poelmans

Radboud University Nijmegen Medical Centre

Background: The gene-gene associations in functionalgenomics are typically operationalized through correla-tional or information-theoretical measures: as an undir-ected graph of pairwise interactions between genes, wherenodes represent genes and edges represent associationsbetween pairs of genes. Such a functional connectivity canbe uninformative as expression of genes tend to be verydensely correlated. Moreover, functional connectivity doesnot contain information about the causal, or directed,interactions between genes. Causal inference would allowto answer the question whether phenotypes are a product ofmultiple gene-gene interactions or rather, if there areepicentres in the genome, leading to the phenotypes byinfluencing a number of genes in the network.Methods: We use open-access data from study by Jaffeet al. (2014), reporting the expression of genes within theDorsolateral Pre-Frontal Cortex (DLPFC) in post-mortemhumans. We selected the data from 239 genes that werefound to be associated with Obsessive Compulsive Dis-order (OCD) in this study, as well as a random selection of

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239 genes that were not found to be associated with OCD.In order to avoid confounders, we only consider thecontrol cohort of N=102 participants. The data werenormalized using log-transform, first gene-wise and thensubject-wise.

The method is based on definition of causality (Pearl,2000): if a high expression level in gene 1 is associated withhigh functional link between gene 1 and gene 2, we can inferthat gene 1 has certain causal effect on gene 2. This influencecan be established by windowing the data. The confidenceintervals are then computed through permutation testing.Results: The results demonstrate that, as opposed tofunctional connectivity, the directed connectivity clearlydifferentiates gene co-expression network associated withOCD from an exemplary co-expression network unrelatedwith OCD. Although inhibition in the network is potentiallypossible (as influence of a value lower than zero), it was notfound. The highest significance was found for the following:MED9 -4 SLC25A3, MED9 -4 RALB, CTSZ -4 GAD1, RGS7 -4DOK1, DCLK1 -4 C6ORF57. These results are interestingsince MED9 takes part in creating new mRNA, therefore itsincrease can indeed influence the transcription of newmRNA.

Also, most connections appear relatively symmetrical,although symmetry is now imposed by the method. How-ever, one particular gene, Calcium/calmodulin-dependentprotein kinase type II subunit beta (CAMK2B), has substan-tially higher influence on the most of the other genes in thenetwork than the feedback influence of these genes onCAMK2B. This suggests that CAMK2B might be a key compo-nent of the gene-expression network underlying OCD.Discussion: Classic interventional studies can be proble-matic in causal research in the gene co-expression networksas often dozens to thousands of genes underlie one pheno-type. In this work, we propose a framework which addressesthis issue and quantifies causal interactions without theneed to employ any experimental manipulation. This canhelp in understanding hierarchy in gene co-expression net-works, and possibly, in localizing the genes lying at thebeginning of a causal chain leading to a particular pheno-type. The method proposed in this study is novel, model-free and nonparametric, and the preliminary results whenapplied to the gene co-expression network of OCD in DLPFCare very promising. Therefore, we believe that it should befurther tested, and validated in larger cohorts.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.208

SU20. FUNCTIONAL LD CLUMP ENRICHMENT TEST(FLEET) DETECTS ENRICHMENT OF RISK LOCI FORSCHIZOPHRENIA AND BIPOLAR DISORDER IN REGULA-TORY ELEMENTS AND PATHWAYS

Jonathan Hessn,1, Stephen J. Glatt2

1SUNY Upstate Medical University

2Medical Genetics Research Center, SUNY Upstate MedicalUniversity

Background: Genome-Wide Association Studies (GWASs)provide a wealth of information that can serve as a back-bone for making biological inferences. There are over 160loci reported with genome-wide significant association withSchizophrenia (SZ) and Bipolar Disorder (BD), and thousandsmore nominally associated loci that contribute to risk(Purcell et al., 2009; Welter et al., 2014). SNPs with thestrongest association to SZ and BD are predominately in non-coding DNA, thus it is often challenging to decipher thefunction of risk SNPs. Functional and regulatory maps fromthe ENCODE and Roadmap projects offer detailed annota-tions of the genome, which can help bridge the gap betweenGWAS signals and biological mechanisms. We present a newsoftware tool called Functional LD-clump EnrichmEnt Test(FLEET) to decode the underlying biology of GWAS signalsvia overlaying information from the ENCODE and RoadmapProjects. Possible utilities of this software include: prior-itizing risk genes for fine-mapping, illuminating potentialregulatory mechanisms that underlie susceptibility, andidentifying molecular substrates that are common to psy-chiatric disorders.Methods: FLEET is available for download on Github(https://github.com/hessJ/FLEET). FLEET is currentlyadapted as a modular script written in R and is under activedevelopment. Users must supply a file of genome-wideassociation summary statistics and modify a few flags inFLEET to run the analysis properly. FLEET performs datareformatting, GWAS pruning, SNP-to-annotation mapping,statistical analyses (i.e., weighted linear regression andpermutations), and plotting of results.Results: GWAS results of SZ (Ripke et al., 2014) and BD(Hou et al., 2016) revealed widespread associations withhistone markers and DNA accessibility in brain, immune andother peripheral tissues. In addition, significant enrichmentwas detected for gene sets that participate in neurotrans-mission and neurodevelopment, histone modificationenzymes, and target sites of transcription factors, micro-RNAs, and RNA-binding proteins.Discussion: Our software provides unique insight intothe underlying biology of SZ and BD risk signals and aframework for hypothesis generation. FLEET is a flexibleand efficient pipeline for analyzing biological relation-ships among GWASs of complex polygenic disorders.FLEET is capable of modeling genome-wide enrichmentstatistics and performing permutation tests on top GWASmarkers; both tests include adjustments for confoundingvariation (i.e., LD and minor allele frequency). Thissoftware is included with a pre-formatted database of45,800 annotations, and users can provide customannotations for analysis.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.209

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SU21. INTEGRATED ANALYSIS OF MICROARRAY ANDPROTEOMICS DATA BY HIPPOCAMPAL RAT NEURONSAND HUMAN IPS NEURONS TREATED WITH DIFFERENTDOSES OF LITHIUM

Vanessa De-Paulan,1, Orestes Forlenza2, Wagner Gattaz2,

Martin Schalling3, Carlos Villaescusa3, Homero Vallada4,Helena Brentani5

1University of Sao Paulo2Laboratory of Neuroscience (LIM-27), University of Sao Paulo3Karolinska Institutet4Karolinska Institutet, Center for Molecular Medicine5Institute of Psychiatry HCFMUSP

Background: Lithium salts have a well-established role inthe treatment of psychiatric disorders as major affectivedisorders and more recently Alzheimer disease. Experimentaland clinical studies have provided evidence that lithium mayexert neuroprotective effects at therapeutically and sub ther-apeutically doses. In animal model and cell culture models,lithium has been shown to increase neuronal viability through acombination of mechanisms that includes the inhibition ofapoptosis, regulation of autophagy, increased mitochondrialfunction, and synthesis of neurotrophic factors.Objective: The Objective of the study is to compare biologicalprocess and pathways enriched in hippocampal neurons treatedwith different doses of lithium (0.02 mM, 0.2 mM and 2 mM)integrating genes and proteins differentially expressed.Methods: Primary cultures of hippocampal neurons;Assessment of cell viability; Experimental design considera-tions, Microarray; LC-MS analyses; Data Analysis; Neuralstem cell differentiation in Random differentiation; StringDatabase and Functional enrichment analysis.Results: The results showed that growing gene networksusing differentially expressed genes and proteins as seedsalterations in mitochondria, ribosome and proteasome wereobserved in all lithium treatment doses. But also morespecific biological process such as mitochondria respiratorychain, energy production (glucose and ATP) and apoptosisbiological functions were enriched in each dose treatment.Discussion: Given all the analyzes we can see that thereis a dissociation dose effect of the treatment with lithium,the dose of 0.02Mm modified genes of degradation pathwayproteins. The dose of 0.2Mm altered pathways of energymetabolism and the dose of 2Mm change related to nuclearand nuclear membrane. we can understand the specificfunction of each dose of the treatment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.210

SU22. BIVARIATE GAUSSIAN MIXTURE MODEL FOR GWASSUMMARY STATISTICS

Oleksandr Frei2, Olav Smelandn,1, Dominic Holland3,

Alexey Shadrin2, Wesley Thompson3, Ole Andreassen2,Anders Dale3

1Oslo University Hospital2University of Oslo3University of California, San Diego

Background: Identifying shared genetics is important asit uncovers hidden relationship between complex traits andimproves our understanding of disease etiology. Todaygenetic correlation is commonly used as the principalmeasure that quantifies genetic overlap. Available methodscan calculate genetic correlation from raw genotypes(restricted maximum likelihood, polygenic risk scores), froma set of Single-Nucleotide Polymorphisms (SNPs) that passgenome-wide significance threshold (Mendelian Randomiza-tion), or utilizing all data from Genome Wide AssociationStudies (GWASes) including SNPs that do not reach genome-wide significance (Cross-Trait Linkage Disequilibrium (LD)Score Regression). These methods for evaluating geneticoverlap are unable to capture a mixture of effect directionsacross shared genetic variants (i.e., only reporting overallpositive, negative or no genetic correlations), while recentanalyses suggest that correlation across polygenic traits inthe effect size and directionality of a SNP is not the sameacross all SNPs.Methods: Bivariate Gaussian Mixture Model provides anovel way to detect and quantify shared genetics indepen-dently from genetic correlation. In the absence of geneticcorrelation we use another measure of polygenic overlap,expressed as the proportion of SNPs associated with bothtraits. To estimate this quantity, we model true per-SNPeffect sizes as a mixture of four bivariate normal distribu-tions: two causal components specific to each trait, onecausal component of SNPs affecting both traits, and a nullcomponent of SNPs with no effect on either trait. Weinterpret the weight of each component in the mixture asthe proportion of SNPs in that component. The parametersof the mixture model are estimated from the summarystatistics data by direct optimization of the maximumlikelihood. Our statistical model relates observed signedtest statistics (GWAS z-scores) to the underlying per-SNPeffect sizes, incorporating effects of LD structure, minorallele frequency, sample size, cryptic relationships / samplestratification, and sample overlap, to capture all theseeffects on GWAS z-scores.Results: We show in simulations that our model differ-entiates cases with no polygenic overlap versus cases withsignificant overlap in the absence of genetic correlation. Weshow genetic overlap between schizophrenia, waist-hip-ratio and triglycerides, despite the fact that geneticcorrelation is close to zero. We apply our model to schizo-phrenia, bipolar disorder and IQ data, and show that in thepresence of genetic correlation our model reports consis-tent results with those from cross-trait LD score regression.Discussion: It appears to be a common practice to inter-pret the lack of genetic correlation as no relation betweentraits. However, lack of correlation does not necessarilyimply independence - a fact well known from statistics.Thus, we advocate that certain important cases of geneticoverlap are not captured by genetic correlation.

Our model quantifies genetic overlap between traits bothwith and without genetic correlation. It controls for the factthat if both traits are highly polygenic then some proportion

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of SNPs is associated with both traits by chance or due to LDstructure. In addition to the insights into genetic architec-ture our model can improve SNP discovery, by estimatingposterior effect size of one trait given observed GWASz-score in another trait. Further, more accurately estimatedeffect sizes can be used for improving polygenic risk scores.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.211

SU23. ASSOCIATIONS OF POLYGENIC RISK OF SCHIZO-PHRENIA AND MAJOR DEPRESSION IN STUDIES OFBIPOLAR DISORDER AND MAJOR DEPRESSION

Cathy Schaefern,1, Khanh Thai1, Eric Jorgenson1,

Yambazi Banda2, Thomas Hoffmann2, Mark Kvale2,Neil Risch2

1Kaiser Permanente Division of Research2University of California, San Francisco

Background: Large Genome-Wide Association Studies(GWAS) have identified common genetic variants that under-lie Schizophrenia (SCZ) and Major Depressive Disorder(MDD), although Bipolar Disorder (BD) remains elusive. Crossdisorder analysis has shown a strong genetic correlation ofSCZ with BD, with modest correlations of SCZ with MDD, andMDD with BD. We used polygenic risk scores to examineshared genetic variation among disorders and to dissect thegenetic contribution to shared clinical features, such aspsychotic symptoms.Methods: Participants from the Kaiser PermanenteResearch Program on Genes, Environment, and Health(9,080 MDD cases; 54,808 controls) and a multi-ethnic GWASof bipolar 1 disorder (BD1) (5,056 cases; 54,808 controls)were genotyped on the Affymetrix Axiom system, usingancestry-specific arrays, and the data imputed to the 1000Genome Project (March 2012 release). We calculated stan-dardized polygenic risk scores for SCZ (SCZ-GRS) and MDD(MDD-GRS) as the weighted sum of risk alleles using 128SNPs and 47 SNPs that were significantly associated with SCZand MDD, respectively, in independent GWAS. Two SNPswere common to both scores. Logistic regression analyses ofthe association of SCZ-GRS and MDD-GRS with BD1 and MDD,separately, included gender, age, and principal componentsfor adjustment of ancestry. Analyses were conducted sepa-rately in race-ethnicity groups and by gender.Results: The SCZ-GRS and MDD-GRS were significantly andindependently associated with BD1 in non-Hispanic whites(3,725 cases, 52,430 controls) in an analysis including both(Odds Ratio (OR)-MDD-GRS=1.138; 95% CI=1.099, 1.178;p= 2.646� 10–13; OR-SCZ-GRS=1.146 95% CI=1.107,1.187; p= 1.241� 10–14), with similar results in the smallersamples of minorities, and in men and women. There was nointeraction between the scores. Among BD1 cases, the SCZ-GRS was significantly associated with psychotic symptomsand hospitalization for BD; the MDD-GRS was also modestlyassociated with psychotic symptoms and nominally with

rapid cycling of moods, a hallmark of BD.In analyses of MDD in non-Hispanic whites (7,833 cases;

43,581 controls), the MDD-GRS was significantly associatedwith MDD (OR=1.147; 95% CI=1.119,1.176; p=3.13� 10–27), but the SCZ-GRS was not (OR=1.017; 95% CI=0.992,1.042; p=0.189). Similar results were found in race-ethnicminorities, and in men and women. There was no interac-tion. Neither the MDD-GRS nor the SCZ-GRS was associatedwith hospitalization or psychotic symptoms in MDD,although the prevalence was much lower in MDD than BD.Discussion: BD has both cognitive and affective compo-nents, most often including depressive episodes like those inMDD, but also frequently including psychotic symptoms, asdoes SCZ. The independent association of the MDD-GRS andSCZ-GRS with BD1 suggests that different genetic variantsmay contribute to the cognitive and affective clinicalfeatures of BD. In this study, genetic variation associatedwith SCZ was not associated with MDD, or with psychoticsymptoms in MDD. Identification of genetic variation thatinfluences specific disorders and specific features of dis-orders increases knowledge about the genetic etiology ofdisorders and may contribute to understanding the under-lying biology of disorders and identification of new targetsfor treatment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.212

SU24. POTENTIAL ALTERATIONS IN LEUKOCYTE MITO-CHONDRIAL DNA COPY NUMBER FROM PATIENTS WITHBIPOLAR DISORDER TYPE I

Euijung Ryun,1, Gregory Jenkins1, Jared Evans1,

Ana Andreazza2, Marquis Vawter3, Susan McElroy4,Mark Frye1, Joanna Biernacka1

1Mayo Clinic2University of Toronto3University of California, Irvine4Lindner Center of HOPE

Background: Mitochondrial dysfunction has been welldocumented in patients with Bipolar Disorder (BD). Studiesdemonstrated that alternations in mtDNA copy number havebeen associated with mitochondrial dysfunction and increasedoxidative stress. However, association between mtDNA copynumber and BD compared to controls has been inconclusive sofar. In this study, we aimed to assess whether mtDNA copynumber is altered in BD type I (BDI) compared to controls. Wealso explored whether the total number of heteroplasmicSingle Nucleotide Variants (SNVs) for a given subject, anothermarker for oxidative stress, is altered in BDI.Methods: One hundred BDI patients were selected forWhole Genome Sequencing (WGS) experiment using leuko-cyte DNA from the Mayo Clinic Bipolar Disorder Biobank. Inaddition, 1000 patients from the Mayo Clinic Biobank, acontrol biobank, were also selected for the experiment.After applying basic quality control filtering (e.g., low

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sequencing coverage and sample contamination) to nuclearDNA sequencing data, this study used 99 BD1 patients and961 controls. MtDNA copy number was defined as therelative quantity of mtDNA compared to nuclear DNA. Foreach SNV, likelihood functions were estimated under twomodels (heteroplasmy and homoplasmy) taking into accountsequencing error, and log-likelihood ratio (LLR) was calcu-lated. The total number of heteroplasmic SNVs for a givensubject was calculated by counting the sites with LLR Z 5.Adjusting for age and sex, regression models were used totest the association between BD status and mtDNA copynumber and the total number of heteroplasmic SNVs afterlog-transformation.Results: BDI patients were younger compared to controls(median age at the biobank enrollment: 45 in BDI vs 61 incontrols) with more females in cases (60% vs 50%). Overall,older age and male sex were associated with lower mtDNA copynumber (P o 10-4). The total number of heteroplasmic SNVswas slightly higher with older age (P=0.041). The medianmtDNA copy number was 84.7 (25th – 75th percentile: 75.2 –

99.6) in BDI and 88.7 (77.6 – 100.6) in controls, respectively.Adjusting for age and sex, the mtDNA copy number wasmarginally lower in BDI patients compared to controls(P=0.055). The total number of heteroplasmic SNVs was similarbetween cases and controls (median: 21 for both groups).Discussion: This small study potentially supports recentfindings on a slight decrease in mtDNA copies among BDI andmore copies in females. This study also shows that mtDNAcopy number decreases with age, while the degree ofheteroplasmy increases. Although the underlying mechanismfor this observation is not clear, it may reflect mitochondrialDNA replication and degradation due to mitochondrial dys-function and premature cellular senescence in BD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.213

SU25. TARGETED NEXT GENERATION SEQUENCING OF187 GENES IN A BULGARIAN PSYCHOSIS SAMPLE

Radka Kanevan,1, Ivan Popov2, Olga Beltcheva1,

Mladen Penchev3, Gyulnas Dzebir2, Elliot Rees4,Radosveta Bozhilova2, Vesela Stoyanova3, Vanyo Mitev2,Michael Owen5, Michael O'Donovan5, George Kirov5,Vihra Milanova3

1Medical University of Sofia2Molecular Medicine Center, Medical University of Sofia3Alexandrovska University Hospital, Medical University ofSofia4Cardiff University5MRC Centre for Neuropsychiatric Genetics and Genomics,Cardiff University

Background: There is strong evidence for partial overlapof genetic influence on Schizophrenia (SCZ), SchizoaffectiveDisorder (SAD) and Bipolar Affective Disorder (BAD). Part of

this is due to common genetic variants, detected by GWAS,with a small individual effect on risk. Recent studies usingnext generation sequencing reveal growing evidence of therole of rare genetic variants in both diseases. We performedtargeted NGS on 187 candidate genes to further investigatethe genetic architecture of Bulgarian patients with bipolardisorder and schizophrenia.Methods: A total of 300 individuals with BAD, 151 withSCZ, 15 SAD according to DSMIV and ICD-10, as well as 85healthy population controls and 40 healthy relatives wererecruited. The samples were sequenced on the Ion PROTONplatform. The sequencing panel comprised of 187 prese-lected strong candidate genes, based on the results fromGWAS and previous NGS studies. Only samples with coverageof at least 95% of the target region at 20x were included inthe analyses. Case-control association testing was doneusing PLINK. The rare variants have been evaluated anddivided into groups based on their functional relevance: LOFvariants (frameshift and nonsense); with potentially dama-ging effect on protein function (splice site, missensevariants, 3’-UTR/5’-UTR variants); and with no knowneffect on function (synonymous and intron variants). Geneswere prioritized by mutation burden analysis based on theaverage number of functional occurrences per 1000 bp ofthe gene CDS. The RVIS scoring system for assessing theintolerance of individual genes to protein-altering variants(Petrovski et al., 2013) was used in conjunction with theburden score for the final ordering.Results: 5373 variants were detected, of which 2826 werefound in affecteds (1831 singletons and 995 recurrent). Nosignificant associations between cases and controls could bedetected, that survived the correction for multiple testing.In total we found in patients 14 rare LOF variants; 889 non-synonymous variants (243 of which were potentially dama-ging); 109 splice site variants and 32 in regulatory regions.Discussion: We could find no significant association ofcommon or rare variants in the analyzed samples, mostlikely due to small sample size. However, we could identifyboth recurrent and singleton rare variants with potentialfunctional relevance in genes associated with ion channels,postsynaptic plasticity, neurogenesis and signalling cascadepathways.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.214

SU26. A WHOLE GENOME SEQUENCING STUDY IDENTI-FIES A RARE VARIANT IN ANK3 THAT MAY CONTRIBUTETO BIPOLAR DISORDER

Joanna Biernackan,1, Gregory Jenkins1, Shannon McDonnell1,

Anthony Batzler1, Hugues Sicotte1, Zachary Fogarty1,Benjamin Welkie1, Saurabh Baheti1, Brandon Coombes1,Susan McElroy2, Mark Frye1

1Mayo Clinic2Lindner Center of HOPE

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Background: Over the last decade, a growing number ofGenome-Wide Association Studies (GWAS) have been per-formed to identify common genetic variation that contri-butes to Bipolar Disorder (BD). These studies have identifieda number of genes harboring common risk variants, and alsodemonstrated that BD has a highly polygenic geneticarchitecture, with many loci with small effects contributingto the disease. The contribution to risk of BD from rarevariants is still not well understood, and whole exome andWhole Genome Sequencing (WGS) studies of BD are onlybeginning to emerge. Here, to investigate the role of rarevariants with potentially greater effect sizes, we used WGS.Methods: WGS was performed for 100 BD cases from theMayo Clinic Bipolar Disorder Biobank and 1000 healthycontrols from the Mayo Clinic Biobank. Following bioinfor-matics processing and genotype calling, Quality Control(QC) was performed. We excluded samples with low cover-age or call rate, failed sex check, sample contamination orrelatedness. We excluded variants with low call rate, failedHWE test, or failed Variant Quality Score Recalibration(VQSR). After QC, 99 cases and 961 controls with 426million Single Nucleotide Variants (SNVs) with Minor AlleleFrequency (MAF) r0.05 remained; sub-setting to anno-tated non-multiallelic variants within genes resulted in411million SNVs for analysis. Rare variant gene-level testswere performed using two approaches: (1) burden test ofnonsense mutations and missense mutations predicted to bedeleterious by SIFT and PolyPhen2; (2) SNP-set kernelassociation test (SKAT) of all variants with MAF weights.We a priori selected 7 genes implicated in BD by GWAS forprioritized analysis: CACNA1C, ODZ4, ANK3, TRANK1,LMAN2L, NCAN, and SYNE1.Results: After restricting analyses to genes in which Z4subjects carried variant alleles, 8,242 genes were analyzedby the burden test, and 25,833 genes were analyzed usingSKAT. Neither of these gene-level testing approaches iden-tified genome-wide significant associations. Among thepreviously implicated candidate genes, only ANK3(p=0.011) and SYNE1 (p=0.006) were associated with BDat a nominally significant level in the burden and SKATanalyses, respectively. In ANK3, the 9 SNVs analyzed by theburden test were observed in 6/99 cases and 18/961controls; the association result was driven primarily byrs148904927, a SNV that was observed in 5 (5%) cases and7 (0.7%) controls [OR (95%CI)=7.2 (2.3–23.3)].Discussion: This pilot WGS study suggests that rare var-iants in ANK3 and SYNE1 may contribute to BD. The ANK3SNV (rs148904927) that we observed in 5% of the cases (and0.7% of controls) is a non-synonymous variant (Ser2409Pro)that may function by modifying the isoforms of ANK3(Ankyrin G), an integral membrane protein that is modu-lated during developmental stages and is associated withseveral neuronal dysfunction disorders. According to Hap-loReg v4.1, Regulome DB, and the UCSC genome browser,this SNV is highly conserved and disrupts multiple bindingfactor motifs. This SNV is located in the most prominentcandidate regulatory element of ANK3 in a DNAse hyper-sensitivity site enriched with regulatory histone mark(H3K27Ac), both features often associated with regulatoryelements. This regulatory element overlaps a large alter-native splice coding exon, suggesting that the variant mayoperate via regulation of transcription levels or isoform.

Replication and functional studies are warranted to furtherinvestigate the role of this variant.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.215

SU27. MOOD STABILIZERS IMPROVE CELL VIABILITY ANDMITOCHONDRIAL MEMBRANE POTENTIAL IN VITRO

Pradip Pauln

, Rashmitha Nayak, Ravikumar Nadella,Somdatta Sen, Biju Viswanath, Meera Purushottam,Preeti G. Joshi, Y.C. Janardhan Reddy, Sanjeev Jain

National Institute of Mental Health and Neurosciences

Background: Lithium and valproate are the first line ofdrugs to treat Bipolar Affective Disorder (BPAD). The role ofmitochondria in BPAD pathophysiology has often beeninvestigated. The current study aims to explore the effectsof lithium and valproate on cell death and mitochondrialmembrane potential using Lymphoblastoid Cell Lines (LCL)model.Methods: The patients were recruited from outpatientservices of NIMHANS, Bangalore. The blood sample for LCLgeneration using Epstein Barr Virus transformation wasobtained from BPAD patients (N=25) and healthy controls(N=11) after obtaining informed consent. The healthycontrols were ethnically matched and selected randomly.Lithium response was assessed for the BPAD subjects using“Retrospective criteria of long term treatment response inresearch subjects with bipolar disorder” for whom NIMH lifecharts were available. Score Z 7 were considered asresponders (N=14) and score o7 as non-responders(N=10).

For the experiment, 5 million cells were treated withmedium containing lithium (1 mM) or valproate (0.7 mM) for7 days. On the 8th day, one million cells were taken for flowcytometric analysis after incubation with the indicator dyes:Sytox Green (an indicator of dead cells) and MitotrackerDeep Red (an indicator of mitochondrial membrane poten-tial; MMP). The experiments were performed in triplicates.FlowJo software was used for flow cytometry analysis andappropriate statistical analyses were performed.Results: At baseline, the population of dead cells wassignificantly higher in BPAD LCLs (po0.01) compared tocontrols. On treatment of these LCLs with lithium orvalproate, a significant reduction in the percentage of deadcells was observed.

The Mitochondrial Membrane Potential (MMP) was sig-nificantly lower in BPAD LCLs (po0.05) compared to con-trols at baseline. On treatment with mood stabilizers, foldchange in the percentage of cells with high MMP wasincreased significantly in BPAD LCLs. Furthermore, whenthis fold change in BPAD LCLs was compared to controls,percentage of cells with high MMP was significantly higher inBPAD LCLs. This trend was seen in both lithium responderlines and non-responder lines.

Analyses were performed at baseline and after mood

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stabilizer treatment between lithium response groups.Neither dead cell population nor high MMP population shownany significant difference between the responders and thenon-responders group.Discussion: BPAD LCL populations showed significantlyhigher cell death and lower mitochondrial membranepotential. On treatment with the mood stabilizer, it wasfound the dead cell population was decreased in LCLs.However, the MMP was found to be increased only in BPADLCLs when treated. In conclusion, the effect of treatmentwas more pronounced in BPAD than in controls. We believeit would be interesting to look into the expression of genesinvolved in the pathways regulating apoptosis and mito-chondrial activity.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.216

SU28. THE GENOMICS OF BIPOLAR AND SCHIZOPHRE-NIC DISORDERS IN A LARGE PEDIGREE FROM A NORTH-ERN SWEDISH ISOLATE

James Crowleyn,1, Poorva Mudgal1, Annelie Adolfsson2,

Karolina Åberg3, Maaike Alaerts4, Giulio Genovese5,Steven McCarroll6, Jurgen Del-Favero7, Rolf Adolfsson2,Patrick Sullivan1

1University of North Carolina at Chapel Hill2Umeå University3Virginia Commonwealth University4Applied Molecular Genomics Group5Broad Institute6Stanley Center for Psychiatric Research, Broad Institute7University of Antwerp

Background: Bipolar (BIP) disorders and Schizophrenia(SCZ), are severe and common psychiatric disorders consti-tuting health care problems of major concern worldwide.Both BIP and SCZ are highly heritable and complex disorders.The genetic risk factors are polygenic and involve bothcommon variants of small effects and rare variants withlarge effects. Using a variety of genomic technologies, weevaluated the Skea pedigree - a very large multi-generationpedigree densely affected by BIP and to a lesser extent bySCZ, originated from the isolated population in the Northeastpart of the county of Västerbotten in Northern Sweden. Theenrichment of these disorders in the Skea pedigree is8.8 times higher than the rest of Sweden. With this approach,we have maximized the chance of finding rare variant riskloci by combining the homogeneity of an isolate populationwith the extreme likeliness of family-members to share riskvariants inherited from a common ancestor.Methods: First, we identified genomic regions sharingIdentity-By-Descent (IBD) using linkage analysis with 472microsatellite markers (408 individuals) and shared segmentanalysis with 730 K SNPs from Illumina Omni Express geno-typing arrays (460 individuals). Second, we hypothesizedthat one of the IBD regions contained an ultra-rare

functional single nucleotide variant (SNV) of high pene-trance. We used exome sequencing (27 BIP cases) and wholegenome sequencing (WGS, 10 BIP cases) to identify SNVs andevaluate the hypothesis. We next evaluated novel and rarestructural variants in these IBD regions. We carried outkaryotyping (9 cases affected by BIP or SCZ) to identifybalanced structural variants (e.g. translocations and inver-sions), and predicted CNV calls from genotyping arrays andWGS. Third, we extended our analysis from IBD regions togenome-wide. Finally, we evaluated the contribution ofcommon variation in the Skea pedigree by calculatingpolygenic risk score with reference to results from PGC2-SCZ and PGC2-BIP, and in comparison to a SCZ case-controlsample collected from Umeå in Northern Sweden.Results: Our comprehensive analysis did not conclusivelyidentify any SNVs or CNVs of near-Mendelian effect in theSkea pedigree. However, the presence of many SCZ commonvariant risk alleles may be partly the reason why there is ahigh incidence of these disorders in the Skea pedigree.Specifically, we found that, using PGC2-SCZ results as thediscovery GWAS, the polygenic risk scores of the affectedindividuals from the Skea pedigree were significantlygreater than that of the Skea controls and the Umeåcontrols (p=2.2e-16), but are similar to the Umeå SCZcases that were ascertained clinically without regard tofamily history (p=0.45). This is consistent with the fact thatwe have not found a near-Mendelian mutation in the Skeapedigree so far. Interestingly, polygenic risk scores based onBIP common variant risk (using PGC2-BIP as discovery GWAS)had little power in predicting the affection status in theSkea pedigree.Discussion: No near-Mendelian variants have been foundin the Skea pedigree so far. However, we cannot exclude thepresence of risk variants with more complex inheritancepatterns, variants with more cryptic functional effects, orvariants missed due to coverage or individuals sequenced.The presence of many SCZ common variant risk alleles maybe partly the reason why there is a high incidence of bipolarand schizophrenia disorders in the Skea pedigree, which canbe due to assortative mating and result in an accumulationof common risk alleles.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.217

SU29. GENETIC DISSECTION OF SLEEP DISTURBANCE INBIPOLAR DISORDER

Katie Lewisn,1, Holly Pearce1, Andrew Bethell1, Liz Forty1,

Katherine Gordon-Smith2, Nick Craddock1, Lisa Jones2,Ian Jones1, Arianna Di Florio1

1Cardiff University2University of Worchester

Background: Bipolar Disorder (BD) is often associatedwith sleep disturbances such as insomnia or excessive sleep,

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even when mood is stable. Sleep loss may trigger the firstepisode of BD or subsequent episodes. Sleep disturbanceshave attracted much attention in the field of BD research,but also in clinical practice, demonstrated in the recentdevelopment of therapies manipulating sleep-wakerhythms. Sleep has been proposed as a biomarker of BDand its disturbance has been implicated in the biology ofmood disorders. However, the mechanisms that link moodand sleep are not fully understood. For example, sleep lossmay be a cause for BD, but the converse is also true.Alternatively, sleep disorders and BD may co-occur becausethey have risk factors in common, with no strong causalrelationship between them. Genomics has already providedimportant insights into the relationship between psychiatricdisorders, and may help disentangle the intricate relation-ship between sleep and mood.Methods: This research project will take advantage of anexisting dataset, the Bipolar Disorder Research Network(BDRN) collection of clinical and genetic data (available forover 5700 participants with BD) to evaluate: (1) themethods researchers and clinicians use to measure sleepin BD, (2) whether sleep characteristics can help identifybiologically valid subgroups of individuals with BD, usinggenomic approaches.We will evaluate a range of sleepmeasures, from low intensity, easy to fill, one-off ques-tionnaires to more intensive daily sleep and mood diaries.We will also include objective measures gathered throughactigraphs. Actigraphs are devices worn on the wrist thatrecord movements and can be used to estimate sleepcharacteristics.

For each person with BD, we will calculate scores fortheir genetic risk for sleep disturbances based on thefindings of large genetic studies of sleep in the UK generalpopulation. We will then compare the scores in individualswith BD with and without sleep disturbances to test theunderpinning biological validity of measured sleep distur-bance in BD.Results: Participants (N=5,728) have been (and continueto be) recruited across the United Kingdom. To date, 5,549participants have been genotyped using the Affymetrix(n=1,868), PsychChip (n=1,104) and Omni-Express(n=2,577) chips. All are at least 18 years old, providewritten informed consent, and have a DSM-IV diagnosis ofBD (I, II, not otherwise specified) or schizoaffective disorder,bipolar subtype.

To date, over 1,500 individuals with BD have completedquestionnaires on circadian preference and sleep disorders.Over 100 individuals with BD have completed 6-weeks ofhigh-intensity sleep and mood monitoring. Preliminary ana-lyses on 36 individuals with BD have shown moderateagreement (0.40 | rs | 0.59) between the low-intensitymeasures (e.g. sleep questions of the Beck DepressionInventory) and high-intensity measures such as actigraphyparameters.Discussion: The proposed research will be the first tosystematically evaluate a range of sleep measures in thelargest study of individuals with BD in the world to date. Theresults will inform the choice and use of sleep measures inlarge-scale BD studies. The genetic analyses planned arewell powered to provide insights into the mood-sleeprelationship, and might pave the way to personalizeddiagnosis and treatment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.218

SU30. RARE VARIANTS WITHIN LOCI HARBORING COMMONVARIANTS ASSOCIATED WITH BIPOLAR DISORDER ANDSCHIZOPHRENIA: FURTHER ELUCIDATING THE GENETICARCHITECTURE OF SEVERE PSYCHIATRIC ILLNESS

Eva Schulten,1, Sergi Papiol2, Monika Budde2,

Urs Heilbronner2, Susanne Bengesser3, Eva Reininghaus3,Dan Rujescu4, Thomas Schulze1

1Institute for Psychiatric Phenomics and Genomics, LudwigMaximilian Universität2Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich3Medical University of Graz4University of Halle

Background: Bipolar Disorder (BP) and Schizophrenia (SZ)are common and genetically complex disorders character-ized by often severe and overlapping symptoms. AlthoughGWAS have identified several common variants increasingdisease risk, a major portion of the heritability of bothdiseases has yet to be explained and may lie hidden in acollection of low-frequency, rare and ultra rare variants(MAF o5%). Identification of such variants harbors greatpotential not only to better understand the genetic archi-tecture underlying the diseases but also to develop moreefficient animal models to study pathophysiology.Methods: Whole exomes of 186 individuals with a DSM-IVdiagnose of type I BP and 173 individuals with a DSM-IVdiagnosis of SZ were sequenced. Variants with MAF o1% inthe NCBI-ESP data and located within one the publishedGWAS loci significantly associated with both BP and SZ (SNP7 100 kb) were included into the analysis.Results: Burden testing (CAST) will be used to test for anoverrepresentation of variants with MAF o 1% in the 359 casescompared to NCBI-ESP exomes (n=5895, European Americansonly) both at whole locus and individual gene level. In a secondstep, we plan to replicate the obtained results by targetedresequencing in a PGC case-control sample.Discussion: Through a combined approach of wholeexome analysis and targeted resequencing, we hope toidentify rare or ultra rare variants within the known GWASloci, increasing an individual's risk of BP and SZ, as havebeen shown to exist for several other common complexgenetic diseases. The identification of such variants wouldnot only complete the picture of the genetic architecture ofboth disorders but could also provide a means to furtherexplore the underlying pathophysiology through the devel-opment of more efficient animal models.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.219

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SU31. ESTABLISHING A BLOOD-BRAIN BARRIER MODELFOR THE ANALYSIS OF ALZHEIMER'S DISEASE USINGPATIENT DERIVED INDUCED PLURIPOTENT STEM CELLS

Carla Hartmannn

, Matthias Jung, Toni Ehrhardt, Ina Giegling,Dan Rujescu

Martin Luther University Halle-Wittenberg

Background: Alzheimer's Disease (AD) is the most com-mon form of dementia. One characteristic of AD is theaccumulation of amyloid-β (Aβ) peptides in different regionsof the brain caused by the sequential cleavage of thetransmembrane amyloid precursor protein. These extracel-lular amyloid plaques are a result of a dysregulated Blood-Brain Barrier (BBB) and emerge either due to an augmentedproduction or a decreased excretion through brain barriers.The BBB with its several transporter systems shows agedependent expression levels of unspecific Aβ transporters.Recently, 19 loci including ABCA7, an ABC transporterresponsible for Aβ efflux at the BBB, were discoveredshowing genome-wide significant association with the spora-dic, late-onset form of AD (LOAD). Together with otherresearch groups we identified several mutations in ABCA7 inAD patients, which is why an analysis of mutated ABCA7 inAD-related BBB models should be considered. We estab-lished patient-specific pluripotent stem cells from ADpatients and healthy donors to differentiate endothelialcells and other related BBB cells for the investigation ofdisease mechanisms related to ABCA7 in AD patients.Methods: Episomal vectors were used for the generationof induced Pluripotent Stem (iPS) cell lines from AD-specificB-lymphoblastoid cell lines (B-LCLs) and control B-LCLs ofhealthy donors. Alkaline phosphatase staining, immuno-fluorescence analysis, transcript analysis, western blotanalysis, and the induction of three germ layers verifiedpluripotency. Successfully established lines were applied forthe generation of BBB cells and neighboring cells. Endothe-lial cells and astrocytes were characterized by transcriptanalysis and flow cytometry. The differentiation process wasanalyzed for the altered expression of ABCA7.Results: AD-specific iPS cells were successfully generatedfrom B-LCLs. We could show alkaline phosphatase activityand the nuclear localization of pluripotency-related tran-scription factors including OCT4, SOX2, and NANOG. Tran-script analysis and western blot analysis verified permanentinduction of pluripotency marker genes including OCT4. Thespontaneous differentiation of iPS cells into derivatives ofthe three germ layers was demonstrated. The efficientdifferentiation of high quality endothelial cells was shownby the expression of endothelial marker genes including vonWillebrand factor. Astrocyte-specific markers includingEAAT1 demonstrated efficient astrocyte differentiation.Discussion: Human iPS cells provide a powerful tool for theanalysis of AD-associated and patient-specific mutations inABCA7. We successfully established endothelial cells andastrocytes representing suitable to study disease mechanismsof the BBB. Accordingly, this approach is an excellent oppor-tunity to analyze pathogenic phenotypes of AD in vitro towardsthe identification of potential therapeutic targets.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.220

SU32. PATIENT-SPECIFIC AD IN VITRO MODELS FOR THEANALYSIS OF LATE-ONSET ALZHEIMER'S DISEASE

Toni Ehrhardtn

, Matthias Jung, Carla Hartmann, Ina Giegling,Dan Rujescu

Martin Luther University Halle-Wittenberg

Background: Alzheimer´s Disease (AD) is the most com-mon form of dementia. Environmental and genetic factorscontribute to the risk for AD, but the underlying diseasemechanisms are poorly understood. AD is genetically com-plex and shows heritability of up to 80%. Glia cells includingastrocytes and microglia are affected in AD patients con-tributing to the tau pathology and the accumulation ofneurotoxic amyloid as well. In recent years, Genome-WideAssociation Studies (GWAS) allowed the identification ofDNA variations associated with an elevated risk for AD.Together with other groups, we identified a number of ADsusceptibility genes including CD33, SORL1, ABCA7 andTREM2, which highly recommends that the immune systemplays a major role in onset, progression and treatment ofAD. Reprogramming of EBV-transformed patient specific celllines for the generation of induced pluripotent stem cells(iPS) enables the patient-specific differentiation into neu-rons, astrocytes, and microglia. Patient-specific cells can beused as a model to functionally characterize disease asso-ciated variants.Methods: Blood was collected from AD patients carryingrisk variants in AD susceptibility genes for the generation ofiPS cells. SNP variants in those genes were genotyped basedon their potential function according to literature andgenomic localization (exonic non-synonymous, bindingdomain, or promoter affecting SNPs). Reprogrammed iPScells carried the genetic background of a certain AD patient.Pluripotency was characterized by alkaline phosphatasestaining, the expression of pluripotency markers, and thedifferentiation into the three germ layers. Crucial pluripo-tency markers are OCT4, SOX2, NANOG, KLF4, MYC, andLIN28. AD iPS cells were differentiated into astrocytes andmicroglia and the differentiation status was characterizedby the expression of crucial glia cell markers. Further, ADsusceptibility genes recently published in GWAS wereanalysed.Results: The protein expression was successfully inducedshown by immunofluorescence and western-blot analysis.Cells were also screened for the most efficient induction ofthe three germ layers and the induction of neural cell fatesincluding glia cell fates. The established AD-specific iPS celllines from AD patients represent a powerful tool for theanalysis of molecular and cellular disease mechanisms. Weestablished 4-step protocol for the generation of AD-specificmicroglia enabling the focused analysis of AD-associated riskvariants. The protocol was verified by morphology, FACS

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analysis, immunofluorescence and RNA expression of crucialmicroglia marker, including hematopoetic lineage markersand the induction of well-described microglia markersincluding IBA1. The disease-specific analysis of the geneticbackground of AD patients represents a completely newapproach for the understanding of AD genetics and AD-associated risk variants.Discussion: Together, combining molecular genetics of ADfor the investigation of risk variants and iPS cell technologyfor the generation of patient- and disease-specific stem cellsprovides a promising approach to characterize known diseasemechanisms, to deepen the understanding of known diseasemechanisms, and to discover unknown disease aspects.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.221

SU33. A GENOME-WIDE ASSOCIATION STUDY IDENTIFIESA NOVEL LOCUS ASSOCIATED WITH DEPRESSIVE STATEIN THE JAPANESE POPULATION

Hisatsugu Koshimizun,1, Shinya Asano2, Shoko Takahashi2,

Kenji Saito2, Tsuyoshi Miyakawa1

1Fujita Health University2Genequest, Inc

Background: Major Depressive Disorder (MDD) is a com-mon and disabling psychiatric disorder. MDD is a multi-factorial disorder with multiple genetic and environmentalfactors with relatively small effects. To date, only a smallnumber of loci have been identified to be significantly (P o5.0E-8) associated with MDD.Methods: To further understand of the genetic basis ofMDD, we conducted a Genome-Wide Association Study(GWAS) in East Asia with more than ten thousand partici-pants of Japanese ancestry. Participants completed a self-administered questionnaire on their medical history andhealth conditions that included the 6-item Kessler screeningscale (K6) for depressive state (cut-off point 4/5; 4,071,depressive group [cases]; 6,749, non-depressive group [con-trols]). The genomic DNA of the participants was extractedfrom saliva and was genotyped for Single-Nucleotide Poly-morphisms (SNPs) using Illumina HumanCore BeadChip(about 300,000 SNPs with add-on 5,000 SNPs). SNPs wereexcluded if the call rate was o 90%, the minor allelefrequency (MAF) was o 1%, or if the Hardy-Weinbergequilibrium P values were o 0.001. A total of 229,276 SNPsfrom 10,892 individuals were used. We sought for depressivestate susceptibility loci and their closest genes.Results: A genome-wide significant association (P=8.8E-9) was observed for a locus in chromosome 20, upstream ofWAP-type four-disulfide core 10B (WFDC10B), a member ofthe WFDC domain family, which has been reported to play aregulatory role in inflammation. On the other hand, therewere no SNPs with genome-wide significant associationswith past medical history of MDD (898, diagnosed group[cases]; 9,992, non-diagnosed group [controls]).

Discussion: This is, to the best of our knowledge, the firstlarge-scale GWAS using data from direct-to-consumer (DTC)genetic tests carried out in a population not of European-ancestry. The present study detected a novel locus signifi-cantly associated with depressive state, but furtherresearch is necessary to replicate the current findings. Thisstudy suggests that DTC genetic tests with self-reportedtrait data can contribute to revealing genetic basis for MDD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.222

SU34. DISTINCT GENETIC PROFILES OF PEPTIC ULCERIN INDIVIDUALS WITH DEPRESSION

Ying-Ting Chaon,1, Shih-Jen Tsai2, Yu-Li Liu3, Albert C. Yang2,

Po-Hsiu Kuo4

1Institute of Epidemiology and Preventive Medicine, Collegeof Public Health, National Taiwan University2National Yang-Ming University3National Health Research Institutes4Institute of Epidemiology and Preventive Medicine,National Taiwan University

Background: Peptic ulcer is a common yet serious diseaseaffected about 4 million people worldwide. Depression isconsidered a risk factor for peptic ulcer and may modify theetiology underlying peptic ulcer. Genetic factors contributeon the risk of developing peptic ulcer, but it remains unclearwhether the genetic influences differ between depressedand non-depressed groups. In this study, we conductedgenome-wide association studies for peptic ulcer stratifiedby depression status in Taiwanese samples.Methods: Subjects in this study were drawn from Taiwanbiobank with detailed demographic and clinical data collec-tion. A total of 10,295 individuals were initially included,and 9,862 participants were retained after quality control,which consisted of 1,218 (12%) depression individuals basedon prior diagnosis of major depressive disorder or highscores of self-report patient health questionnaire fordepression and anxiety (scores greater than 3). Geneticassociation analyses were performed using logistic regres-sion models while adjusted for age and sex. A p-value lessthan 10-5 was considered with suggestive associationsignals.Results: Within depressed group, the top three associatedSNPs were rs4775785 (P-value=1.20� 10-7), rs10162880(P=4.38� 10-7) and rs7177833 (P=5.17� 10-7). After genemapping, these top SNPs were all map to the SHC4 gene, aprotein coding gene on chromosome 15. In the non-depressed group, a different set of associated SNPs wereobserved, with rs11238817 (P=2.16� 10-6) and rs11637781(P=4.41� 10-6) showing suggestive signals without mappedto known coding genes.Discussion: There is no overlapping markers or genes forpeptic ulcer between the depressed and non-depressedgroups, indicating different genetic profiles among the

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two groups. A replication study is needed with larger samplesize, especially for the identified gene located on chromo-some 15 in depressed individuals.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.223

SU35. EVALUATING THE IMPACT OF PHENOTYPIC DEFI-NITIONS ON STATISTICAL POWER IN MAJOR DEPRESSIONGENETICS

Karen Hodgsonn

, Niamh Mullins, Cathryn Lewis

King's College London

Background: Obtaining sufficient statistical power hasbeen a key issue in the study of genetics in depression;only recently have samples become large enough to identifyany genome-wide significant hits for this phenotype.Researchers have used a range of different approaches totackle the issue of balancing sample size with phenotypicdepth, and here we evaluate the statistical power achievedwith these different methods.Methods: We collated details of published genome-wideassociation studies exploring major depression or depressivesymptoms. For each study we assessed sampling methods,phenotyping criteria and sample size, and use GPC (GeneticsPower Calculator, Purcell et al. 2003) and extension meth-ods (Yang et al. 2010, Traylor et al. 2015) to calculatestatistical power, and compare approaches within theliterature. We compared the statistical power (as capturedby the non-centrality parameter) of each cohort across arange of allele thresholds and genetic effect sizes, con-trasting different methodologies of cohort ascertainmentwithin the depression literature.

We evaluate how statistical power is affected by theselection of potentially more homogenous but less prevalentdepression phenotypes, the potential impact of misclassifi-cation in large cohorts which have employed brief pheno-typic screening questions, and the value of dimensionalmeasures of depression symptoms in population-basedcohorts.Results: We confirm the findings of Traylor et al. apply inthe case of depression; that in the analysis of specificsubtypes of depression performed in datasets includingPGC2 (2013, secondary analysis of recurrent, early-onsetrecurrent and typical-like depression, observed in approxi-mately 75%, 50% and 40% of cases respectively) and CON-VERGE (2015, secondary analysis of melancholia observed inapproximately 85% of cases), very modest increases ingenotypic relative risk (GRR) are required to achieveequivalent power with the whole sample analyses, particu-larly for less common risk allele frequencies and lower indexGRR. We also compare the statistical power of the PGC2case-control sample (discovery sample n=18,759) and thestudy from the CHARGE Consortium (discovery sample n=34,549, Hek et al. 2013) looking at depression symptoms,observing that with a sample size which is 54% of that in

CHARGE, the PGC2 dataset has less than half the statisticalpower to detect genetic effects.Discussion: Given range of approaches, here we giveevaluation of expected statistical power across a range ofapproaches specific to the field of major depression genet-ics. We compare the statistical power achieved in thecurrent literature and evaluate how different phenotypicapproaches affect this.

If the ultimate aim of our research is to improve out-comes for patients with depression, our phenotypic defini-tions must be informed by clinical relevance. Butnevertheless, an understanding of how statistical power isimpacted by these definitions is key to optimal study designfor the identification of the genetic variants associated withdepressive disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.224

SU36. ADVERSE LIFE EVENTS, PSYCHIATRIC COMORBID-ITY, AND BIOLOGICAL PREDICTORS OF POSTPARTUMDEPRESSION IN AN ETHNICALLY DIVERSE SAMPLE OFPOSTPARTUM WOMEN

Jerry Guintivanon,1, Patrick Sullivan1, Alison Stuebe1,

Thomas Penders2, John Thorp1, David Rubinow1,Samantha Meltzer-Brody1

1University of North Carolina at Chapel Hill2East Carolina University

Background: Race, psychiatric history, and adverse lifeevents have all been independently associated with Post-partum Depression (PPD). However, the role these playtogether in Black and Latina women remains inadequatelystudied. Therefore, we performed a case-control study ofPPD, including comprehensive assessments of symptoms andbiomarkers, while examining the effects of genetic ancestry.Methods: We recruited our sample (549 cases, 968 con-trols) at six weeks postpartum from obstetrical clinics inNorth Carolina. PPD status was determined using the MINI-plus. Psychiatric history was extracted from medicalrecords. Participants were administered self-report instru-ments to assess depression (Edinburgh Postnatal DepressionScale) and adverse life events. Levels of estradiol, proges-terone, Brain-Derived Neurotrophic Factor (BDNF), oxyto-cin, and allopregnanalone were assayed. Principalcomponents from genotype data were used to estimategenetic ancestry and logistic regression was used to identifypredictors of PPD.Results: This population was racially diverse (68% Black,13% Latina, 18% European). Case status was predicted by ahistory of major depression (p=4.01E-14), lifetime anxietydisorder diagnosis (p=1.25E-34), and adverse life events(p=6.06E-06). Genetic ancestry was not a predictor of PPD.There were no significant differences between groups in anyhormones or neurosteroids.

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Discussion: Psychiatric comorbidity and multiple expo-sures to adverse life events were significant predictors ofPPD in a population of minority and low-income women.Genetic ancestry and hormone levels were not predictive ofcase status. Increased genetic vulnerability in conjunctionwith risk factors may predict the onset of PPD, whereasgenetic ancestry does not appear predictive.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.225

SU37. RESTING STATE FUNCTIONAL DYNAMICS INMAJOR DEPRESSIVE DISORDER AND RELATIONSHIPWITH POLYGENIC RISK LOADING: EVIDENCE FROMUK BIOBANK

Xueyi Shenn

, Simon Cox, Jude Gibson, Mark Adams,David Howard, Andrew McIntosh, Heather Whalley

University of Edinburgh

Background: Major Depressive Disorder (MDD) is a com-mon psychiatric illness. Neuroimaging studies have indi-cated the involvement functional networks in the disorder.Resting-state functional magnetic resonance imaging (rs-fMRI) provides a non-invasive, task-free way of studyingsuch distributed functional dynamics of the brain. Previousstudies have found significant alteration in rs-fMRI func-tional connectivity in MDD patients. Hyperactivity of defaultmode network (DMN) has been reported to be associatedwith rumination of negative emotional stimuli, and abnor-mal connectivity between DMN and task-positive networkswas associated with cognitive impairment within MDD,however other studies do not report such effects. Previousrs-fMRI studies were however often conducted on smallsample sizes which may account for inconsistency in theliterature, and few studies were conducted on the associa-tion between genetic risk of MDD and rs-fMRI functionalconnectivity. Therefore, the present study used imagingdata from a large-population based sample from UK Biobankto test the association of brain functional connectivity withMDD status and its genetic risk.Methods: We used IDPs (Imaging-Derived Phenotypes)from UK Biobank imaging project. The imaging data wascollected on a single scanner and preprocessed using FSLpackages by UK Biobank. Data was parcelled into 21 non-noise functional networks, and the L2-regularised partialcorrelation was estimated between each pair of networks.These estimated connections were then used for furtheranalysis in the current study.

MDD status was derived based on self-reported depres-sive symptoms and history of hospital admission data (Case:N=256, Control: N=488,). Polygenic risk of MDD (MDD-pgrs)was calculated based on the summary statistics from thePGC (N=914).

Regression models were applied to test the MDD case-control difference and the associations of MDD-pgrs with rs-

fMRI functional connectivity. Age, age2, sex and assessmentcentre were controlled for in the model of case-controldifferences, and genotype batch and the first 15 principalcomponent of genetic variance were additionally controlledfor MDD-pgrs. FDR correction was applied. All effect sizesreported were standardised.Results: MDD cases showed higher positive connectivitybetween the precuneus, the bilateral superior posteriorcingulate cortex and temporal-parietal junction (β=0.292,pcorr=0.047); all components of DMN.

Higher MDD-pgrs was associated with less connectivitybetween posterior motor area and posterior parietal gyrus(PPG) (β=-0.123, pcor=0.045), less negative connectivitybetween precuneus and PPG (β=0.122, pcor=0.045) andhigher negative connection of right fronto-temporal net-work (FTN) and left fronto-parietal network (FPN) (β=-0.124, pcor=0.045).Discussion: In the present study, MDD cases exhibitedsignificantly higher connection between two DMN compo-nents, and a higher negative connection between FTN andFPN. Conversely, higher genetic risk for MDD was associatedwith decreased connectivity between DMN regions and task-positive networks.

These results were highly consistent with previous stu-dies which found that altered functioning of DMN wasrelated with MDD status. The present study also foundfunctional connections that involve with DMN, FTN andFPN associated with MDD-pgrs.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.226

SU38. A STUDY OF 42 INFLAMMATORY MARKERS IN 321CONTROL SUBJECTS AND 887 MAJOR DEPRESSIVE DIS-ORDER CASES: THE ROLE OF BMI AND OTHER CON-FOUNDERS, AND THE PREDICTION OF CURRENTDEPRESSIVE EPISODE BY MACHINE LEARNING

Timothy Powelln,1, Helena Alexandra Gaspar1,

Raymond Chung1, Aoife Keohane1, Cerisse Gunasinghe1,Rudolf Uher2, GENDEP Study Team1, SELCoH Study Team1,David Collier3, Hong Wang3, Gerome Breen1

1King's College London2Dalhousie University3Eli Lilly and Company, Ltd

Background: Inflammatory markers, such as circulatingcytokines, influence neurotransmitter systems and brain func-tionality related to psychiatric disease pathology. Previousstudies have revealed heightened circulating levels of pro-inflammatory cytokines in the blood of Major DepressiveDisorder (MDD) patients, which suggests they may have utilityas clinically informative biomarkers to aid in the diagnosis ofMDD. However, most previous studies have only focused on asmall number of inflammatory markers (e.g. C-reactive protein,

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interleukin-6) and most have failed to co-vary for potentiallyimportant confounding factors.Methods: We assessed 42 inflammatory markers in theblood (serum) of 321 control subjects and 887 MDD casesusing multiplex electrochemiluminescence methods. Wetested whether individual inflammatory marker levels weresignificantly affected by MDD case/control status, currentepisode, or current depression severity, co-varying for age,sex, Body Mass Index (BMI), smoking, current antidepressantuse, ethnicity, assay batch and study effects. We furtherused machine learning algorithms to investigate if we coulduse our data to blindly diagnose MDD patients or discrimi-nate those in a current episode. We used the false discoveryrate (qo0.1) to account for multiple testing.Results: We found broad and powerful influences of con-founding factors on log-protein levels. Notably, IL-6 levelswere very strongly influenced by Body Mass Index (BMI;p=1.37� 10–43, variance explained=18%), while Interleu-kin-16 was the most significant predictor of current depres-sive episode (p=0.003, variance explained=0.9%, q o 0.1).No single inflammatory marker predicted MDD case/controlstatus when a subject was not in a depressed episode, nor didany predict depression severity. Machine learning resultsrevealed that using inflammatory marker data with clinicalconfounder information significantly increased the precisionof blind diagnoses when patients were in episode.Discussion: To conclude, a wide panel of inflammatorymarkers alongside clinical information may aid in predictingthe onset of symptoms via a machine learning approach, butno single inflammatory proteins are likely to representclinically useful biomarkers for MDD diagnosis or prognosis.Our study also highlights the need for confounding factors,particularly BMI, to be considered in all future studiespertaining to inflammatory markers.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.227

SU39. GENOME WIDE ASSOCIATION STUDY OF TREAT-MENT RESPONSE TO COGNITIVE BEHAVIORAL THERAPYFOR DEPRESSION

Evelyn A. Hagenn,1, James Crowley2, Anna Kähler1,

Robert Karlsson1, Manuel Mattheisen3, Martin Schalling1,Catharina Lavebratt1, Julia Boberg1, Erik Forsell1,Samir El Alaoui1, Erik Hedman1, Viktor Kaldo1,Nils Lindefors1, Patrick Sullivan2, Christian Ruck1

1Karolinska Institutet2University of North Carolina, Karolinska Institutet3Aarhus University, Karolinska Institutet

Background: Major Depressive Disorder (MDD) is a ser-ious, but treatable, disorder where Cognitive BehavioralTherapy (CBT) is a first line treatment. However, a sig-nificant number of patients (40–60%) are not responding totreatment and understanding more about the disorder and

who responds to treatment is crucial to improve outcomes.In the past year, there have been marked advances in thegenomics of MDD thanks to large consortia GWAS efforts.Here we leverage summary statistics derived from the latestMDD GWAS in order to test whether individual MDD poly-genic risk scores (PRS) associate with baseline severity andCBT response in a sample of 971 MDD cases undergoinginternet-based CBT (iCBT). Our aim is to calculate MDDPolygenic Risk Scores (PRS) and examine their relationshipwith a key measure of disease severity and treatmentresponse with longitudinal follow up data.Methods: We collected DNA from 971 Swedish MDD cases(66% female) who took part in a 12-week course of iCBT. Theprimary outcome variable was the Montgomery ÅsbergDepression Rating Scale – Self-rating (MADRS-S) and wasmeasured pre-treatment, weekly, post treatment and at6 months follow-up. For genotyping, the Illumina GlobalScreening Array (GSA) was used for the 971 samples. Forpopulation-specific controls, we will calculate MDD PRS for aset of 3,000 Swedish individuals with no history of MDD. Weuse the latest MDD summary statistics to calculate PRS foreach individual to examine the relationship between poly-genic load and a key measure of disease severity andtreatment response. Further, we calculate PRS for a rangeof other traits which may influence disease severity ortreatment response: neuroticism, bipolar disorder, subjec-tive well-being and educational attainment.Results: We will present results detailing the relationshipbetween MDD PRS and disease severity (baseline MADRS) aswell as treatment response (change in MADRS followingiCBT) and treatment adherence. Further, we will presentresults demonstrating how PRS for a range of other traitsinfluence disease severity or treatment response.Discussion: In other psychiatric disorders, such as schizo-phrenia, polygenic risk score analyses and treatmentresponse of pharmacological interventions have been inves-tigated with interesting outcomes. In our future work, wewill contrast genetic predictors with non-genetic predictorsderived from the Swedish registers (e.g. pre- and perinatalrisk factors), to try to understand even more about thebiological underpinnings of MDD and response to treatment.We believe performing these analyses will bring us one stepcloser to determining whether genomics can help persona-lize MDD treatment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.228

SU40. DISTINCT GENETIC VULNERABILITIES-BY-STRESS-FUL LIFE EVENTS INTERACTIONS PROPOSE ADDITIONALRISK FOR DEPRESSIVE SYMPTOMS

Aleix Arnau Solern,1, Pippa Thomson1, Andrew McIntosh2,

Caroline Hayward3, Mark Adams2, Toni Clarke2,Donald MacIntyre2, Keith Milburn4, Lauren Navrady2,Generation Scotland1

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1Centre for Genomic and Experimental Medicine, Instituteof Genetics and Molecular Medicine, Universityof Edinburgh2University of Edinburgh3QTL in Health and Disease, Institute of Genetics andMolecular Medicine, University of Edinburgh4Health Informatics Centre, Ninewell Hospital & MedicalSchool, University of Dundee

Background: Stressful Life Events (SLEs) and genetic riskfactors both contribute to the aetiology of Major DepressiveDisorder (MDD). Although SLEs are considered to be anenvironmental factor, studies suggest that they may act inpart through interaction with the known genetic risk factorsin MDD or more unexpectedly, through interaction withnovel genetic factors specific to SLEs. Polygenic Risk Scores(PRS) reflect an individual's genetic vulnerability to developdepression. Such vulnerability to MDD has been commonlybased on main additive effects, although a genetic con-tribution has been suggested for SLEs on risk of MDD. Weused PRS for MDD and for a novel stress-sensitivity trait,derived from a Genome-Wide Interaction Study (GWEIS), totest these hypotheses.Methods: We performed a GWEIS in UK Biobank (N=23,092;UKB), modeling the interaction between SNP allele and MDDstatus on neuroticism score (EPQ-N). The effect size of theinteraction term was used to create a measure of geneticMDD-dependent stress-sensitivity (SS). The genetic vulnerabil-ity-stress model was tested using PRS weighted by MDD usingPsychiatric GWAS Consortium MDD summary statistics (MDD-PRS), or PRS weighted by MDD-dependent stress-sensitivityeffect (SS-PRS) in GS:SFHS STRADL (Stratifying Depression andResilience Longitudinally; N=4,919). GS:SFHS STRADL has dataon symptoms of depression assessed by General Health Ques-tionnaire (GHQ-28) and past 6 month SLEs using the List ofThreatening Experiences (LTE-Q).Results: MDD-PRS, SS-PRS and main effects of SLEs signifi-cantly predicted symptoms of depression (MDD-PRS:P=5.48� 10-9; SS-PRS: P=2.63� 10-4; SLEs: P=1.01� 10–58, using best predictor at full cohort). The MDD-PRS-by-SLEsinteraction significantly contributed to the risk of MDD atpopulation level (p-threshold=0.01, β=0.028, SE=0.014,R2=0.077%, P=4.91� 10-2), although this was stronger infemales (p-threshold=1� 10-5, β=0.044, SE=0.018,R2=0.19%, P=1.84� 10-2) and not significant in males(p-threshold=0.1, β=0.04, SE=0.022, R2=0.16%, P=6.37�10-2). The SS-PRS-by-SLEs interaction significantly contribu-ted to the risk of MDD in males (p-threshold=0.01, β=0.078,SE=0.022, R2=0.6%, P=3.38� 10-4) but not in females (p-threshold=0.05, β=-0.027, SE=0.018, R2=0.075%, P=0.14)or in the full cohort (p-threshold=1� 10-5, β=0.025,SE=0.014, R2=0.063%, P=7.75� 10-2), This SS-PRS-by-SLEsinteraction in males explained almost as much as thevariance explained by the main MDD-PRS effect at their bestpredictor (p-threshold=0.102, β=0.081, SE=0.022, R2=0.66%, P=2.09� 10-4).Discussion: Significant genetic vulnerability-SLEs interac-tions predict and additional MDD risk for individuals withhigh predisposition and high number of reported SLEs.However, the results suggest distinct interactions betweengenetic vulnerabilities and SLEs on the aetiology of

depression in males versus females, although replicationon a larger sample would be required.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.229

SU41. WHO RESPONDS TO THERAPEUTIC SLEEP DEPRI-VATION? A NATURALISTIC CLINICAL STUDY

Jerome Foon

, Nina Trautmann, Josef Frank, Stephanie Witt,Fabian Streit, Steffen Conrad Von Heyedendorff,Maria Gilles, Michael Deuschle, Marcella Rietschel

Central Institute of Mental Health

Background: Sleep Deprivation (SD) treatment is knownfor its striking and immediate, but transient effects improv-ing symptoms in 50–70% of patients suffering from depres-sion. SD thus offers the opportunity to study clinical andbiological factors preceding and accompanying moodchanges and to identify underlying mechanisms of depres-sion. The aim of this naturalistic study was to examine i.)clinical and genetic factors predicting response to SD, ii.)clinical and behavioural changes during the course of SD andiii.) the impact of SD on further course of the disorder.Methods: Patients undergoing an episode of majordepression (n=78, 34 F/44 M, 71 major depression, 7 bipo-lar) underwent one night of SD. Depressive symptoms wereassessed via standardized expert and self-ratings the daybefore and up to one month after SD. From the morningprior to SD until the evening after, mood and tiredness wereassessed every 2 hours via visual analogue scales, andlocomotor activity was concurrently measured via actigra-phy. Genome-wide genotyping was carried out using the GSAchip and polygenic risk scores (PRS) were calculated basedon genome-wide association data from the PGC MDD con-sortium. Response to SD was evaluated the day after SDbased on global clinical impression (CGI). Logistic regressionand mixed models were applied to analyse factors predict-ing SD and explore the trajectory of changes during andafter SD.Results: 70% of patients showed immediate antidepres-sant response. Before SD, responders and non-respondersdid not differ in self and expert-ratings of depression. Abinary logistic regression model found that lower age andlater age at disease onset were significantly associated withhigher likelihood of response; lower polygenic score fordepression, male sex, positive family history of psychiatricdisorder and diagnosis of bipolar disorder were associatedwith increased likelihood response at the trend level. Noeffects were found for season, diurnal variation, depressivesymptom scores and thyroid stimulating hormone levels.Through the course of SD, responders and non-respondersdiffered in mood, with diverging mood trajectories becom-ing clear the morning and afternoon after SD. Meanwhile,tiredness did not differ between groups. Increased locomo-tor activity was observed in non-responders in the eveningbefore SD until midnight. Following SD, depressive symptom

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scores decreased in both groups, but more in responders, inwhom the effect was sustained over the entire time ofobservation.Discussion: The current research shows that, in accor-dance with previous findings, response to SD is associatedwith specific clinical features and locomotor activity.Furthermore, PRS were examined in this context for thefirst time, suggesting that a genetic component may con-tribute to response to SD. In-depth investigation of theunderlying causes of these results is a promising approachfor future research in depression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.230

SU42. DISCOVERY AND REPLICATION STUDIES FORMICROBIOTA SIGNATURES IN MAJOR DEPRESSIVEDISORDER

Yu-Chu Ella Chungn,1, Hsi-Chung Chen2,

Hsiang-Chin Lori Chou3, Meei-Shyuan Lee4,Li-Chung Chuang5, Yen-Hsuan Ni2, Wei-Liang Shih1,Po-Hsiu Kuo3

1College of Public Health, National Taiwan University2National Taiwan University Hospital3National Taiwan University4School of Public Health, National Defense Medical Center5Cardinal Tien Junior College of Health

Background: Growing evidence suggests the link betweengut microbiota and mood regulation. While previous studiesreported several microbiota targets for Major DepressiveDisorder (MDD), the influence of dietary patterns is notconsidered. The current study aims to identify microbiotatargets for MDD depression in two independent Taiwanesedatasets while taking nutrient elements into consideration.Methods: We separately analyzed fecal samples from twoindependent datasets. The discovery set consisted of 9 MDDpatients and 11 healthy controls while replication setcomprised of 15 MDD patients and 25 healthy controls.Illumina Miniseq or Miseq platform were applied for 16 srRNA sequencing. We further assessed food frequencyquestionnaires and Beck depression inventory to obtainthe information of nutrients and depressive status. Weapplied linear discriminant analysis effect size (LEfSe) totest associations between depression and microbiota andadjusted for nutrient status.Results: In the discovery data, the microbiota exhibitedsignificant group differences in genus level, includingincreased abundance of Bilophila and Gillisia, anddecreased abundance of Clostridium. The results remainedsignificant after adjusted levels of carbohydrates, proteinand fat intake.

The replication study is underway.

Discussion: Our results revealed novel targets to beassociated with depression and are independent of dietaryinfluences. These results awaiting replication and furthervalidation for depression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.231

SU43. AFFECTIVE TEMPERAMENT AND POLIMORPHISMSIN GENES CODING ELEMENTS OF DOPAMINERGIC PATH-WAYS IN OBESITY SUBJECTS

Maciej Bielińskin

, Natalia Lesiewska, Alina Borkowska

Nicolaus Copernicus University

Background: Temperament is a group of inherited per-sonality traits that emerge in the early stages of human life.Such temperament is the basis of personality formation. TheHagop Akiskal, based on the theorems of Kraepelin andKretschmer, established the existence of five types ofaffective temperament: depressive, hyperthymic, cyclothy-mic, irritable and anxious. It is now accepted that tempera-ment is a constant, hereditary core of the personality that isvirtually unchanged throughout life.Methods: 506 patients diagnosed with obesity wereincluded to the study after exclusion of significant psychiatricillnesses. Patients were subjected to clinical, psychologicaland genetic evaluation. The psychological assessment con-sisted in determining the severity of depressive symptoms(using the Beck Depression Inventory and Hamilton's Depres-sion Scale) and the assessment of the affective temperamentprofile using TEMPS-A. Genetic evaluation consisted in thedetermination of polymorphisms DAT1 VNTR (SLC6A3) andcathelol-O-methyltransferase COMT (Val158Met).Results: The results indicated an association betweenCOMT and DAT1 alleles with depressive symptoms, BMI andas well as temperamental dimensions. Val homozygotes inCOMTanalysis scored less in both depression scales also theywere less depressive, cyclothymic, irritable and anxious.Subjects homozygous for the nine-repeat allele scoredhigher in BDI (p=0.02) and HDRS (p=0.00001), suggestinghigher intensity of depression, in both sexes. This allele wasalso associated with the highest Body Mass Index (BMI,p=0.001).Discussion: Polymorphisms in the DAT1 and COMT genesare associated with greater intensity of depressive symp-toms as well as higher BMI and affective temperamentdimensions in obese individuals.

Disclosure: Group Medical Practices – Employee, Self &Spouse

http://dx.doi.org/10.1016/j.euroneuro.2017.08.232

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SU44. CORRELATION BETWEEN GENE EXPRESSIONCHANGE AND HORMONE CHANGE DURING REFEEDINGIN ANOREXIA NERVOSA

Jessica Bakern,1, Yunjung Kim1, James Crowley1,

Sara Trace1, Kimberly Brownley1, David Pisetsky2,Cynthia Bulik1

1University of North Carolina at Chapel Hill2Duke University

Background: Anorexia Nervosa (AN) is an eating disordercharacterized by extreme food restriction, resulting in abody weight that is less then minimally expected. Geneticfactors contribute to its etiology with heritability estimatesranging between 48%-74%. The first genome-wide significantlocus for AN has been identified, and AN shows moderateand significant genetic correlations with additional psychia-tric and somatic phenotypes. Transcriptome expressionprofiling has also been applied to AN to assess whethergene expression levels change with AN treatment. Onestudy completed whole transcriptome expression profilingand compared expression levels at hospital admission anddischarge. Sixty-seven genes were significantly differen-tially expressed. Similarly, other biological factors changeduring the treatment process for AN. Norepinephrine andghrelin levels decrease with weight gain whereas adiponec-tin, estradiol, and glucose increase. It is unclear howchanges in gene expression are associated with changes inother biological factors during weight gain—which weexamine here.Methods: Change in gene expression from inpatientadmission (T1) to discharge (T2) has been previously identi-fied. We explore associations between the top 10 differen-tially expressed genes and change in appetite (leptin,ghrelin) and reproductive hormones (estradiol), an inflam-matory marker (TNF-α), and glucose. Subjects were6 females receiving treatment for AN. Blood samples weretaken at T1 and T2; a PAXgene tube used to collect blood forRNA. 12 samples were sequenced using 1 μg of total RNA asinput. Samples were randomized and sequencing librariesprepared using Illumina TruSeq RNA Sample Preparation Kitv2. Libraries were quantitated using fluorometry and sam-ples were pooled at equimolar concentrations prior tosequencing. Two lanes of Illumina HiSeq. 2000 generated atotal of 381million 100 bp paired-end reads. Followingquality control, we used a standard RNAseq alignment andanalysis pipeline. A difference score (T2- T1) was createdfor the variables to explore the association between geneexpression change and change in other biological factors.Results: The top 10 previously identified differentiallyexpressed genes included in this study: C16orf11, CYP11A1,DEFA10P, LINC00235, DSP, OLR1, CPA3, FMO3, AKAp12, andGATA2. Two significant correlations (p o .05) were observedbetween change in leptin and CPA3 (r=.87) and GATA2(r=.84) gene expression change. Although this study wasexploratory, the preliminary results should be interpretedwith caution given the small sample size and that p-valueswere unadjusted for multiple testing.

Discussion: Change in CPA3 and GATA2 expression werepositively associated with change in leptin. Little is knownabout the function of these genes. However, CPA3 isexpressed in mast cells, which are immune cells contribut-ing to the pathogenesis of obesity, diabetes, and otherinflammatory diseases. GATA2 may be involved in dendriticcell, monocyte, B lymphocyte, and natural killer lympho-cyte deficiency. In turn, leptin represents a link betweennutritional status and immune response. Thus, factors thatrepresent indirect makers of the body's immune and inflam-mation response appear to move in tandem during therefeeding process in AN. This aligns with work suggestinggenetic overlap between AN, autoimmune disease, andmarkers of metabolic health. The genetic architecture ofAN suggests it may be best conceptualized as both ametabolic disease and a psychiatric illness.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.233

SU45. BLOOD-BASED AUTISM SPECTRUM DISORDERSIGNATURES FROM THE ITALIAN AUTISM NETWORKCOLLECTION

Michele Filosin,1, Bertram Mueller-Myhsok2,

Pierandrea Muglia3, Enrico Domenici1

11CIBIO, University of Trento2Max-Planck-Institute of Psychiatry, Statistical GeneticsGroup2University of Toronto

Background: A substantial genetic component accountsfor Autism Spectrum Disorders (ASD) etiology. Some rareand, more recently, common genetic risk factors for ASDhave been identified, thanks to recent large consortiumefforts. The availability of blood samples from thoroughlycharacterized ASD families becomes an essential step tocharacterize genotype-phenotype correlations and identifynovel candidate biomarkers. The Italian Autism Networkholds a collection of about 250 families with extensiveclinical information and a biobank of DNA, RNA and plasmaderived from ASD patients and first-degree relatives (for atotal of more than 800 subjects) enabling multidisciplinaryresearch of ASD.Methods: Here we present a study conducted on 76 siblingpairs from the Italian Autism Network (ITAN) collectionselected from families formed by a proband and at leastone unaffected sibling. RNA sequencing was conducted onPAX-gene blood samples and whole-genome genotype wasderived by analysis on custom DNA arrays (PsychArray). Toidentify differential gene expression signature, a paireddesign model based on negative binomial distribution wasused, correcting the model for batch effect, age, ethnicityand genetic similarity scores. In addition, based on therecent availability of GWAS data for ASD from a large meta-analysis, individual Polygenic Risk Score (PRS) for each

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subject was calculated and included in the gene expressionmodel to highlight differences in gene expression betweencases and controls independent from their burden ofcommon risk factors.Results: We have identified a gene expression signaturefor ASD which appears to reflect an unbalanced immune cellfunction. Using PRS as a covariate increased the number ofgenes above the statistical threshold. The gene set thusidentified, being unrelated to the common genetic riskcomponent, should more closely reflect disease status.Analysis of the PRS distribution confirms a higher score foraffected versus unaffected siblings in spite of high similaritybetween related samples.Discussion: As shown by investigations on ASD brainsamples, dysregulation of gene networks both causallyrelated (e.g. synaptic genes) and unrelated (e.g. immunefunction genes) to ASD etiology occur at transcriptomelevel. Additive effects of common variants likely playinga considerable role in ASD risk can be captured by PRS basedon large GWAS datasets. By integrating transcriptome datawith PRS it appears to be possible to tease apart the geneticand environmental factors affecting peripheral gene expres-sion in ASD, suggesting novel candidate biomarkers fordisease status.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.234

SU46. PSYCHIATRIC GENETIC COUNSELING:CHALLENGES IN AUTISM SPECTRUM DISORDERS

Weiyi Mun

Johns Hopkins University

Background: Autism Spectrum Disorders (ASD) have oneof the highest estimates of heritability among psychiatricconditions. Genetic testing is now considered standard ofcare for diagnosis of ASD etiology, and is increasinglyavailable, affordable, and offered to patients and theirfamilies. The 2013 American College of Medical GeneticsPractice Guidelines estimates a genetic diagnostic yield of30–40% in ASD cases, recommending Chromosome Microar-ray (CMA), single gene testing such as FMR1, as well as othertesting such as metabolic studies. As of 2017, more than 20academic and commercial laboratories have developedclinical genetic tests specific for ASD, which are beingmarketed as diagnostic testing to clinicians worldwide.However, these gene panels often have low clinical validity,and often include genes where the associations between theloci and ASD are unclear. Little is known regarding thepractical experience of individuals with ASD undergoinggenetic testing. Here, we present five illustrative casesand suggest standardized approaches for genetic counselingin ASD.Methods: Since 2013, clinical genetic testing has beenroutinely offered to individuals with ASD in our Geneticsclinic. The most common test offered was CMA, followed by

FMR1 and whole exome sequencing. Through retrospectivechart review, five representative cases were selected tohighlight the diagnostic and counseling complexities.Results: From 2013 to 2016, we provided genetic counsel-ing to 29 individuals with ASD, resulting in at least a partialgenetic diagnosis in 34% of cases, a variant of unknownsignificance in 10% of cases, and incidental findings in 7% ofcases. We present five cases of nonsyndromic ASD withvariable genetic testing results (1q21.1 deletion, 16p11.2duplication, 15q13.3 duplication, AUTS2, 47, XYY) anddiscuss the genetic counseling issues for each. In ourcollective experience with these and other cases, we havefound that diagnostic challenges include phenotypic andlocus heterogeneity, variable expressivity, reduced pene-trance, causative versus risk alleles, and changing geneticassociations as research progresses. Psychosocial challengesinclude misleading information online, illness representa-tion beliefs of patients and families, stigma, guilt andshame, and family communication.Discussion: It is not enough to know that certain geneticfactors are associated with ASD. Translating this informationin a meaningful way for patients and families is the ultimategoal of all clinically-directed research. The reactions of thefamilies described in this case series illustrate these chal-lenges. We recommend standardizing informed consent forgenetic testing in ASD, especially regarding the inherentuncertainties, and to include referral to a clinical geneticspecialist if available. Careful and informed genetic coun-seling is crucial and may lead to improved coping andadaptation, and may reduce negative consequences ofstigma and discrimination.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.235

SU47. BEHAVIOURAL CHANGES AFTER PSYCHIATRICGENETIC COUNSELING: AN EXPLORATORY STUDY

Emily Morrisn

, Stephanie Huynh, Angela Inglis,Jehannine Austin

University of British Columbia

Background: Though often thought of as an interventionexclusively concerned with delivering information aboutgenetic testing/recurrence risk, Genetic Counseling (GC) isactually “a process of helping people to understand andadapt to the medical, psychological, and familial implica-tions of genetic contributions to disease.” There is currentlylimited data relating to the effect of genetic counseling(rather than information) on patients’ health behaviors.With its focus on strategies to protect mental health,Psychiatric Genetic Counseling (PGC) is conceptually posi-tioned to produce health behavior changes. Indeed,research shows that PGC leads to increased patient empow-erment and self-efficacy – both of which are necessary forpatients to engage in behavior change. No studies have yet

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examined if PGC can evoke patient health behaviorchanges.Methods: We conducted semi-structured interviews witheight patients with a personal history of psychiatric illnesswho had received PGC in Vancouver, Canada within theprevious year, to explore its effect on health behaviors.Interviews focused on (i) experience with PGC services, (ii)perception of the etiology of mental illness and risk ofdeveloping symptoms, (iii) views on their past and currentbehavior and ability to change, and (iv) changes in theirbehavior since their PGC session. Guided by groundedtheory, we used a constant comparative approach to dataanalysis.Results: Participants reported increases in use of protec-tive behaviors such as exercise, improving sleep habits,adhering to prescribed medication, seeking professionalhelp and engaging in self-care. Participants reportedincreased sense of control, confidence and acceptance oftheir psychiatric disorder after PGC. This arose from havingtheir feelings of guilt, shame, fear and hopelessness, andmisconceptions and/or uncertainties about the etiology ofpsychiatric disorders and recommended risk-reducing beha-viors addressed. PGC reframed participants’ initial percep-tion of mental illness by separating cause into controllableand uncontrollable factors, discussing strategies to addressthe controllable factors and reiterating that everyone has avarying degree of susceptibility –some may be higher thanothers- but symptoms of mental illness are notpredetermined.Discussion: Overall, participants reported health behaviorchanges and improved mental health outcome after PGC.Future studies could explore these changes quantitatively.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.236

SU48. HERITABILITY OF HAIR CORTISOL AND GENETICOVERLAP WITH PSYCHOLOGICAL VARIABLES

Fabian Streitn,1, Liz Rietschel2, Gu Zhu3, Kerrie McAloney3,

Tina Binz4, CORtisolNETwork Consortium,Major Depressive Disorder Working Group of the PsychiatricGWAS Consortium, Narelle K. Hansell3, Margie Wright3,Nathan Gillespie5, Markus Nöthen6, Markus Baumgartner4,Lucia Colodro Conde3, Nick Martin7, Marcella Rietschel1

1Central Institute of Mental Health2University Clinic Hamburg Eppendorf3QIMR Berghofer Medical Research Institute4Centre for Forensic Hair Analysis, Institute of ForensicMedicine5Virginia Institute for Psychiatric and Behavioral Genetics6University of Bonn7Queensland Institute of Medical Research

Background: Measuring cortisol in hair is a promisingmethod to assess the regulation of the Hypothalamus-Pituitary-Adrenal (HPA) axis which is altered in psychiatricdisorders. First studies indicate a contribution of genetic

factors to inter-individual variance in Hair Cortisol Concen-tration (HCC). Evidence for a genetic overlap between HCCand psychological variables would indicate a true biologicallink pointing at a causal involvement of the HPA axis in thevulnerability for psychiatric disorders. The aims of thepresent study were (1) to assess the heritability of HCC(2) to estimate the genetic and environmental association ofHCC and perceived stress, depressive symptoms and neuro-ticism using twin models and a molecular genetic approach,i.e. Polygenic Risk Scores (PRS).Methods: Hair samples from 671 individuals (meanage=14.5 years) including 183 dizygotic twin-pairs wereanalyzed. PRS scores were based on large published gen-ome-wide association studies for depression, neuroticismand plasma cortisol, and analyzed in 432 individuals.Results: The twin model revealed (1) a heritability of HCCof 72%, but (2) no phenotypic nor genetic overlap of HCCwith psychological variables.Discussion: HCC is highly heritable, but shows no phenotypic/ genetic correlation with any of the studied psychologicalvariables in our young individuals from the general population.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.237

SU49. IDENTIFICATION OF NOVEL GWAS HITS FORSEMANTIC VERBAL FLUENCY: RESULTS FROM AFAMILY-BASED STUDY

Tâmara Taporoskin,1, Malcolm Von Schantz2,

Andréa R.V.R. Horimoto1, Núbia E. Duarte3,Sabine Pompeia4, Simon Evans2, José E. Krieger1,Homero Vallada1, Andre Brooking Negrao1,Alexandre C. Pereira1

1University of Sao Paulo2University of Surrey3National University of Colombia4Federal University of São Paulo

Background: Semantic verbal fluency is broadly used in bothclinical and non-clinical research, mainly because its sensitivityto several neurobiological conditions associated with cognitiveimpairment. In order to provide additional insights into geneticcomponent contributing to normal variation on speech produc-tion, we conducted a Genome-Wide Association Study (GWAS)of semantic verbal fluency in a family-based cohort from theBaependi Heart Study. Cognitive performance was analysedconsidering not only the total number of words produced in 60 sbut also subdivided into four 15-s time-quartiles because of theinvolvement of different cognitive processes- predominantlyautomatic at the beginning and controlled/executive at the endof the task.Methods: We analysed cognitive performance of 1,735 parti-cipants from 134 extended families (mean age7SD 46716.2,60% female). Participants were asked to orally name as manyanimals as possible within 60 s avoiding repetitions and varia-tions of the same animal. Scores were the numbers of

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exemplars produced in 60 s, which were broken down into four15-s time-quartiles [0–15 s (T1), 16–30 s (T2), 31–45 s (T3), 46–60 s (T4)]. Heritability estimates were obtained by an adjustedvariance component model. The Baependi cohort was geno-typed using different GWAS platforms (custom arrays to capturethe tri-ancestry genetic structure of the Brazilian population;Affymetrix Axiom Incor array and Affymetrix SNP chip 6.0;Affymetrix, Santa Clara, CA).Results: All performed analysis were adjusted for sex,age, education and time of day since these sociodemo-graphic variables affected means. Heritability calculationsshowed an estimate of: 60 s=0.21 (po0.01), T1=0.17(po0.01), T2=0.09 (po0.01), T3=0.12 (po0.01) andT4=0.00 (p=0.50). Education was the major factor in theadjusted model decreasing the estimate. GWAS evidencedsignificant associations for total score (60 s), T1, T2 and T3but not T4. The strongest cluster of coding variants includedthe hit for the Single-Nucleotide Polymorphism (SNP)rs72687454 (p=4.7� 10-8) in the gene for regulating synap-tic membrane exocytosis 1 (RIMS1).Discussion: Using a family-based cohort with a wide dis-tribution of schooling years and, partitioning word productionalong time-quartiles contributed to the finding of specificgenetic markers for verbal fluency at 60 s, T1, T2 e T3.Importantly, the gene influencing score for 60 s (RIMS1) hasbeen previously reported to play a role in cognitive perfor-mance and schizophrenia. Our findings provide, on a biologicallevel, grounds for the presence of distinct cognitive processesrecruited during semantic verbal fluency since different loci areimplicated with each one of the time-intervals.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.238

SU50. THE NDE1 GENOMIC LOCUS CAN AFFECT TREAT-MENT OF PSYCHIATRIC ILLNESS THROUGH GENEEXPRESSION CHANGES RELATED TO MICRORNA-484

Nicholas Bradshaw2, Liisa Ukkola-Vuoti3, Maiju Pankakoski4,Amanda Zheutlin5, Alfredo Ortega-Alonso3,Minna Torniainen4, Vishal Sinha6, Sebastian Therman4,Tiina Paunio4, Jaana Suvisaari4, Jouko Lönnqvist4,Tyrone Cannon5, Jari Haukka6, William Hennah

n,1

1Institute for Molecular Medicine, University of Helsinki2Heinrich Heine University3Institute for Molecular Medicine4National Institute for Health and Welfare5Yale University6University of Helsinki

Background: Genetic studies of familial schizophrenia inFinland have observed significant associations with a group ofbiologically related genes, DISC1, NDE1, NDEL1, PDE4B andPDE4D, the DISC1 network. Here, we utilize gene expressionand psychoactive medication use data to study their biologi-cal consequences and potential treatment implications.

Methods: Gene expression levels were determined in 64individuals from 18 families, whilst prescription medicationinformation has been collected over a ten-year period for931 affected individuals.Results: We demonstrate that the NDE1 SNP rs2242549associates with significant changes in a large number of probes(n=2,908), of which 944 genes were replicable. A significantnumber of the total genes altered (347 out of 2,510,p=3.0� 10-8) were predicted targets of microRNA-484, locatedon a non-coding exon of NDE1. Variants within the NDE1 locusalso displayed significant genotype by gender interaction toearly cessation of psychoactive medications metabolized byCYP2C19. Furthermore, we demonstrate that miR-484 canaffect the expression of CYP2C19 in a cell culture system.Discussion: Thus, mutations at the NDE1 locus may alterrisk to mental illness, in part through modification of miR-484, and such modification alters treatment response tospecific psychoactive medications, leading to the potentialuse of this locus in targeting treatment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.239

SU51. MIR-34A IN NEUROPSYCHIATRIC RESEARCH ANDFUNCTIONAL ANALYSIS TO DEFINE ITS REGULATORYEFFECTS

Ashish Kumarn,1, Sobha Puppala1, Ellen Quillen1,

Jennifer L. Neary2, Joanne E. Curran3,Ravindranath Duggirala3, David C. Glahn4, John Blangero3,Dianne Cruz5, Mark Z. Kos3, Melanie A. Carless1

1Texas Biomedical Research Institute2Avagen Health3University of Texas Rio Grande Valley4Yale University5Duke Kathleen Price Bryan Brain Bank and Biorepository

Background: We recently assessed blood-based miRNAexpression profiles for association with age in a cohort of 895Mexican Americans. Of 2,747 miRNAs that were tested (includ-ing SNP-derived and novel miRNAs in addition to those reportedin miRBase 21), we identified significant associations for 46known miRNAs (po1.82� 10-5) and chronological age. miRNAover-representation analysis through the miEAA tool identifiedAlzheimer's disease as the top-ranked disease category(p=5.31� 10–34) over-represented in our data set. Severalpublished studies have identified multiple miRNAs associatedwith Alzheimer's disease, including miR-34a-5p, which has beenproposed as a biomarker for diagnosis and was significantlyassociated with age in our study (p=1.14� 10–11). In addition,miR-34a-5p has been implicated as either a peripheral biomar-ker, or within brain tissue, in unipolar and bipolar depressionand schizophrenia. Published cell studies implicate miR-34a inneuronal differentiation and maturation and animal studiesindicate involvement in Alzheimer's disease pathology andrelated cognitive deficits, as well as in learning and emotion.

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Methods: We conducted in vivo studies to test for correla-tions between blood and brain miR-34a-5p expression acrossseven brain regions in four baboons. Then, to investigatethe consequences of increased miRNA expression on geneexpression, we transfected four neuronal and glial cell lines(CHP-212, HCN-2, SVG-P12 and A172) with a miR-34a-5pmimic. We performed functional annotation of genes thatwere at least 2-fold up- or down-regulated in each of thecell lines using DAVID.Results: Our in vivo studies using baboons as a modelorganism show moderate to strong correlation of miR-34a-5p expression across blood and amygdala (r=0.69), dorsalanterior cingulate cortex (r=0.95), hypothalamus (r=0.77),lateral orbitofrontal cortex (r=0.81) and medial orbitofron-tal cortex (0.56), further strengthening its potential role inneuropsychiatric disease. Our in vitro studies identifiedseveral functional categories and gene ontologies that wereconsistent across two or more cell lines, including phospho-protein, alternative splicing, protein binding and cell cycle.Discussion: Through a combination of in vivo, in vitro andin silico studies, we strengthen the argument for miR-34a-5p as an important player in neuropsychiatric research. Ourfindings suggest important downstream consequences ofinduced overexpression of miR-34a-5p. We are currentlytrying to develop a novel unbiased in vitro method to detectmiRNA-mRNA binding interactions that would be broadlyapplicable to any cell type using miR-34a-5p as a model.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.240

SU52. UTILITY OF PERIPHERAL miRNA EXPRESSIONPROFILES AS BIOMARKERS AND PATHOLOGICAL INDICA-TORS OF NEUROPSYCHIATRIC DISEASE

Melanie Carlessn,1, Sobha Puppala1, Ellen Quillen1,

Jennifer Neary2, Peter Fox3, Rene Olvera3, Joanne Curran4,Ravindranath Duggirala4, Cun Li5, David Glahn6,John Blangero4, Dianne Cruz7, Peter Nathanielsz5

1Texas Biomedical Research Institute2Avagen Health3University of Texas Health Science Center at San Antonio4University of Texas Rio Grande Valley5University of Wyoming6Yale University7Duke University

Background: Given the inaccessibility of brain tissue forlarge cohort-based and longitudinal studies, analysis ofperipheral blood as a surrogate tissue has become a mainstaywithin the neuropsychiatric field for analysis of gene andmiRNA expression and DNA methylation. Although the impor-tance of peripheral biomarkers as diagnostic and prognosticindicators is well recognized, translation of findings intomeaningful pathology is more difficult to achieve. Lack of

validation of peripheral biomarkers in brain tissue may beconfounded by smaller sample sizes, investigation of inap-propriate brain regions, or post-mortem complications.Methods: To shed some light on the utility of blood-basedbiomarkers to inform upon pathology of disease, we inves-tigated correlations between miRNA expression levels inblood and brain tissue from 14 cortical and subcorticalregions within two groups of baboons (n=4, n=6; 7 brainregions each). To better understand how blood-brain corre-lations might relate to human biology and disease, weinvestigated a subset of 212 miRNAs whose peripheral bloodexpression was at least moderately correlated (rZ0.5) with50% or more of the brain regions examined in a family-basedcohort of Mexican Americans (n=896) for whom we haveextensive neurocognitive and neuroanatomical phenotypesas well as peripheral blood miRNA profiles. We tested 145human peripheral blood-expressed miRNAs for associationagainst 34 cortical and 10 subcortical structures (usingmagnetic resonance imaging data), and 24 neurocognitivephenotypes. Due to high inter-relatedness and potentiallyunknown correlations across many of the phenotypesassessed, we corrected only for the number of miRNAstested, setting the significance threshold at po3.45� 10-4.Results: The overall correlation (r) of miRNA expressionprofiles between blood and 14 different brain regions inbaboons ranged from 0.62–0.66. We identified 444 miRNAsthat were expressed in 90% of all samples analyzed and ofthese, 212 showed at least moderate correlation (rZ0.5)between blood and 50% or more of the brain regionsexamined. Within this subset of baboon-defined correlatedmiRNAs, we identified 145 that were also expressed in atleast 90% of our human cohort and tested these forassociation with neurological traits. We identified 34 sig-nificant associations between miRNAs and neurologicaltraits. Of these, one of the most interesting findings wasassociation of peripheral miR-144-3p expression with amyg-dala (p=8.50� 10-5) and hippocampus (p=5.86� 10-5)volumes, as well as thickness of the fusiform gyrus(p=1.98� 10-5). In our baboon study, peripheral expressionof this miRNA was highly correlated with expression in theamygdala (r=1.00) and hippocampus (r=0.66), expressionwas not measured in the fusiform gyrus.Discussion: Prior studies have shown that overexpressionof miR-144-3p in the basolateral amygdala of mice rescuedimpaired fear extinction, and also that expression of miR-144-3p is increased in the hippocampus of rats followingchronic treatment of both lithium and valproate moodstabilizers. Our studies highlight the utility of using periph-eral blood as a surrogate tissue for miRNA profiling andindicate that disease associations identified using peripheralblood may point toward pathological processes within thebrain, particularly for miRNAs whose expression is corre-lated between blood and brain.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.241

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SU53. GENOME-WIDE DNA METHYLATION ANALYSIS INTHE SALIVA OF CRACK COCAINE DEPENDENTS

Caroline Camilon,1, Mariana Maschietto2,

André Brooking Negrão1, Marcelo Ribeiro3,Ronaldo Laranjeira3, Helena Brentani1, Homero Vallada1

1University of São Paulo Medical School2Brazilian Bioscience National Laboratory, National Centerfor Research in Energy and Materials3Federal University of São Paulo

Background: DNA methylation has been increasinglyrecognized in the etiology of drug dependence. Due to thedifficulties in assessing brain tissue in living humans,peripheral cells such as blood and saliva have been exploredas alternatives to explore the involvement of DNA methyla-tion in drug dependency. Here, we characterized DNAmethylation changes in the saliva from crack cocaine userscompared to health controls.Methods: DNA was extracted from saliva of 128 crackcocaine dependents and 109 health controls (males, age34.8 +/- 9.9 years). Bisulfite converted DNA was hybri-dized in the Illumina Infinium MethylationEPIC BeadChiparrays. Cellular composition heterogeneity was cor-rected using RefFreeEwas followed identification ofdifferentially CpG sites using limma (DMSs). Using DMSswith pvalueo0.05, the Differentially Methylated Regions(DMRs, at least seven CpG sites in 300 bases, adjustedp-valueo0.05) were identified using bumphunter. DMRslocated in gene promoters were analyzed using Func-tional Epigenetic Modules (FEM) package to identifygene-gene interaction networks potentially involvedwith crack cocaine use.Results: Comparison between crack cocaine depen-dents and controls revealed 3,857 DMRs which wereinvolved with metabolic processes related to nucleicacid, ncRNA and rRNA processing, gene expression andprotein-DNA complex assembly. The gene-gene interac-tion analysis revealed three networks: one containing 11genes, which were enriched for biological processesrelated to mitochondrial function; a second networkcomposed by 36 genes which was enriched mainly forglycosylphosphatidylinositol (GPI) activity and extracel-lular membrane interaction biological processes; and athird network with 22 genes that was enriched forsynapse related processes (GABaergic, serotononergicand cholinergic synapses) and, interestingly, biologicalprocesses related to visual perception.Discussion: These results suggest that the use of salivamay help to understand the mechanisms underlying thepathology of drug abuse. Changes in DNA methylationfound in the saliva revealed perturbation in pathwaysrelated to the reward system, often found affected indrug dependents. Moreover, the enrichment analysis ofthe networks replicated our previous study performed inperipheral blood where molecular functions related toprotein activity were associated with cocaine and crackdependency.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.242

SU54. A PILOT METHYLATED DNA IMMUNOPRECIPITA-TION SEQUENCING: HYPERMETHYLATION OF THEDEATH-ASSOCIATED PROTEIN 3 (DAP3) AND MIR2110IN FIBROMYALGIA ASSOCIATED WITH CHILD ABUSEHISTORY AMONG AFRICAN AMERICAN FEMALES

Hyunhwa Leen,1, Annette Mullis1, Sijung Yun2, Katrina Isla1,

Jonica Estrada1, Nada Lukkahatai3, Leorey Saligan4,Brian Walitt4

1University of Nevada, Las Vegas2Yotta Biomed, LLC3Johns Hopkins University4National Institutes of Health

Background: Epigenetics, such as DNA methylation, hasbeen hypothesized as one possible mechanism to explainthe association between adverse childhood experiences andlater health problems. The goal of this study was to identifygenome-wide DNA methylation markers from peripheralblood associated with child abuse history among 6 AfricanAmerican adult females with Fibromyalgia Syndrome (FMS)using Methylated DNA Immuno-Precipitation sequencing(MeDIP-Seq).Methods: Data were from a fibromyalgia, natural historystudy approved by the MedStar Health IRB. FMS wasdiagnosed using the 1990 or the 2010 American College ofRheumatology criteria and the Widespread Pain Index. Pain,fatigue, anxiety, depression, and cognitive function wereassessed. A detailed abuse history was obtained, includingage at the time and type of abuse (i.e., emotional, physical,or rape). A total of 6 FMS African American females,including 4 with any abuse before age 18 (Abused FMSfemale; AbFF) and 2 without (Non-abused FMS female; NFF),were selected in this study.

Using peripheral blood collected from the subjects’genomic DNA was extracted. DNA fragments containingmethylated CpG were enriched and sequenced in theHiSeq-2500 system using MeDIP-Seq. Reads were aligned tothe reference human genome of hg38. Generated sam fileswere sorted according to chromosomal position. Peaks werecalled using MACS version 2.1.1.20160309, to identifymethylated DNA regions. DiffBind software package wasused to perform clustering, Principal Component Analysis(PCA), and differential peak interval analysis with FalseDiscovery Rate (FDR) of 0.05 cutoff.Results: All of the 6 subjects with FMS met both the 1990and 2010 criteria, except 1 NFF who only met the 1990criteria. Age ranged from 45 to 56 years (mean=53.5,SD=4.23). The majority (66.7%) did not have a collegeeducation, unemployed, or divorced or widowed. Amongthe 4 AFFs, 1 reported rape + physical abuse, 2 reportedrape only, and 1 reported emotional abuse. No significant

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differences were found in clinical symptoms or character-istics between AbFFs and NFFs.

The number of methylated intervals per each subjectranged from 234,842 to 454,508. With the union of all theseintervals, we obtained 412,226 methylated intervals, over-all. Both of clustering analysis and PCA clearly separatedAbFFs and NFFs. The differential analysis with FDR of 0.05identified 15 intervals hypermethylated for AFPs andanother 15 intervals hypermethylated for NFPs. Afterexcluding ambiguous regions to interpret (e.g., repetitiveDNA regions such as ribosomal repeating regions, the humanalpha satellite repeat region) we identified DAP3 andmir2110 hypermethylated for AbFFs compared to NFFs.Discussion: This study suggests hypermethylation in DAP3and mir2110 could be used as candidates for novel biomar-kers associated with child abuse history in African Americanfemales with fibromyalgia. Epigenetic inactivation patterns,especially one in DAP3, are found in numerous tumor cellsand negatively affect cancer prognosis. Reduced DAP3expression affects its normal regulation of cell respirationand apoptosis induced by oxidative stress, which is impor-tant of cell death pathways related to the ischemia-reperfusion injury. Further study is required to confirm thisfinding with more clinical samples.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.243

SU55. FETAL ALCOHOL EXPOSURE IN RATS LEADS TOLONG-TERM CHANGES IN DNA METHYLATION PATTERNSOF TASTE-RELATED GENES IN POSTNATAL TONGUE

Qian Dun,1, Steve Youngentob2, Frank Middleton1

1SUNY Upstate Medical University2The University of Tennessee Health Science Center

Background: Considerable evidence indicates that thereare potential long-term consequences of maternal alcoholconsumption. Such exposures can lead to postnatal changesin the formation and function of brain circuits involved inlearning, memory, and reward processing, and increasesubsequent risks of alcohol abuse in later life. Althoughmuch interest has focused on the central areas affected bysuch exposures, less attention has been paid to the effectssuch exposures produce in the peripheral gustatory system.Here, we studied the potential molecular adaptationsproduced by fetal alcohol exposure in the postnatal che-mosensory system by studying DNA methylation changes inCircumvallate Papillae (CV) taste cells in postnatal rats.Methods: Pregnant Long Evans rats were divided into twoweight-matched groups. Within each group the dams wererandomly assigned to one of two dietary treatments (ET:ethanol, FCL: free choice liquid). Dams in the ET group weregiven ad libitum access to a liquid ethanol containing diet,with increasing amounts of ethanol between gestational(G) days 6–10, and full strength dose during G11-20. In thefull strength diet, ethanol provided 35% of an animal's daily

calories. Moreover, the timing of these administrations alsoexposed the fetus to ethanol during the developmentalperiod (G11–20) of olfactory and orosensory systems. Afterdelivery, rats born to dams in the ET group or the FCL groupwere chosen at random and sacrificed during mid-adoles-cence at P42. DNA samples were isolated from the CV oftongues, followed by genome-wide differential methylationanalysis using the Rat Methyl-Seq DMR Capture kit (Agilent)and Illumina NexteraXT sequencing protocol.Results: Differentially methylated cytosine residues wereobserved within and at the promoter regions of a largeamount of olfactory receptor, taste receptor, oral-irritation,and gustatory signal transduction genes. Detailed examina-tion of the methylation patterns of oro-sensory genesrevealed interesting features of alternation. We also testedthe ability of Partial Least Squares Discriminant Analysis(PLS-DA) to identify specific cytosine residues that couldseparate the two groups of ET and FCL prenatal-exposedrats. This indicated that cytosine resides with the mostdistinguishing power appeared to be located in closeproximity to each other, corroborating the Runs test results.Thus, prenatal ET exposure could lead to the formation ofcis-acting methylation blocks that strongly regulate orcoordinate the expression of chemosensory-related genes,and fundamentally alter taste perception and taste prefer-ences. Furthermore, pathway analysis revealed enrichmentof genes involved in signal transduction pathways andepigenetic modification pathways, including genes such asGrm3, S1pr1, Prkacb, Hdac7 and Kcnmb4.Discussion: Our results are the first evidences indicatingthat in addition to central nerves system effects, fetalalcohol exposure induced alcohol preference in later lifecould also be produced by altered patterns of DNA methyla-tion in the peripheral gustatory system, via dysregulatedexpression of oro-sensory-related genes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.244

SU56. DIFFERENTIAL DNA METHYLATION AT BIRTHASSOCIATED WITH MENTAL DISORDER IN INDIVIDUALSWITH 22Q11.2 DELETION SYNDROME

Anna Starnawskan,1, Christine Hansen2, Thomas Sparsø3,

Wiktor Mazin4, Line Olsen5, Marcelo Bertalan6, Alfonso Buil6,Jonas Bybjerg-Grauholm2, Marie Bækvad-Hansen7,David Hougaard2, Preben Bo Mortensen1,Carsten B. Pedersen8, Mette Nyegaard1, Thomas Werge9,Shantel Weinsheimer9

1Aarhus University2Statens Serum Institut3Mental Health Centre, Sct Hans4Pediatric Oncology Research Laboratory, University Hospi-tal Rigshospitalet5Research Institute of Biological Psychiatry6Institute for Biological Psychiatry

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7Section of Neonatal Genetics, Danish Center for NeonatalScreening, Statens Serum Institut8Centre for Integrated Register-based Research, AarhusUniversity9Institute for Biological Psychiatry, MHC Sct. Hans, MentalHealth Services

Background: Individuals with 22q11.2 Deletion Syndrome(DS) have an increased risk of comorbid mental disordersincluding schizophrenia, attention deficit hyperactivity dis-order, depression, as well as intellectual disability. Whilemost 22q11.2 deletion carriers have the long 3 Mb form ofthe hemizygous deletion, there remains a large variation inthe development and progression of psychiatric disorders,which suggests that alternative factors contribute to thepathogenesis. In this study, we investigated whether neonatalDNA methylation signatures in individuals with the 22q11.2deletion associate with mental disorder later in life.Methods: Subjects with 22q11.2 deletion were selectedfrom The Danish Cytogenetic Central Register. DNA methyla-tion was measured genome-wide with the use of InfiniumHumanMethylation450 BeadChip from neonatal dried bloodspots in a cohort of 164 individuals with 22q11.2DS, including48 diagnosed with a psychiatric disorder. Epigenome-WideAssociation Study (EWAS) was performed to determine differ-ential DNA methylation among 22q11.2 deletion carriersdiagnosed with mental disorder compared to carriers withno current or past mental disorder diagnosis. Most associatedsites were used for Gene Ontology pathway enrichmentanalysis. Moreover, we evaluated four sub-classes of mostcommonly observed psychiatric diagnoses (intellectual dis-ability: F70-79, behavioral disorders: F90-98, disorders ofpsychological development: F80-89 and schizophrenia spec-trum disorders: F20-29) in the cohort and compared theirmethylome profiles to the non-psychiatric controls. Regres-sion models, adjusted for sex, type of 22q11.2 deletion, andage of the blood spot card, were used for all EWAS analysesto identify differentially methylated sites.Results: Among several CpG sites with p-value o 10-6, weidentified cg23546855 (p-value=2.15� 10-7) mapping toSTK32C to be associated with a later psychiatric diagnosis.Pathway analysis of the top findings resulted in the identi-fication of several Gene Ontology pathways to be signifi-cantly enriched (p-value o 0.05 after BH correction),among them: neurogenesis, neuron development, neuronprojection development, astrocyte development, axonogen-esis, and axon guidance. Additionally, we identified differ-entially methylated CpG sites in LRP2BP (p-value=5.37� 10-8) to be associated with intellectual dis-ability, in TOP1 (p-value=1.86� 10-7) with behavioral dis-orders, in NOSIP (p-value=5.12� 10-8) with disorders ofpsychological development, and in SEMA4B (p-value=4.02� 10-7) with schizophrenia spectrum disorders.Discussion: In conclusion, our study suggests an associa-tion of DNA methylation differences at birth with develop-ment of mental disorder later in life in 22q11.2DSindividuals. Differentially methylated sites were located ingenes enriched in those involved in neurogenesis, nervousdevelopment, and neuron projection development, what

supports previous studies that suggested mental disorders tohave an early neurodevelopmental component.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.245

SU57. PRENATAL STRESS AND EPIGENETIC PROFILE INNEONATES1

Verônica Luiza Euclydesn,1, André Barbosa1, Laura Bastos1,

Alexandra Brentani2, Gunter Fink2, Caroline Camilo1,Mariana Machietto3, Helena Brentani1

1University of São Paulo2Harvard University3Brazilian Bioscience National Laboratory, National Centerfor Research in Energy and Materials

Background: Environmental factors during intrauterinelife play an important role in neurodevelopmental disorders.Maternal metabolic and psychosocial stress in pregnancy hasbeen suggested to influence the infant neurodevelopment,which may be mediated by DNA methylation (DNAm). In thisstudy, we investigated the relationship between exposition toprenatal stress and changes in DNAm of the cord blood asoutcome.Methods: DNA was collected from 89 cord blood samples,bisulfite converted and hybridized to the Illumina Human-Methylation450 Beadchip array. Mothers have an age range of26 years (SD76) and were assessed for weight gain, BMI,psychiatric disease and psychosocial stress during pregnancy.We applied a Principal Components Analysis (PCA) to evaluatethe maternal variables and k-means clustering to identifysubgroups. Furthermore, Differential Methylation Regions(DMRs) were identified between groups using bumphunteras implemented in ChAMP, considering a minimum of six CpGsites in the same direction within 300 base pairs.Results: Three components explained 60% of variationbetween all characteristics of the mothers. Clustering ana-lysis revealed two clusters that grouped mothers with abetter (group 1) or worst (group 2) profile for metaboliccharacteristics (higher pre-gestational BMI and weight gainduring gestation) and psychic stress (psychiatric disease andpsychosocial stress). We identified 18 DMRs (adjusted p-valueo0.05) between groups, mainly related to metabolic path-ways, energy metabolism and global developmental delay.Discussion: Genes associated to the differential methylationbetween mothers from group 1 and group 2 were associatedwith metabolism, cell matrix, neurotransmitters precursors anddevelopmental delay biological processes. Maternal stress dur-ing pregnancy increases the energy demand by the placentacells, which could indicate a possible programmed susceptibilitythat may have adverse consequences on the fetal neurodeve-lopment. We suggest that identification of DNA methylationchanges in the cord blood could be explored as a predictive

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feature for the outcomes of psychosocial and emotional stressassociated with biological factors during pregnancy.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.246

SU58. EPIGENOME-WIDE ASSOCIATION ANALYSIS ANDREPLICATION IMPLICATES DEREGULATION OF PCSK9 INALCOHOL USE DISORDER

Falk Lohoffn,1, Jill Sorcher1, Allison Rosen1, Kelsey Mauro1,

Leandro Vendruscolo1, George Koob1, Gin Gao1,Christine Muench1, Zachary Kaminsky2

1National Institutes of Health2Johns Hopkins University

Background: Alcohol Use Disorder (AUD) is a common andchronic disorder with substantial effects on personal andpublic health. The underlying pathophysiology is poorlyunderstood but strong evidence suggests significant rolesof both genetic and epigenetic components.Methods: Given that alcohol affects many organ sys-tems, we performed a cross-tissue and cross-phenotypicanalysis of genome-wide methylomic variation using Illu-mina HM450 and EPIC chip arrays in AUD samples from3 discovery, 4 replication, and 2 translational cohorts.The discovery samples consisted of postmortem braintissues (n=46), bloods form a resting-state functionalconnectivity imaging endophenotypes (n=68) and post-mortem brain tissues sorted into neuronal and non-neuronal cells (n=58).Results: Overrepresentation analyses identified 68 sig-nificant CpG probes of which the most significantlyassociated probe cg01444643 was in in the promoter ofthe proprotein convertase subtilisin/kexin 9 (PCSK9)gene (p=0.002). Biological validation showed that PCSK9promoter methylation is conserved across tissues (brain-blood-liver) and positively correlated with expression.Replication in AUD datasets confirmed PCSK9 hypomethy-lation (n=392, po0.05) and a translational mouse modelof AUD showed that alcohol exposure leads to PCSK9mRNA and protein downregulation (po0.0001). Postmor-tem human liver tissue analyses in control (n=47) andliver transplant cases due to alcohol cirrhosis (n=50)showed marked increase of methylation at cg01444643(Po0.0001) and significantly decreased PCSK9 expres-sion (po0.01). PCSK9 is primarily expressed in theliver and regulates low density lipoprotein cholesterol(LDL-C).Discussion: Our finding of alcohol-induced epigeneticregulation of PCSK9 represents one of the underlyingmechanisms between the well-known effects of alcohol onlipid metabolism and cardiovascular risk, with light alcoholuse generally being protective while chronic heavy use hasdetrimental health outcomes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.247

SU59. EVALUATION AND CO-EXPRESSION OF MARKERGENES OF CELL TYPES IN BRAIN

Rujia Dain,1, Chuan Jiao1, Yu Chen1, Chao Chen1, Chunyu Liu2

1The State Key Laboratory of Medical Genetics, CentralSouth University2University of Illinois at Chicago

Background: There are many types of cells in the brain.They form the structure and execute the function of thebrain. Cell classification conventionally uses location, mor-phology, and electrophysiological characteristics, oftencombined with cell type-specific markers. The cell type-specific marker gene is important for identifying cells in thebrain and understanding the cell-specific mechanism under-lying psychiatric disorders. However, the definition of thecell type-specific marker is frequently inconsistent acrosssources and studies. The relationship between cell typesand psychiatric disorders is not clear.Methods: The transcriptome and proteomics data of braincells from human and mouse, by RNA-Seq and microarrayfrom acutely isolation cell and primary culture cell werecollected. We followed the convention quality control andanalytical processing on the raw data. We collected 543“putative” marker genes for ten cell types that have beencommonly used from literature, In Situ Hybridization (ISH)databases and antibody companies. We defined generalmarker gene as their expressions in claimed target cells isthe highest across all cell types tested. The expressiondifference for the rigorous marker gene defined as dividingthe second highest expression level across all the other celltypes by the expression level in target cell type. We set thefold change threshold for rigorous marker gene as at least 2.Parietal cortex tissue specimens from the Stanley MedicalResearch Institute (SMRI) Neuropathology Consortium andArray collections included schizophrenia, bipolar disorderand control samples were used for Weighted Gene Co-Expression Network Analysis (WGCNA).Results: With the datasets collected and the criteriaprovided, we found that 44 general marker genes showedstable specificity across all data collected. That included 29neuron markers, eight astrocyte markers, seven oligodendro-cyte markers. The averaged correlation values of specificmarker genes between human and mouse, transcriptome andproteome, RNA-Seq and microarray, acutely isolation andprimary culture were 0.50, 0.58, 0.51 and 0.43, respectively.According to the criterion for rigorous marker genes, 23 ofthe 44 marker genes showed more than two-fold changes inat least seven data sets evaluated. The most specific markergene (fold change=710.31) is RELN, a neuron marker gene. Itis not clear whether the non-specificity of rest of markergenes is related to data quality or technical artifacts in the

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data we can use for the assessment. In the WGCNA analysis,we found general marker genes of astrocyte were signifi-cantly enriched (po2.2e-16) in disease associated module.The enriched six astrocyte marker genes (ALDH1L1, ALDOC,CLU, GJA1, SLC1A3, SLC4A4) showed co-expression withsignificant GWAS loci of schizophrenia and bipolar disorderin previous studies.Discussion: Based on transcriptome and proteomics ofdata of isolated cells, we confirmed a small set of 44 genesto be cell-type-specific in the brain while many othercommonly-used marker genes will require additional studiesto verify their specificity. Studies using these marker genesto tag cell types should exercise caution. Moreover, astro-cyte marker genes enriched in disease-associated moduleco-expressed with known GWAS loci for schizophrenia andbipolar disorder. Further study and more data is need forevaluation of the rest non-specific marker genes and the co-expression of brain cell marker genes with psychiatricdisorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.248

SU60. MOLECULAR STUDIES OF THE ANKRYIN3 BIPO-LAR DISORDER GWAS GENE IMPLICATE A ROLE INMICROTUBULE DYNAMICS

Jacob Garza2, Xiaoli Qi2, Klaudio Gjeluci2, Melanie Leussis3,Gerard Martens4, Geert Poelmans4, Tracey Petryshen

n,1

1Massachusetts General Hospital, Harvard Medical School2Massachusetts General Hospital3Emmanuel College4Radbound University Nijmegen Medical Centre

Background: Ankyrin3 has been identified as a risk genefor Bipolar Disorder (BD) and autism spectrum disorders bymultiple genome-wide and targeted association studies aswell as sequencing studies. Carriers of the BD risk alleleshave reduced ankyrin3 expression in the brain, suggestingthat ankyrin3 suppression contributes to disease. However,the mechanism through which ankyrin3 confers risk isunknown. Ankyrin3 encodes the ankyrinG protein thattethers integral membrane proteins to the cytoskeleton.We previously reported that Ank3+/- heterozygous mice,which have �50% reduced ankyrinG in the brain, exhibitbehavioral changes reminiscent of bipolar mania (impulsiv-ity, increased motivation for reward), and altered expres-sion of proteins involved in neuron axonal transport. Boththe behavioral and protein expression changes in Ank3+/-mice are normalized by lithium treatment, supporting thedisease relevance of these findings. This study sought tofurther examine the molecular mechanism underlying thebehavioral and neuronal changes induced by ankyrin3suppression in brain.Methods: We performed RNA sequencing of hippocampusfrom Ank3+/- heterozygous and Ank3+/+ wildtype mice,followed by identification of differentially expressed genes

using the Tuxedo package. Biological pathways implicatedby RNAseq analysis were verified by Western blot ofhippocampal protein and live cell imaging of forebrainprimary neurons. CRISPR/dCas9 technology was used torepress ankyrin3 transcription in a mouse neuronal systemin order to conduct in-depth biochemical analysis. Neuronswere treated with lithium and CHIR-99021, a selectiveinhibitor of the lithium target GSK3B, as well as an inhibitorof CRMP2, an axon-specific substrate of GSK3B.Results: RNAseq identified 283 differentially expressedgenes between Ank3+/- and Ank3+/+ mouse hippocampus(fold change41.2, po10-3). There was enrichment ofgenes involved in microtubule-mediated processes (e.g.,cytoskeleton, cargo trafficking), implicating altered micro-tubule functions in Ank3+/- mice. Western blot confirmedincreased expression of the microtubule interacting proteinEB3 in the hippocampus of Ank3+/- compared to Ank3+/+mice (40% increase, po0.01), supporting microtubuleinstability. Live cell imaging of EB3 movement in primaryneurons verified microtubule instability in Ank3+/- mice(p=0.002). This was further confirmed in ankyrin3 repressedneurons (i.e., 420% increased EB3, po0.01; 25% lowerpolymerized tubulin, po0.01), and was reversed by treat-ment with lithium and CHIR-99021. Increased GSK3B-speci-fic phosphorylation of CRMP2-Thr514 (430%, po0.003)indicated impaired CRMP2 activity in ankyrin3 repressedneurons. Treatment with a CRMP2 inhibitor blocked lithiumand CHIR-99021 reversal of elevated EB3, indicating thatCRMP2 dependent signaling is involved in the microtubuledefects of Ank3+/- mice.Discussion: Ankyrin3 disruption in mice is associated withaltered neuronal microtubule dynamics. Lithium reversal ofboth the microtubule and behavioral changes of Ank3+/-mice suggest that microtubule defects underlie manic-likebehaviors observed in these mice. Our results support theinvestigation of risk genes using mouse and neuronal modelsto elucidate the neural mechanisms underlying psychiatricillness.

Disclosure: Biohaven Pharmaceuticals – Royalties, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.249

SU61. ASSESSING BEHAVIOR AND ANXIETY IN THEDHCR7Δ3-5/T93M MOUSE MODEL OF SMITH-LEMLI-OPITZ SYNDROME

Joanna Crossn,1, Margaret Keil1, Forbes Porter1,

Frances Platt2

1National Institutes of Health2University of Oxford

Background: Smith-Lemli-Opitz Syndrome (SLOS) is anautosomal recessive inborn error of cholesterol synthesiscaused by mutation of the 7-dehydrocholesterol reductase(DHCR7) gene. This results in abnormal sterol levels,increased 7-dehydrocholesterol and typically decreasedcholesterol. Although SLOS has a characteristic physical

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phenotype, with the most common finding being 2-3 toesyndactyly, there are also multiple behavioral abnormal-ities. These include cognitive deficits, anxiety, hyper-activity, sleep cycle disturbance, language impairment andautism spectrum behaviors.Methods: There are currently two main mouse models ofSLOS; a homozygous null, Dhcr7Δ3-5/Δ3-5, and a modelcombining the null mutation and the common p.T93Mmissense mutation, Dhcr7Δ3-5/T93M. Unlike the nullmodel, the hypomorphic Dhcr7T93M/Δ3-5 mice can live toadulthood and are therefore suitable for behavioral studies.Anxiety can be measured via multiple commonly usedprotocols; elevated plus maze (EPM), open field test andassessing burrowing and nesting behavior.Results: Although there was variation in all genders andgenotypes, overall the Dhcr7T93M/Δ3-5 mice were margin-ally more likely to have increased burrowing compared tocontrols. However, this was only significant at 4 months inthe overnight study. In contrast, the Nestlet test and EPMare both suggestive of decreased anxiety in the Dhcr7T93M/Δ3-5 mice. Additional histological analysis showed thatDhcr7T93M/Δ3-5 mice tended to have a smaller hippocam-pus and anterior commissure than age and gender matchedcontrols.Discussion: The increased burrowing could be showingthe increased anxiety phenotype or hyperactivity, which isalso noted in the increased gait speed of the Dhcr7T93M/Δ3-5 mice in the open field test. However, the results of theNestlet test and EPM are opposite to what is typicallyobserved in patients, therefore these findings are eitherthe result of a secondary defect or suggest that theDhcr7T93M/Δ3-5 model does not replicate the behavioraltraits of patients. The hippocampus is the part of the brainresponsible for learning, memory and spatial awareness. Assuch, the changes seen in the hippocampus could explainthe decreased shredding observed in the Nestlet test andthe potential delayed learning of the Dhcr7T93M/Δ3-5mice, observed by the normalization of the behaviors inthe EPM and open field tasks. These results are suggestive ofsubtle structural defects and justify further analysis, parti-cularly using mice with an isogenic background where thedifferences may be more distinct. As SLOS does not have anoptimal treatment pathway, if the results suggested bythese tests are accurate, it could help aid the developmentof therapeutic interventions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.250

SU62. A CHROMATIN CATALOG FOR THE INTERPRETA-TION OF GENETIC ASSOCIATIONS OF PSYCHIATRICDISORDERS

Paola Giusti-Rodriguezn,1, Leina Lu2, Cheynna Crowley1,

Julien Bryois3, Xiaoxiao Liu2, Amir Sariaslan3, Ivan Juric4,Joshua Martin1, NaEshia Ancalade1, Daniela DeCristo1,Craig Stockmeier5, Ming Hu4, Fulai Jin2, Yun Li1,Patrick Sullivan1

1University of North Carolina at Chapel Hill2Case Western Reserve University3Karolinska Institutet4Lerner Research Institute, Cleveland Clinic Foundation5University of Mississippi School of Medicine

Background: Schizophrenia is an often devastating psy-chiatric disorder with substantial morbidity, mortality, andpersonal and societal costs. Genome-wide association, CopyNumber Variant (CNV), and exome studies have demon-strated that schizophrenia is a complex genetic disorder,with likely hundreds of genes contributing to its geneticarchitecture. For most schizophrenia GWAS loci, we areunable to pinpoint the specific genes that connect withthese GWAS signals or the direction of association. Thismarkedly limits the biological, clinical, and therapeuticutility of these findings. Prior studies have demonstratedthe importance of chromatin looping as a regulatorymechanism and as a way to connect Single NucleotidePolymorphisms (SNPs) to genes. We aim to facilitate theinterpretation and prioritization of genomic findings fromschizophrenia and other psychiatric disorders by generatinga catalog of chromatin interactions in fetal and adult brainusing easy Hi-C (eHi-C, a variation of Hi-C). Generating CNS-specific functional genomics data is critical for the devel-opment of a mechanistic understanding of genetic findingsin psychiatric disorders.Methods: Chromosome conformation capture methodsenable the identification of chromatin interactions in vivo. Inthis study, we implemented eHi-C to generate a comprehensivemap of brain-specific chromatin interactions in fetal (n=3) andadult frontal cortex (n=3) at a genome-wide level (�1 billionreads/sample). We used in-house pipelines to process the Hi-Cdata in line with established methods. As part of qualitycontrol, we examined summary statistics of Hi-C reads, includ-ing total number of reads, total number of uniquely mappedreads, total number of intra-chromosomal reads, and totalnumber of intra-chromosomal reads which are 415 kb. HiC-Norm was used to normalize raw Hi-C contact matrices. Weused the insulation square method to identify the boundaryregions of topologically associating domains. We used Fit-Hi-Cto detect chromatin interaction peaks for all intra-chromosomalinteractions within 2 Mb. We further applied HiCNormCis toidentify the frequently interacting regions (FIREs), and per-formed GREAT analysis to assign biological meanings to thedetected FIREs. We used HUGIn to visualize Hi-C data andrelated genetic and epigenetic features.Results: All summary statistics from both fetal and adultsamples were comparable to previous Hi-C studies. Biologi-cal replicates for each sample, showed high reproducibility(Pearson correlation coefficients 4 0.96). We were able toconnect several loci to genes for the recent PGC MajorDepressive Disorder (MDD) GWAS that identified 44 loci. Weare applying our chromatin catalog to emerging geneticfindings of psychiatric disorders and to the identification ofdevelopmentally relevant chromatin interactions.Discussion: We used eHi-C to generate high-resolutionchromatin interaction data from human brain, at twodevelopmental time points, to facilitate the interpretationand prioritization of genetic findings from GWAS. Large-scale connection of GWAS loci to specific genes could yield

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“actionable” findings, which may lead to the developmentof more targeted therapies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.251

SU63. GENETIC EFFECTS ON MICRORNA EXPRESSION INTHE DEVELOPING HUMAN BRAIN

Carolina Tosten,1, Heath O'Brien1, Michael O'Donovan2,

Matthew Hill2, Nicholas J Bray3

1Cardiff University School of Medicine2Cardiff University3King's College London

Background: MicroRNAs (miRNAs) are small (18–22nucleotide) RNAs that regulate the expression of othergenes in the developing and adult brain by binding to theirmRNA and causing translational repression and / or mRNAdestabilization. Altered miRNA expression has beenreported in the post-mortem brains of individuals withvarious psychiatric disorders, including schizophrenia, bipo-lar disorder and autism. Moreover, genes encoding miRNA /molecules involved in miRNA biogenesis are located atseveral high confidence genomic risk loci for psychiatricdisorders, consistent with an etiological role in theseconditions. However, despite the known importance ofmiRNA in brain development, effects of genetic variationon miRNA expression in the prenatal human brain have yetto be investigated.Methods: We are performing small RNA sequencing on alarge collection (4120) of human brain samples from thesecond trimester of gestation. We will combine these datawith genome-wide genotype information from the samesamples with the aim of identifying eQTL for miRNA in thedeveloping brain. We will test for association betweenidentified miRNA eQTL and risk variants for neuropsychiatricdisorders.Results: Details of miRNA and genetic variants influencingtheir expression in the human fetal brain will be presented.Discussion: Our data will provide important informationon miRNA expression and its genetic regulation in thedeveloping human brain.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.252

SU64. NEURAL MECHANISMS MEDIATING GENE-BEHA-VIOR ASSOCIATIONS IN AGGRESSION

Marjolein van Donkelaarn

, Janita Bralten, The ENIGMA2Consortium, EAGLE Consortium, Jan Buitelaar,Martine Hoogman, Barbara Franke

Radboud University Nijmegen Medical Centre

Background: Aggression is a heterogeneous and heritable(�50%) phenotype, associated with a substantial financialand emotional burden on society. A better understanding ofaggression etiology is needed to improve prevention andtreatment options. Genome-wide association studies ofaggression have identified several regions that may containgenetic risk factors for aggression. Imaging studies indicatethat subcortical structures involved in emotion processingand decision making play an important role in aggressionetiology. In the current study, we aimed to gain more insightinto the mechanisms leading from genetic risk factors foraggression to aggression phenotypes, by evaluating neuralcorrelates mediating gene-behavior associations.Methods: We first conducted genome-wide cross-traitmeta-analyses of aggression and different brain volumemeasures, to identify genes influencing both aggressionand brain volume. We used data of two large-scale gen-ome-wide association studies of 1) aggressive behavior inchildren and adolescents (EAGLE, N=18,988) and 2) Mag-netic Resonance Imaging (MRI)-based volume measures ofaggression-relevant brain regions (ENIGMA2, N=13,171).Competitive gene-wide analyses with a 50 kb flanking regionaround genes were performed for each phenotype, followedby fixed-effects meta-analyses using the weighted Stouffer'sZ method as implemented in MAGMA software.Results: The Vasopressin Receptor 1 A gene (AVPR1A)passed the gene-wide threshold (po2.7e-06) for associationsignificance in the meta-analysis of aggression and amygdalavolume (p= 8.78e-07), a stronger association compared tothe separate analyses of aggression (p=6.21e-05) andamygdala volume (p=3.10e-03).Discussion: Our finding suggests that an effect on amyg-dala volume may underlie the mechanism through whichAVPR1A influences aggressive behavior. AVPR1A codes forthe primary receptor of arginine vasopressin (AVP) in thebrain, a neuropeptide which has been strongly implicated incomplex social and emotional behaviors including aggres-sion. As different subtypes of aggression may be mediatedby unique underlying neurocognitive systems, we will followup by assessing gene-wide association of AVPR1A withsubtypes of aggression in our own sample of healthy adults,who have both anatomical MRI data and questionnaire dataon aggression subtypes available (BIG, N=703). Additionally,we will use mediation analysis to test whether the observedlink between the AVPR1A gene and amygdala volume isrelevant for aggressive behavior.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.253

SU65. ASSOCIATION OF POLYMORPHISM RS934945GENE PER2 WITH SLEEP DISODERS IN THE MALE POPU-LATION 25–44 YEARS IN NOVOSIBIRSK

Valery Gafarov2, Elena Gromova1, Igor Gagulin1,Dmitriy Panov

n,1, Almira Gafarova1, Eldar Krymov1

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1FSBI Institute of Internal and Preventive Medicine SB RAMS2Collaborative Laboratory of Cardiovascular DiseasesEpidemiology SB RAMS

Background: To study the prevalence and associations ofgene PER2 with sleep disorders.Methods: A random representative sample of the malepopulation aged 25–44 years who were residents of one ofNovosibirsk district was examined in 2014–2016.Results: The most common genotype of rs934945 PER2 genewas genotype G / G - 65,36%. A/G was in 30.17% and genotypeA/A was in 4,47% of men. Those carriers with the A/A genotypehas an increasing tendency of anxious dreams during sleepcompared to carriers of other genotypes. Carriers of genotype A/ A often wake up during the night. Sleep was the strongest inmen with A / G and G / G genotype. Lack of sleep (5 hours orless) is also more common in persons who had genotype withhomozygous allele A was presented in.Discussion: The gene PER2 (rs934945) in our populationhas a relationship with various chronotype that plays animportant role in understanding the basics of sleep disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.254

SU66. PATTERNS OF NONRANDOM MATING WITHIN ANDACROSS PSYCHIATRIC POPULATIONS

Ashley Nordslettenn,1, Jonathan Hess2, Stephen Glatt2,

Henrik Larsson1, Paul Lichtenstein1, Ming Tsuang3,Catarina Almqvist4, Manuel Mattheisen5, James Crowley6,David Mataix-Cols1

1Karolinska Institutet2SUNY Upstate Medical University3University of California, San Diego4Astrid Lundgren Children's Hospital5Aarhus University6University of North Carolina

Background: Psychiatric disorders are heritable, poly-genic traits, which are known to share risk alleles and forwhich non-random mating has been observed in conveni-ence samples. If present at the population level, suchselection has been posed to have significant implicationsfor the maintenance of psychiatric disorders, as the sys-tematic pairing of individuals who share any heritable traitwill result in offspring with increased, additive geneticvariance for these (and any correlated) traits. Large-scaledata repositories and genotyped cohorts are, only now,emerging at the scale needed to explore non-randommating for psychiatric traits at the population level. InSweden, national registers have permitted the first epide-miological examination of this phenomenon within andacross clinical diagnoses. In tandem, advancements in thePolygenic Risk Scoring (PRS) of psychiatric traits haveopened up avenues for assessing the evidence of nonrandommating directly at the molecular level. This poster

summarizes the insights derived, to date, from these novelresources regarding the patterns and possible mechanismsof spousal resemblance for psychiatric features.Methods: For phenotypic work, participants were all Swed-ish pairs in which at least one member of the couple had aregistered (1973-2009) psychiatric or non-psychiatric diagnosisof interest. General population samples were also derived,matched 1:5 with probands. Analyses examined the correla-tion in diagnostic status between mates, within and acrossdisorders. Conditional logistic regressions were further used toestimate the odds of each diagnosis in the mates of caseprobands, relative to matched population controls. Thegenotype work utilized 1678 Taiwanese parental pairs, derivedfrom parent-proband (schizophrenia) trios of Han Chinesedescent. Summary statistics based on Genome-Wide Associa-tion Study (GWAS) meta-analyses were used to computePolygenic Risk Scores (PRS) for both psychiatric conditionsand comparison traits including childhood Intelligence Quoti-ent (IQ). Multiple linear regressions were applied to assesssimilarities in spousal scores for each trait, while covarying forgenotype-based principal components.Results: In the Swedish sample, positive correlations indiagnostic status were broadly observed, with inter-disordercorrelations (range: 0.11-0.48) ranging slightly higher thanthose observed across disorders (0.01-0.42). These ranges wererestricted, but remained significant, when corrected forpopulation prevalence of the respective conditions (0.08-0.31; Peyrot et al., 2016). The odds of diagnosis in the partnersof case probands were significantly elevated relative tomatched controls, with magnitude varying by disorder. Theseassociations were significantly attenuated in non-psychiatricgroups. Significant, positive genotypic associations wereobserved in the Taiwanese sample, most markedly for riskrelating to ADHD, ASD, and an intermediate bipolar/schizo-phrenia phenotype. Results for comparison conditions alignedlargely with prior phenotypic findings (e.g., strongest associa-tion for IQ). Across analyses, the magnitude of resemblanceranged higher for psychiatric traits, with the largest coeffi-cients for risk of ADHD (≤0.19), and ASD (≤0.14).Discussion: Phenotypic and genotypic estimates convergeon the suggestion of nonrandom mating for psychiatricdisorders, with patterns consistent with the assumption ofassortative mating as the mechanism of such resemblance.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.255

SU67. INTERACTIVE EFFECTS OF FAMILY HISTORY,POLYGENIC RISK AND AGE ON CORTICAL THICKNESS INYOUNG PEOPLE AT HIGH GENETIC RISK OF BIPOLARDISORDER

Rhoshel K. Lenroot2, Bronwyn Overs1, Gloria Roberts2,Andrew Frankland2, Florence Levy2, Claudio Toma1, CyndiShannon Wieckert1, Peter Schofield1, Philip Mitchell3,Janice Fullerton

n,1

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1Neuroscience Research Australia2School of Psychiatry, University of New South Wales3University of New South Wales

Background: Bipolar Disorder (BP) is a highly heritablemood disorder as demonstrated by a 5 to 10 fold increasedrisk amongst first degree relatives of BP probands. Structuralimaging differences and clinical symptoms have also beenobserved amongst those with familial risk (At-Risk or AR)prior to any diagnosis of BP. Alternatively, a Polygenic RiskScore (PRS) based on known risk alleles for BD can be used asan index for increased genetic risk, facilitating an examina-tion of the biological mechanism of BP pathogenesis.Methods: Within a group of 50 young first-degree relativesof BP probands (mean age 22.6 years, SD 4.2) and 50 genderand age matched controls (22.5 years, SD 4.3) we exploredthe main and interactive effects of familial and polygenicrisk for BP on brain structure. A PRS was derived for eachsubject from 32 replicated BP associated risk alleles fromthe first Psychiatric Genomics Consortium genome-wideassociation study. Using familial risk, PRS, age, and genderas independent factors, a series of general linear modelswere applied to both vertex-wise cortical thickness dataand subcortical regions of interest segmentations extractedfrom T1-weighted magnetic resonance images.Results: While familial risk was associated with greatercortical thickness in the right inferior frontal gyrus, greaterPRS was associated with a thicker cortex in AR, and thinnercortex in controls. Age-dependent effects of PRS were alsoobserved in AR individuals, with the youngest subjectsdemonstrating the thickest cortex. For all subcorticalregions of interest examined, no main or interaction effectswere observed for familial or polygenic risk.Discussion: These findings of differential PRS effects inAR and controls subjects point to the modulating role ofother genetic and familial risk factors in the effects of PRSon brain structure. The age dependence of PRS effects inthose with familial risk indicates the possibility of a complexdevelopmental trajectory and highlights the need for long-itudinal studies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.256

SU68. COMMON VARIANTS OF NRXN1, LRP1B ANDRORA ARE ASSOCIATED WITH INCREASED VENTRICULARVOLUMES IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Ney Allieyn,1, Elliot Gershon1, Tamar A. Grey2,

Rebecca Shafee3, Neeraj Tandon3, Lucas Coppes1,Sarah Keedy1, Steven McCarroll4, Godfrey Pearlson5,M. Keshavan3, Brett A. Clementz6, C. Tamminga7,The Bipolar, Schizophrenia Network on IntermediatePhenotypes Consortium

1University of Chicago2Massachusetts Institute of Technology3Harvard Medical School

4Stanley Center for Psychiatric Research, Broad Institute ofMIT and Harvard5Yale University School of Medicine6University of Georgia7UT Southwestern

Background: Schizophrenia, schizoaffective and bipolardisorder probands share many behavioral and biologicaltraits including brain morphology features, as well as apartially overlapping complex polygenic basis. Ventricularvolume enlargement is one of the most enduring anatomicalfindings in these disorders, representing a quantitative traitassociated with severity.Methods: We performed GWAS on a multi-ethnic samplefrom the Bipolar and Schizophrenia Network for Intermedi-ate Phenotypes study (B-SNIP1) containing 1,115 unrelatedcases and controls. FreeSurfer-processed volumes fromstructural MRI were used as quantitative phenotypes inGWAS with PsychChip genotypes imputed to the 1000Genomes reference panel.Results: Genome-wide significance was reached in asso-ciations with two regional volumes within the ventricularsystem: (1) The volume of the Temporal Horn of the LeftLateral Ventricle was associated with a SNP marker ofNRXN1 (P= 1.156E-11), and (2) The volume of the CavumSeptum Pellucidum was associated with markers in LRP1B(P=1.661E-11) and RORA (P=1.72E-10).Discussion: NRXN1 rare structural variants have beenalready associated with psychosis and cognition, but this isthe first report of common SNP variants associated withincreased ventricular volume. Presumably, the observedNRNX1 effect on temporal horn volume reflects sharedregulation of morphometric characteristics of the surroundinglimbic structures of the medial temporal lobe, not evidentwhen these structures are considered separately. Previousresearch associated Cavum Septum Pellucidum persistencewith schizophrenia, and this is the first report of a commongenetic variant associated with its persistence related toneuropsychiatric disease. Co-expression analysis of NRXN1and LRP1B identified genes involved in cell adhesion andneurotransmission. Our findings represent novel genetic asso-ciations implicated in the molecular basis of neuropsychiatricdisorders at the stage of brain development.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.257

SU69. DECIPHERING THE ASSOCIATION BETWEEN POLY-GENIC RISK FOR SCHIZOPHRENIA AND HIPPOCAMPALFUNCTION

Qiang Chenn,1, Gianluca Ursini1, Richard E. Straub1,

Eugenia Radulescu1, Karen F. Berman2, Venkata S. Mattay1,Daniel R. Weinberger1

1Lieber Institute for Brain Development2Clinical & Translational Neuroscience Branch, NationalInstitute of Mental Health

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Background: In recent years, Polygenic Risk Profile Scores(PRS's) are being increasingly used to indirectly measure theaggregate genetic effect of many weakly associated mar-kers on the risk for a neuropsychiatric disorder. While theuse of PRS's has supported the polygenic architecture ofschizophrenia, a link between PRS's and the pathophysiologyof this disorder is still missing. In this study, we analyze theassociation between PRS's for schizophrenia and hippocam-pal function during a simple declarative memory task inhealthy volunteers. We then used regularized regression, amachine learning method, to further investigate the geneticstructure that drives the association between schizophreniaPRS's and altered hippocampal engagement.Methods: Two hundred and five healthy volunteers under-went BOLD fMRI (3 T) during a Simple Declarative MemoryTask (SDMT), which included incidental encoding and retrie-val of visual scenes. For both the encoding and retrievalsessions, the scenes were presented in a blocked fashion,with 4 blocks of neutral scenes and 4 blocks of visual scenesalternating with 9 blocks of resting state (fixation crosshair). In the current study, we focused on the encodingphase for neutral scenes only (Rasetti et al. 2014). PRS'swere calculated for each individual as the weighted sum ofthe number of reference alleles on preselected markersbased on PGC GWAS study (PGC 2014), with p-value thresh-old at 0.05 (24,670 SNPs). Imaging space association studywas conducted using multiple regressions in SPM8. Region ofinterest (ROI) was defined as averaged signal within a 6 mmsphere around the peak of association between PRS andright hippocampus. Regularized regression was run using ROIin R using glmnet package (Zou et al. 2005).Results: The PRS constructed with 24,670 SNPs (withassociation with schizophrenia at scoring threshold ofp=0.05) is significantly associated with hippocampal activa-tion (z=4.48, p=0.004, FWE corrected in bilateral hippo-campal ROI), so that higher PRS corresponds to bluntedhippocampal activation. Using the regularized regressionwith shrinkage factor lambda=0.001, we identified 255SNPs driving this association, so that the associationbetween the PRS based on these 255 SNPs (PRS255) andhippocampal activation increases dramatically (z=7.14,po0.001, FWE corrected in whole brain); PRS255 accountedfor 8.9% of the variance in right hippocampal activation.Discussion: Our results show that PRS's for schizophreniaare significantly associated with altered hippocampal func-tion during a simple declarative memory task even inhealthy volunteers. Using regularized regression, we areable to find a small subset of SNPs that drive the associationand account for high percentage of variance in hippocampalactivation. The use of machine learning techniques fordimension reduction allows disentangling the cumulativeeffect of risk genes on brain function.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.258

SU70. DNA METHYLATION CHANGES IN THE RAT STRIA-TUM DUE TO L-DOPA TREATMENT IN A TIC ANIMALMODEL

Luca Pagliaroli2, Ester Nespoli3, Abel Fothi4, Piroska Devay4,Istvan Liko4, Borbala Veto4, Tamas Orban4,Bastian Hengerer3, Csaba Barta

n,1, Tamas Aranyi4

1Semmelweis University2Institute of Medical Chemistry, Molecular Biology andPathobiochemistry, Semmelweis University3Boehringer Ingelheim, Biberach an der Riß4Institute of Enzymology, Research Centre for NaturalSciences, Hungarian Academy of Sciences

Background: Tourette Syndrome (TS) is a neurodevelop-mental disorder characterized by motor and vocal tics. Thecause of TS remains elusive but dopamine (DA) has a centralrole within the cortico-striatal pathway. TS has high herit-ability and a complex genetic background, but environmen-tal factors also play an important role in the development ofthe disorder. These factors often operate via epigeneticmechanisms (i.e. covalent chromatin modifications).Methods: We used a rodent tic model to test the epige-netic alterations in the striatum. Juvenile male Wistar Kyotorats were injected with 6-OH-dopamine in the left medialforebrain bundle resulting in degeneration of nigrostriataldopaminergic neurons. Chronic application of L-DOPA afterconsolidation of the lesion leads to motor tics due to thestriatal hypersensitivity to DA. We studied genome-wideDNA methylation by Reduced Representation BisulfiteSequencing technique (RRBS) in 3 groups: animals under-going lesion only, animals treated with L-DOPA after thelesion and animals co-treated with L-DOPA and riluzole(medication used in TS) after the lesion.Results: Surprisingly, by investigating the striata wedetected only a few DNA methylation changes betweenthe lesioned and control sides of the brain in each group.However, when we compared the control or the lesionedstriata of the three groups of animals we more abundantmethylation differences. L-DOPA treatment brought aboutstatistically significant DNA hypermethylation at over 1000CpG sites and hypomethylation at around 300 sites genome-wide. Several dozens of genes were identified in the vicinityof hypermethylated sites, while considerably less werehypomethylated. Some of the relevant hits include genescoding for neurotransmitter transporters, such as SLC6A2(Norepinephrine transporter), Cacna1h (Calcium channelalpha 1 h subunit), Tnfrsf8 (TNF receptor superfamily mem-ber 8), HAT1 (histone acetyltransferase 1), plus severalmicroRNA genes.Discussion: This project is a methylome study on aTourette Syndrome animal model that may provide novelcandidate genes and a better understanding of the mole-cular mechanisms behind the pathophysiology of TS.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.259

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SU71. BDNF GENE AND OBSESSIVE COMPULSIVE DISOR-DER – DO SYMPTOM DIMENSIONS HAVE SPECIFICGENETIC CORRELATES?

Meera Purushottamn

, Reshma Taj M.J., Suhas Ganesha,Sayali Deolankar, Ravikumar Nadella, Somdatta Sen,Biju Viswanath, Y.C. Janardhan Reddy, Sanjeev Jain

National Institute of Mental Health and Neurosciences

Background: Obsessive Compulsive Disorder (OCD) is acommon neuropsychiatric disorder with a worldwide 12-month prevalence ranging from 1% to 2% across studies(Weissman et al., 1995; Ruscio et al., 2010). Characterizedby repetitive intrusive thoughts, images and impulses(obsessions) and repetitive behaviors or mental acts (com-pulsions), the clinical phenotype of OCD appears to becomplex. Genetic etiology of Obsessive Compulsive Disorder(OCD) has been investigated extensively, with mixed resultsacross candidate gene studies. In this study, we perform acase control analysis of association of a single nucleotidepolymorphism rs6265(Val66Met) in Brain Derived Neuro-trophic Factor gene, that has been previously implicatedin a variety of psychiatric syndromes, and examine itsassociation with symptom dimensions of OCD.Methods: Patients (n=377) diagnosed with OCD by DSM IV –

TR were recruited from a specialty OCD clinic at theNIMHANS, Bengaluru, INDIA. Patients were assessed onsocio-demographic data, detailed history of illness, presenceof common co-morbid disorders, family history of OCD andmajor psychiatric disorders, and treatment details. Patientswere additionally assessed on Yale Brown Obsessive Compul-sive Scale (YBOCS), Mini International Neuropsychiatric Inter-view plus (MINI plus) Clinical Global Impression scale (CGI).Control population (n=449) consisted of healthy individualsalso of south Indian origin. MINI plus was administered toscreen and rule out psychiatric diagnosis in this group. DNAsamples were genotyped for polymorphism rs6265 (Val66Met)using Quantitative Real time PCR.Results: Factor analysis yielded five factor solutions as thebest fit for the data explaining 65% of the variance asfollows - Factor-1 with robust loading on hoarding obsession(0.891) & collecting compulsions (0.913). Factor-2 withObsessions of need for symmetry (0.821) & ordering compul-sions (0.864). Factor-3 with Pathological doubts obsessions(0.824) & checking compulsions (0.819). Factor-4 with Sex-ual (0.680), religious (0.655) &aggressive obsessions(0.554), mental rituals compulsions (0.630) and Factor-5with Contamination obsessions (0.919) & washing compul-sions (0.893). The allele ‘A’ frequency was found to besignificantly higher in the controls, as compared to casessuggesting a protective effect. Among the clinical variablestested in univariate analysis by genotype, factor-5 (con-tamination obsessions with washing compulsions) and factor1 (hoarding), dimension scores was significantly lower in ‘A’carriers in subjects with OCD compared to homozygous Gcarriers (GG).

Discussion: Our findings suggest a protective effect of therarer Met allele in OCD. The lower factor-5 scores in Metcarrier patients and its confirmation after controlling for theconfounders further suggests a probable specific protectiveeffect in contamination-washing dimension of OCD. Thisdimension, which is one of the most commonly observedclinical phenotype, may represent a more homogenousgroup, with specific biological underpinnings. Functionalimaging studies show that the same sub-group of OCDpatients demonstrate specific regional activation in ventro-medial prefrontal regions in symptom provocation paradigm(Mataix-Cols et al., 2004). The Met allele of rs6265 has alsobeen associated with volumetric reduction in the sameregion (Yu et al., 2009). These findings suggest a need forfuture imaging and genetic studies in specific symptomdimensions of OCD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.260

SU72. TRANSCRIPTOME STUDY IN OBSESSIVE COMPUL-SIVE DISORDERS

Bianca Lisboan,1, Ana Carolina Tahira1, Arthur Sant'Anna2,

Katia Oliveira1, Euripedes Constantino Miguel1,Marcelo Hoexter1, José Marcelo Farfel1, Helena Brentani3

1University of Sao Paulo2UFABC3Institute of Psychiatry HCFMUSP

Background: Obsessive Compulsive Disorder (OCD) is apsychiatric disorder characterized by obsessions and com-pulsions. The features of OCD are intrusive thoughts (obses-sions) and repetitive behavior (compulsions). Functionalneuroimaging studies indicate that OCD is a heterogeneousdisorder related to the cortical-striatal thalamic circuitry(CSTC) and the areas that compose this circuitry include thenucleus accumbens (NAC), Putamen (PT), Caudate Nucleus(CN), Orbitofrontal Cortex (OFC) and subgenual cingulategyri (ACC). Each brain area has a relevant role in theaffective, dorsal cognitive and ventral cognitive cortico-striatal loops (CSTC). Our proposal is compare the geneexpression from transcriptome of post mortem brain fromaffective and ventral cognitive cortico-striatal circuitry.Methods: The brains are part of the psychiatric collectionof Brain Bank of Brazilian Aging Brain Study Group (Psy-BBBABSG). All cases and controls were 50 years and older,non-demented and without previous factors that could because hypoxia or autolysis of the brain. We analyzed 56samples sourced from 8 OCD cases and 8 controls aligned bygender, age and hemisphere. The clinical, functional andpsychiatric assessment evaluation was made by next-of-kinof the deceased answered a screening with semi-structuredquestionnaires. The library was constructed with ribosome

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depletion and the RNA sequencing was performed in auto-matic sequencer lluminaHiSeq 2500. The reads were eval-uated to control quality using FastQC and aligned withgenome using TopHat (genome reference hg38). We useCuffilinks to perform the transcript assembly and HTSeq-count to determine the reads counts to gene in eachsample. The gene expression was evaluated using DESeq2and enrichment analysis was performed with WegGestalt.Results: To each circuitry we analyzed DifferentiallyExpressed Genes (DEGs), comparing OCD and controls ineach brain area. Were observed 400 DEG in NAC and 512 inthe ACC in the affective circuitry, with 16 DEG common toeach area. Enrichment analysis showed involvement of theexclusive DEGs from NAC in regulation of synaptic plasticity,glutamatergic and dopaminergic synapses, while exclusiveDEGs from ACC enriched to infection disease and metabolicprocess. To ventral cognitive circuitry, were observed 619DEG in PT and 444 in the OFC, with 25 DEG common andenrichment analysis showed exclusive DEGs from PTinvolved with regulation of neurological system processand stimulus responded, whereas exclusive DEGs from OFCinvolved with gliogenesis, ensheathment of neurons anddrug metabolic process.Discussion: We analyzed 2 circuitry involved with OCD, theaffective and ventral cognitive cortico-striatal circuitry. TheNucleus Accumbens (NAC) in striatum and subgenual cingulategyri (ACC) in cortex are involved with affective circuitry; andPutamen (PT) in striatum and Orbitofrontal Cortex (OFC) areinvolved with ventral cognitive circuitry. We found differentialgene expression between the areas with different biologicalfunctions. The next step will be the evaluation of thecoexpression networks between the two circuitry.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.261

SU73. GENE EXPRESSION IN BLOOD OF ADOLESCENTSWITH PSYCHIATRIC DISORDERS

Leticia Spindolan,1, Marcos Santoro1, Pedro Pan1,

Fernanda Talarico1, Gabriela Xavier1, Carolina Carvalho1,Ary Gadelha1, Giovanni Salum Junior2,Euripedes Constantino Miguel3, Luis Rohde4,Evelin Aline Zanardo3, Leslie Domenici Kulikowski3,Rodrigo Bressan1, Vanessa Ota1, Sintia Belangero1

1Federal University of Sao Paulo2Hospital De Clinicas De Posto Alegre3University of Sao Paulo4Federal University of Rio Grande do Sul

Background: Neuropsychiatric disorders represent a largepublic health and economic burden at a national and globallevel, and delineating the genetic architecture of mentaldisorders across molecular levels will aid in the develop-ment of novel treatment and prevention strategies.Whereas most psychiatric disorders are moderately to highlyheritable and there are evidences of shared genetic etiology

for psychiatric disorders, we aimed to investigate geneexpression profiling in adolescents with psychiatric disordersfrom a large prospective community school-based study inBrazil, the High Risk Cohort (HRC) Study for PsychiatricDisorders.Methods: This is a cross-sectional study comprised ofadolescents from the HRC. Participants were assessed usingthe structured diagnostic interview Development and Well-Being Assessment (DAWBA) to evaluate psychiatric diagnosisaccording to the DSM-IV and psychopathology measureswere assessed using Child Behavior Checklist (CBCL). Tran-scriptome in blood was compared between 23 adolescentswith at least one psychiatric disorder (PD group) and 25healthy controls (HC group) with no previous psychiatricdisorder and low psychopathology symptoms. Blood geneexpression profiling was measured using HumanHT-12 v4.0Expression BeadChip (Illumina) and the 100 most associatedgenes list was brought forth to assess whether they wereenriched for any Gene Ontology (GO) Biological Processcategory or canonical pathway (by KEGG - Kyoto Encyclo-pedia of Genes and Genomes) using the Enrichr tool.Results: The most prevalent diagnosis in PD group wasanxiety disorders (44%), followed by major depression(28%), conduct disorders (28%) and attention deficit hyper-activity disorder (ADHD – 24%), knowing that some of thosediagnoses were overlapped. We have not found differen-tially expressed genes between the PD and HC groups aftermultiple comparisons correction. The 100 most associatedgenes were enriched with GO “proteasome-mediated ubi-quitin-dependent protein catabolic process” (p=0.0005)and “proteasomal protein catabolic process” (p=0.0007);and with the KEGG “proteasome Homo sapiens” (p=0.020)and “lysosome Homo sapiens” (p=0.023) canonicalpathways.Discussion: Although we have not found a significant geneexpression profiling, likely by the sample size, our cohort isa very well clinically characterized and unique sample ofadolescents with psychiatric disorders and healthy controlsfrom HRC Study. Degradation of proteins by the ubiquitin-proteasome system is an essential biological process in thedevelopment of eukaryotic organisms. The proteasomepathway has been associated with neurodevelopmentalsyndromes and early onset of some psychiatric disorder.Therefore, our results suggest that this pathway could beassociated with early onset psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.262

SU74. COMMON GENETIC VARIANTS ASSOCIATED WITHPERSONALITY DIMENSIONS IN THE HEIDELBERGCOHORT STUDY OF THE ELDERLY (HeiDE): AN UPDATE

Urs Heilbronnern,1, Till Andlauer2, Sergi Papiol1,

Monika Budde1, Jana Strohmaier3, Fabian Streit3,Josef Frank3, Manfred Amelang4, Til Stürmer5,Bertram Muller-Myhsok2, Marcella Rietschel3,Thomas G. Schulze1

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1Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich2Max Planck Institute of Psychiatry3Central Institute of Mental Health, Medical FacultyMannheim, University of Heidelberg4University of Heidelberg5UNC Gillings School of Global Public Health

Background: The HeiDE study is an ongoing longitudinalinvestigation that started in the 1990s and, at baseline,assessed an array of personality tests in 5,114 individuals.Principal components factor analysis was used to identifyfive latent personality dimensions (“The Heidelberg Five”),interpreted as emotional lability (ELAB), lack of behavioralcontrol (LBCN), type-A-behavior (TYAB), locus of controlover disease (LOCC), and psychoticism (PSYC). At follow-up,a subset of responding participants (n=2,734) were geno-typed using Illumina PsychChip arrays. We conducted fiveinitial GWAS, analyzing common genetic variants underlyingthe previously identified orthogonal personality dimensionswith factor scores as phenotypes. For ELAB, we observed alocus that was genome-wide significant (rs79136259;p=8.2� 10-9). Recently, genome-wide data from a secondsample of the HeiDE study became available and we havenow jointly analyzed both samples and combined resultsusing meta-analysis (n=2,387 and n=881; post-QC).Methods: In both samples, we imputed common variants(MAFZ0.01) using the 1000 Genomes Phase 3 referencepanel. Data were analyzed using PLINK 1.07 (http://zzz.bwh.harvard.edu/plink/) with sex, age and the first fourancestry principal components as covariates. Fixed-effectsmeta-analysis was conducted using METAL (http://genome.sph.umich.edu/wiki/METAL). SNP-based heritability esti-mates and genetic correlations were calculated using GCTA(http://cnsgenomics.com/software/gcta/index.html),jointly on all available individuals.Results: The association of SNP rs79136259 with ELAB,discovered in the initial HeiDE sample, did not replicate inthe second sample. Association strength in the fixed-effectsmeta-analysis of both samples decreased to a nominal level(p=1.3� 10-4). For TYAB, an InDel variant on chromosome 8(rs58535027, p=1.1� 10-8) that was not significant ineither sample alone reached genome-wide significance inthe meta-analysis. No genome-wide significant associationswere found in the meta-analyses for LBCN, LOCC or PSYC.

SNP-based heritability estimates of the joint genotypedata are: 28.8% (ELAB; p=0.014), 27.3% (LBCN; p=0.019),8.4% (TYAB; p=0.262), 8.4% (LOCC; p=0.269) and 23.6%(PSYC; p=0.028). Genetic correlations between The Heidel-berg Five will be presented at the meeting.Discussion: The HeiDE cohort represents a unique oppor-tunity to study the association of personality, genetics, andlongitudinally defined phenotypes. Using an extended sam-ple, we did not find evidence for the previously reportedassociation of rs79136259 with ELAB but found evidence fora genetic variant influencing TYAB. Significant SNP-basedheritability estimates of The Heidelberg Five demonstratebiological validity of some latent personality dimensions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.263

SU75. ASSOCIATION OF PTSD WITH TELOMERE LENGTHIN FEMALE RAPE VICTIMS

Carolina Carvalhon,1, Bruno Messina Coimbra1,

Gabriela Xavier1, Fernanda Talarico1, Marcos Santoro1,Vanessa Ota1, Patricia Moretti2, Andrea Feijó Mello1,Marcelo Feijó Mello1

1Federal University of Sao Paulo2University of Brasilia

Background: Posttraumatic Stress Disorder (PTSD) is aclinical condition that occurs after experiencing a traumaticexternal stressful situation, such as exposure to sexualassault or rape. Previous studies suggested that PTSD maybe associated with shortened Leukocyte Telomere Length(LTL), in war veterans. Telomeres are repetitive DNAsequences located at the ends of chromatids that becomeshorter after each cell division. Some findings proposed thatstress induced by trauma is a probable cause of acceleratedtelomere shortening. We examined a cross-sectional asso-ciation between LTL and PTSD or psychopathological mea-sures in rape victims.Methods: The study population consisted of 32 womenrape victims with PTSD diagnosis (PTSD group) and 34healthy controls women without history of sexual traumaand mental disorders (HC group), with ages between 18 and43 years. All participants were evaluated using the MiniInternational Neuropsychiatric Interview (MINI) compatiblewith Diagnostic and Statistical Manual of Mental Disorder(DSM-V), Clinician-Administered PTSD Scale (CAPS), whichassesses PTSD symptoms, and Life Events Checklist for DSM-V, which appraises the trauma exposure. DNA was extractedfrom peripheral blood leukocytes and telomere repeat copynumber relative to single gene copy number (relative T/Sratio) was determined by quantitative real-time PCR telo-mere assay. We used logistic and linear regression models toassess associations between relative T/S ratio and PTSD orits symptoms, respectively.Results: The relative T/S ratio was determined in allsamples and we found that PTSD diagnosis was associatedwith longer LTL, after adjusting for age at blood draw(p=0.008; β=3.796; 95% confidence interval: 1.409 –

10.229), indicating elongation LTL in PTSD group (relativeT/S ratio mean=0.336; Std Deviation=0.109) compared toHC control (relative T/S ratio mean=-0.316; Std Devia-tion=0.161). However, LTL was not associated to PTSDsymptom severity, measured by CAPS (t=-0.993; p=329).Discussion: Our study found evidence of longer telomerelength in women with PTSD diagnosis compared to healthycontrols. In contrast, only one study showed accelerated LTLshortening in women rape victims with PTSD diagnosis,although, this study must be interpreted with caution, asthe sample size was very small (n=9). Nevertheless, the LTLwas not significantly associated with CAPS scores, possibly

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due to our sample size. Only one study found PTSDsymptoms were associated to shorter telomeres in womenexposed to different traumas, include rape, interpersonalviolence, sudden death of a loved one. The telomeredynamics in PTSD is unclear; few studies investigated therelationship between LTL and PTSD, in women rape victims.Different mechanisms may contribute to LTL in PTSD,including neuroprogression it was also associated withelongation of LTL in schizophrenia. Our results show thatPTSD was associated to longer LTL in rape victims, perhaps,due to the action of neuroprogression in PTSD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.264

SU76. INCREASED FREQUENCY OF RARE GENETIC DIS-EASE VARIANTS IN LARGE SCHIZOPHRENIA, BIPOLAR,AND DEPRESSION POPULATIONS

Venuja Sriretnakumarn

, Ricardo Harripaul, Kirti Mittal,John B. Vincent, James L. Kennedy, Joyce So

Centre for Addiction and Mental Health

Background: Genetic diseases are individually rare butcollectively common. Many genetic conditions can mimicmental health disorders, with psychiatric symptoms that aredifficult to treat with regular medications. Treatment of theunderlying genetic disease can cure the associated psychia-tric symptoms or help regular medications work better.Discovery of rare genetic diseases in psychiatric patientswould reveal specific treatment options, and give informa-tion about the chances of other family members beingaffected. In this study, we test the hypothesis that psychia-tric populations are enriched for pathogenic variants asso-ciated with selected treatable genetic disorders.Methods: Using targeted exome sequencing, we screened2,046 schizophrenia, bipolar and major depressive disorderpatients for variants in genes associated with Niemann-Pickdisease type C (NPC), Wilson Disease (WD), Homocystinuria(HOM), and Acute Intermittent Porphyria (AIP).Results: Our study is the first to explore the prevalence ofNPC, WD, HOM and AIP gene variants in well-definedpsychiatric populations. We found carrier rates of 0.88%,0.88% and 0.20% for NPC, WD and HOM, respectively.Furthermore, an AIP affected rate of 0.20% was observedacross the entire psychiatric cohort, a 200X enrichment incomparison to what is expected in the general population.Discussion: Discovering genetic diseases in psychiatricpatients will shift how health care is delivered to thesevulnerable patients by addressing underlying conditionsrather than masking symptoms with medications and willespecially help patients who don't respond to regularmedications. This will lead to significant cost savings tothe health care system.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.265

SU77. GENOME-WIDE ASSOCIATION STUDY IN VESTIBU-LAR NEURITIS

Dan Rujescu2, Annette Hartmannn,1, Ina Giegling2,

Bettina Konte1, Marko Herrling2, Susanne Himmelein3,Michael Strupp3

1Martin Luther University Halle-Wittenberg2German Center for Vertigo and Balance Disorders, Ludwig-Maximilians University, Psychotherapy and Psychosomatics,Martin Luther University Halle-Wittenberg3German Center for Vertigo and Balance Disorders, Ludwig-Maximilians University

Background: Virus infections affecting the central nervoussystem are discussed as causative risk factors for a variety ofconditions, among those diseases as diverse as Alzheimer'sdisease and vestibular neuritis. Vestibular neuritis is the thirdmost common cause of peripheral vertigo and is character-ized by an acute onset of sustained spinning vertigo, lastingfor many days. Although there is indirect evidence that itmay be caused by the reactivation of Herpes Simplex Type 1(HSV-1), its etiology is largely unknown.Methods: A genome-wide association study approach wasused, including 131 patients with vestibular neuritis and2609 healthy controls.Results: Genome-wide associations with vestibular neuritiswere detected in 5 regions containing protein coding genesassignable to two functional groups: virus hypothesis andinsulin metabolism. Genes of set 1 are related to viralprocesses: 1) Nuclear receptor subfamily 3 group C member2 (NR3C2) is a receptor for mineralocorticoids and glucocorti-coids and was shown to be a host factor for HSV-1 replication.2) Ankyrin repeat domain-containing protein 30 A (ANKRD30A)is a host factor for human immunodeficiency virus-1 (HIV-1)infection. It shows rapid evolution and is induced by interferonstimulation. 3) Mediator of RNA polymerase II transcriptionsubunit 30 (MED30) is an essential member of the mediatorand has been shown to be involved in replication of HIV-1, aknockdown leading to impaired viral replication. The secondset of genes (LMX1 A, SLC30A8, HTR2C) is associated to insulinmetabolism and resistance, a feature of some patients withtype 2 diabetes as an accompanying comorbidity of VN.Discussion: Using a GWAS approach to evaluate the etiol-ogy of vestibular neuritis these findings give another piece ofevidence that it may be caused by a viral inflammation.Apart from replication of these results in larger cohorts acloser look at a possible genetic and phenotypic overlapbetween HSV-1 induced diseases is necessary.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.266

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109PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

SU78. GENOME–WIDE ASSOCIATION STUDY OF LEARN-ING DISORDERS IN THE DANISH POPULATION

Veera Rajagopaln,1, Esben Agerbo2, Allan Timmermann2,

iPSYCH-Broad Consortium3, Anders Børglum1,Ditte Demontis1

1Aarhus University2Centre for Integrated Register-based Research, NationalCentre for Register-based Research, Aarhus University3Aarhus University, Broad Institute

Background: Learning disabilities are around 5–10 per-cent prevalent among children in the school-age. Thesedisorders grouped under the term ‘Specific DevelopmentalDisorders of Scholastic Skills’ (ICD-10: F81) demonstratesubstantial aggregation within families of affected mem-bers. They co-occur frequently with other psychiatric dis-orders such as Attention Deficit Hyperactivity Disorder(ADHD), Autism Spectrum Disorder (ASD) and Major Depres-sive Disorder (MDD). Twin based studies report heritability-estimates ranging from 30 to 70 percent. Despite compre-hensive multidisciplinary studies over the past decades, thespecific causal mechanisms are unknown.Methods: This study was based on 1,206 cases diagnosedwith any learning disorder according to the ICD-10 criteria(ICD-10: F81) and 13,955 controls. The cases originate fromthe iPSYCH consortium established to study six majorpsychiatric disorders. The cases are therefore enriched forcomorbidity with ADHD, ASD and MDD. Hence, we includedindividuals in the control group, with these disorders (but nodiagnosis of learning disability) in the same proportions asobserved among the cases. The diagnosis information wasobtained from the Danish Central Psychiatric Register.Subsequently Guthrie cards with dried blood spots fromthe Danish Newborn Screening Biobank were retrieved.From the blood spots, the genomic DNA was isolated, wholegenome amplified in triplicates and genotyped using theIllumina Psych chip for 500,000 markers spanning entiregenome. The non-genotyped variants were imputed with1000 genome phase-3 as reference. After extensive qualitycontrol, a GWAS was conducted for �9.7 million variants.Only Europeans and unrelated individuals were included.Significant principal components were added as covariatesto adjust for population stratification.Results: We found two genome-wide significant loci; onelocated in chromosome 11 in the intron of the gene DUSP8(p=4.12� 10e-8) and the second in chromosome 10 in aintergenic region (p=5.12� 10e-8). These two loci have notbeen previously demonstrated for association with readingdisorders or any other trait. Functional annotation of variantslocated within 1MB region of the loci did not pinpoint anyspecific risk-gene in relation to learning disabilities. Genebased analysis using MAGMA identified no exome-wide sig-nificant gene. Transcriptome wide association approachbased on imputed gene expressions using PrediXcan revealedno significant genes either. Heritability estimate based onGCTA REML analysis was 0.06 (0.04) under an assumption offive percent prevalence. Polygenic risk score analysis of 27traits revealed a significant inverse correlation with humanintelligence (p=0.00003; R2=0.002).

Discussion: We conducted a GWAS of reading disabilitiesbased on the medical register data and found two genome-widesignificant loci. We also show significant inverse geneticcorrelation between reading disabilities and human intelli-gence. Since the cases and controls comprise predominantlyindividuals with major psychiatric disorders such ADHD, ASD andMDD, our findings could reflect learning disabilities originatingbased on a genetic background enriched for risk-variants forpsychiatric disorders and we therefore need replication beforerelating the findings to the general population.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.267

SU79. RESILIENCE MARKERS IN FAMILIES OF STRESSEDPATIENTS: ReMaFaSt STUDY

Alejo Corralesn,1, Andrea Lopez Mato2, Tomas Maresca2,

Gustavo Tafet3, Pablo Beretta2, Marta Cortelezzi2,Elvira Covini2

1AAPB2Institute of Biological Psychiatry3Maimonides University

Background: ReMaFaSt study is the first Argentineanstudy aimed to evaluate the biochemical markers of resi-lience. Resilience is the capacity and dynamic process ofadaptively overcoming stress and adversity while maintain-ing normal psychological and physical functioning. Stressfullife events, trauma, and chronic adversity can have asubstantial impact on brain function and structure, andcan result in the development of Post-Traumatic StressDisorder (PTSD), depression and other psychiatric disorders.However, most individuals do not develop such illnessesafter experiencing stressful life events, and are thusthought to be resilient. The risk of mental illness is definedby the relationship between genetic predisposition andenvironmental factors after a life stress. Early stress factorsare a key for “turning on” diseases. Several resilience orvulnerability (features and state) markers have been iden-tified in patients. Often the patient´s relatives share thetraumatic experience. Our patients develop depression orPTSD but often their families do not, despite enduring thesame traumatic experience. So why do not relatives developillness? The aim of the study is to look at missing markers ofresilience (genetic and PINE markers) as well as lowerenvironmental vulnerability.Methods: Adult first degree healthy relatives of patientswere invited to participate in the ReMaFaSt study. Allparticipants gave written informed consent before theprocedures and the aim of the study were explainedcompletely. A total of 25 first degree patients relatives.First degree relatives were defined as father, mother,brothers, sisters and children. Inclusion criteria: first degreerelatives psychiatrically healthy, aged between 21–70 y/ohave undergone the same traumatic experience as ourpatients with depression or PTSD (DSM V). Exclusion criteria:

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psychopathic features, severe organic diseases or psychia-tric disease. Beck, HAM D, CAPS-5, neurocognitive testing,Trail Mb were used to evaluate the psychiatric condition ofthe participants. Thus, our aim was to determine geneticvariants of 5-HTTLPR among other biochemical tests; meta-bolic testing (BMI, Glycosylated, hemoglobin, lipids profile,Waist-hip ratio), and PNIE testing –periferical- (cortisolrhythm, FUC, DHEA, Thyroid profile, NK cells, CD4/CD8ratio).Results: The preliminary results show an increase in l/lvariant of 5-HTTLPR among (at least one l allele has beenfound) first degree relatives of depressive and PTSD patientscompared to affected patients. Immunological response,rhythm of cortisol secretion and metabolic determinationtrend were normal in our sample.Discussion: This is an ongoing study with a very smallsample. However, the normal clinical test and the l/lgenotype suggest a protective factor for PTSD and MDD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.268

SU80. LEUKOCYTE TELOMERE LENGTH ANALYSIS INCHILDREN AND ADOLESCENTS AT RISK OF DEVELOPINGMENTAL DISORDERS

Danilo Micali1, Gabriela Xaviern,1, Leticia Spindola1,

Vanessa Ota1, Pawan Murawa1, Priscila Tampaku1,Patricia Moretti2, Pedro Pan1, Luis Rohde3, Ary Gadelha1,Diego Mazzotti4, João Sato5, Giovanni Salum Junior6,Rodrigo Bressan1, Sintia Belangero1

1Federal University of Sao Paulo2University of Brasilia3Federal University of Rio Grande do Sul4Chidren's Hospital of Philadelphia5Universidade Federal do ABC6Hospital das Clínicas de Porto Alegre

Background: Telomeres are DNA-protein complexes thatconstitutes the terminal portions of chromosomes, providingthem stability and protection and go through physiologicalshortening along cell cycles. However, this shortening canbe intensified by cytokines, stress hormones and oxidationexposition. After reaching a critical length, telomere short-ening leads to senescence or apoptosis. Telomere Length(TL) is altered in cancer, diabetes, cardiovascular andautoimmune diseases. Additionally, TL has been describedas related to psychiatric disorders like Major DepressiveDisorders (MDD), Bipolar Disorder (BD) and Schizophrenia(SCZ). TL was found to have a dose-dependent associationwith stress in childhood, however it is not clear whether thisshortening can be used as a diagnosis and progressionbiomarker. This study investigated the association betweenleucocyte TL and psychiatric diagnosis, psychiatric symp-toms and child maltreatment and also verified association ofTL with age and gender.

Methods: The 559 participants of this study were asubsample of the High Risk Cohort (HRC) Study for Psychia-tric Disorders in Childhood, a large prospective communityschool-based study in Brazil. Blood sample were collected6 to 8 months after parent interview, in which participantswere assessed using Development and Well-Being Assess-ment (DAWBA) to evaluate psychiatric diagnosis accordingto the DSM-IV. Psychopathology was assessed by the ChildBehavior Checklist (CBCL). DSM-oriented scaled were usedand grouped in Internalizing and Externalizing groups ofsymptoms. Child Maltreatment (CM) measure was based onfour questions answered by parents and children about thehistory of physical abuse, neglect, emotional maltreatmentand sexual abuse. The 394 children and adolescents with noDSM-IV disorder in DAWBA assessment composed the healthycontrol group. Leucocyte TL measurement was performedby quantitative qPCR. Study population description as wellas CBCL and CM means between case and controls wereanalyzed by Student's T test. Association of TL with genderand age or psychiatric symptoms was analyzed by general-ized linear model (GLzM).Results: In this study population, no association betweenTL and age or gender was observed. Equally, absence ofdistress, fear and behavior disorders showed no associationwith TL. The weak positive correlation (r2=0,01) betweenexternalizing CBCL and TL obtained was proved not sig-nificant after Bonferroni correction. And no associationsbetween TL and CM or between CM and gender were shown.However, after sorting the cohort by gender, a negativecorrelation (p=0,014; OR=0,938; IC 95%=0,891 – 0,987;r2=0,021) between TL and CM were observed in boys.Discussion: This was a cross sectional study which does amomentary analysis of the TL and the mental state ofindividuals. The number of participants and the completepsychiatric framework brings to it a strong statistical powerand although there is no association between TL and age,gender, CBCL, absence of distress, fear and behaviordisorders were observed, a correlation between TL and CMwas found only in boys but not in girls. The high levels ofestrogen in girls might act as a protective factor indirectlyinfluencing TL in this gender. Thus, this study points out thatmales who experienced more early life traumas seem tohave shorter TL.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.269

SU81. COMPREHENSIVE EVALUATION OF ENRICHMENTFOR CIRCADIAN CLOCK GENE SETS IN PSYCHIATRICTRAITS: SPECIFIC ENRICHMENT IN CLINICAL RESPONSETO LITHIUM

Sergi Papioln,1, Urs Heilbronner2, Liping Hou3, (ConLiGEn)

The International Consortium on Lithium Genetics,Michael McCarthy4, Caroline Nievergelt4, Enda Byrne5,Francis McMahon3, Thomas Schulze1

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1Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilian-University of Munich2Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich3Intramural Research Program, National Institute of MentalHealth, National Institutes of Health, US Department ofHealth & Human Services4VA San Diego Healthcare System, University of CaliforniaSan Diego5Queensland Brain Institute, The University of Queensland

Background: A disrupted circadian clock has been linkedto the risk of several neuropsychiatric disorders. Likewise,circadian rhythms have been suggested as mediators of themechanism of action of lithium in bipolar disorder. None-theless the relationship between the ‘clock genes’ thatregulate circadian rhythms and lithium treatment responseis not completely understood. To our knowledge there hasnot been a systematic pathway / enrichment analysis of clockgenes in the context of psychiatric traits, in general, and ofclinical response to lithium, in particular. The objective ofthis study was to perform formal gene set enrichmentanalyses for circadian clock genes, using publicly availableGWAS summary statistics from several psychiatric disorders,as well as the results from The International Consortium onLithium Genetics (ConLiGen) GWAS (Hou et al., 2016).Methods: Based on previous literature (Pizarro et al.,2013; Chen et al., 2016) and available resources (e.g.http://circadb.hogeneschlab.org/) curated gene sets relatedto circadian control were generated. These sets can bedivided in three categories: clock modulator (upstream)genes, core clock genes and clock controlled (downstream)genes. GWAS summary statistics from schizophrenia, bipolardisorder, major depressive disorder, ADHD, autism, Alzhei-mer's disease and continuous/dichotomous lithium responsewere used as reference. Gene set enrichment analyses werecarried out using both INRICH and MAGMA.Results: Gene set enrichment analyses using INRICH andMAGMA reported a significant enrichment of a set of 19genes that constitute the ‘core clock’ in the dichotomouslithium response phenotype (INRICH: empirical P=0.001;corrected P=0.008; MAGMA: competitive P=0.005; cor-rected P=0.0336). None of the circadian gene sets showeda significant enrichment in any of the other psychiatrictraits included in this study (all corrected P40.05).Discussion: Our results suggest the involvement of thosegenes that constitute the core clock machinery in thedetermination of the clinical response to lithium in bipolardisorder patients. The specificity of these results suggeststhat the participation of circadian rhythms is especiallyrelevant in the modulation of lithium response rather thanin the overall risk of mental illness. A better understanding ofpotential links between circadian mechanisms, genetic riskfactors, and the lithium treatment response may open newavenues into the clinical management of bipolar disorder.

Funding:

DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; Lisa-Oehler-Foundation. SP was supported by a 2016 NARSAD Young

Investigator Grant from the Brain and Behavior ResearchFoundation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.270

SU82. RNA SIGNATURE OF TREATMENT RESPONSE INFIRST-EPISODE PSYCHOSIS

Réjane Troudetn,1, Wafa Bel Haj Ali2, Caroline Barau3,

Anne Boland-Auge4, Jean-François Deleuze4,Marion Leboyer5, Stéphane Jamain2, OPTiMiSE Consortium6

1Inserm U955, Psychiatrie Translationnelle, Université ParisEst, Faculté de Médecine2Inserm U955, Psychiatrie Translationnelle, Université ParisEst, Faculté de Médecine, Fondation FondaMental, CréteilFrance3AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme deRessources Biologiques, Créteil, France4Commissariat à l'Energie Atomique, Institut Génomique,Centre National de Génotypage, Evry, France5Inserm U955, Psychiatrie Translationnelle, Université ParisEst, Faculté de Médecine, Fondation FondaMental, AP-HP,Hôpital H. Mondor – A. Chenevier, Pôle de Psychiatrie,Créteil, France6Optimization of Treatment and Management of Schizo-phrenia in Europe, European Community's Seventh Frame-work Programme, European Union, France

Background: Despite nearly fifty years of pharmacologi-cal research, the treatment of schizophrenia remains achallenge and clinical outcomes are still far from optimal.One of the major shortcomings in the current treatment ofschizophrenia is that we have no valid criteria in clinicalpractice to predict who will respond to antipsychotictreatment and how long the treatment should be main-tained before changing therapeutic strategy. The identifica-tion of blood-based biological markers of drug response witha good sensitivity and specificity would enable physicians touse these tests prior to choosing the antipsychotic treat-ment and therefore help the practitioner in his daily clinicalpractice.Methods: Through a European consortium on Optimizationof Treatment and Management of Schizophrenia in Europe(OPTiMiSE), we conducted a transcriptome analysis on 163subjects with first episode psychosis. Patients were alltreated for four weeks with amisulpride. Blood sampleswere collected at inclusion and after treatment and totalRNA was analyzed by RNA-Seq for each patient before andafter treatment as well as according to treatment outcome.After quality control, the detection of differentiallyexpressed genes have been achieved using the DESeq.2 package and in regards to biological processes andsymptom improvement, with the aim of characterizing abiological signature of treatment response in first-episodepsychosis.

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Results: The transcription level of 10,683 expressed geneshas been analyzed in peripheral blood mononuclear cells.We detected 499 and 84 genes that were differentiallyexpressed after 4-week treatment with amisulpride inremitted and non-remitted patients, respectively, showingenrichment in differentially expressed genes in remitterswhen compared to non-remitters (p=0.02). We also foundthat for some of these genes, the expression level wassignificantly correlated with clinical outcome. A secondanalysis revealed that 39 of the 499 differentially expressedgenes had a different expression level before amisulpridetreatment between patients who will be in remission after4-week treatment, suggesting these genes may help inpredicting treatment response.Discussion: We demonstrated here that amisulpridetreatment affects gene expression in peripheral bloodmononuclear cells, mainly in patients who will be inremission after four weeks of treatment, and that geneexpression may be associated with symptom improvement.Further replications on independent samples are needed toconfirm molecular mechanisms associated with clinical out-come and should help both in the identification of biologicalsignatures of treatment response as well as in the develop-ment of new therapeutic strategies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.271

SU83. COMBINATORIAL PHARMACOGENOMIC TESTINGIMPROVES GENERALIZED ANXIETY DISORDER TREAT-MENT RESPONSE AND DECREASES BENZODIAZAPINE USE

Arun Tiwarin,1, Clement Zai1, Gwyneth Zai2, Sheraz Cheema1,

Nicole Braganza1, Daniel Mueller3, Catherine Passariello4,Lisa Brown4, Bryan Dechairo4, James L. Kennedy1

1Centre for Addiction and Mental Health2Centre for Addiction and Mental Health, University of Toronto3University of Toronto4Assurex Health

Background: Controlled substance prescription use andabuse in the United States has become a public healthepidemic. Specifically, benzodiazepine abuse in 2013 hasincreased as much 400 percent since 1996. GeneralizedAnxiety Disorder (GAD) was the most frequent reason thesemedications were given, accounting for 56% of prescrip-tions. Previously, GeneSight, a psychiatric pharmacoge-nomic decision support tool, was reported to significantlyimprove depression symptoms in treatment-resistantdepression patients, reduce costs associated with prescrip-tions, and decrease polypharmacy.Methods: To evaluate the combinatorial pharmacoge-nomics report as a tool to treat GAD and reduce the amountof benzodiazepines used, we analyzed data from two sepa-rate studies: (1) Individualized Medicine: PharmacogeneticAssessment and Clinical Treatment (IMPACT) study, a long-itudinal pilot research program , where 315 participants with

anxiety disorders (N=210 with GAD) and follow-up data onsymptom severity using the GAD-7 questionnaire were iden-tified; and (2) MEDCO dataset (Winner et al., 2015; Curr MedRes Opin.;31:1633-43) in which patients (n=660) who wereprescribed at least one benzodiazepine six months pre-testing and were followed six months post-testing.Results: The analyses in the IMPACT study sample showedthat medication treatment decisions congruent with thecombinatorial pharmacogenomics GeneSight test results canhelp guide clinician treatment of GAD and result in significantlymore improvement of anxiety symptom severity (congruent:-44.9735.9% versus non-congruent: -25.5731.8%; t=2.19;p=0.031). In the MEDCO dataset, we found that 18% (n=116) of the patients originally taking at least one benzodiaze-pine pre-testing (n=660) ceased their use of benzodiazepinespost-testing with a significant decrease in benzodiazepine drugcounts and refills after testing (mean count 1.2 vs. 0.9; p o0.001 and mean refill 3.3 vs 2.9; p o 0.001).Discussion: The GeneSight test can lead to more effectivetreatment of the anxiety symptoms in GAD patients and maylead to beneficial decrease in benzodiazepine use.

Disclosure: Patent application submitted for a modelpredicting antipsychotic induced weight gain - Patent, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.272

SU84. THE GLUTAMATE RECEPTOR - GRM3 GENE ANDANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA

Cheng Chenn

, Arun K. Tiwari, James L. Kennedy

Centre for Addiction and Mental Health

Background: Schizophrenia (SCZ) is a chronic, debilitat-ing mental disorder characterized by positive, negative andcognitive symptoms. Currently, Antipsychotics (AP) are thebest treatment for SCZ, but the clinical responses are highlyvariable across individuals. Many hypotheses have beenproposed to explain the inter-individual difference in APresponse. The glutamate system is a target for studying thepharmacogenetics of AP based on the research drug poma-glumetad (GRM2/3) that showed similar efficacy to olanza-pine in clinical trials, as well as some evidence of geneticassociation from previous studies. Also, Bitopertin, a glycinereuptake inhibitor also showed promise in alleviating nega-tive symptoms in SCZ. Glycine acts as co-agonist for theNMDA receptor thus influencing glutamate signaling in thebrain. The glutamate genes that have been investigated fortheir roles in predicting AP response in SCZ include GRIN2A,GRM3 and GRIA1. We conducted an association studybetween variants in the GRM3 gene and AP using the CATIEsample (n=306). 23 SNPs were extracted from the sample.Methods: We investigated 23 SNPs across the GRM3 geneusing the CATIE sample. We selected 306 European ancestrypatients that have been treated with one of 4 AP (olanza-pine, risperidone, quetiapine, and ziprasidone). Treatmentresponse was evaluated using the Positive and NegativeSyndrome scale (PANSS). All SNPs with the GRM3 gene were

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selected from the UCSC genome browser (GRCh36/hg19)and extracted from the CATIE sample using PLINK 1.9. CATIEinvestigators arranged the genotyping at Perlegen Scienceusing the Affymetrix 500 K two chip genotyping platformplus a custom 164 K fill-in chip. Linkage disequilibrium andHardy-Weinberg equilibrium calculations were conductedusing HaploView 4.2, and all statistical analyses wereperformed using IBM SPSS v24.Results: Among the 23 SNPs obtained from the CATIEdataset, only rs274621 was significantly associated with APresponse (p=0.02) under a recessive model. However, theresults did not remain significant after correction forindependent tests.Discussion: Several association studies have investigatedGRM3 polymorphisms versus clinical response to AP andyielded promising results in the past. We found a trend forrs274621 to be associated with AP response. The rs274621marker is an upstream variant which may be located in thepromoter region of GRM3 and may affect the transcriptionof the gene. Interestingly, rs274621 was also significantlyassociated with bipolar disorder in the University CollegeLondon 1 (UCL1) subsample GWAS.

Overall, the analyses of the European ancestry subsam-ple of CATIE did not provide significant evidence for a role ofGRM3 in AP responses. However, further studies of theglutamate system in AP response are required.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.273

SU85. WHOLE EXOME SEQUENCING REVEALS RISK FAC-TORS IN TREATMENT RESISTANT DEPRESSION

Alessandro Serrettin,1, Chiara Fabbri2, Diego Albani3,

Siegfried Kasper4, Joseph Zohar5, Daniel Souery6,Alexander Kautzky4, Stuart Montgomery7,Julien Mendlewicz8

1Institute of Psychiatry2University of Bologna3IRCCS Istituto di Ricerche Farmacologiche "Mario Negri"4Medical University Vienna5Sheba Medical Center, Tel Hashomer, and Sackler School ofMedicine, Tel Aviv University6Laboratoire de Psychologie Médicale, Université Libre deBruxelles and Psy Pluriel - Centre Européen de PsychologieMédicale7Imperial College School of Medicine8Universite´ Libre de Bruxelles

Background: Treatment Resistant Depression (TRD) is acommon complication (�1/3 of patients) of Major Depres-sive Disorder (MDD) that contributes to the huge personaland socio-economic burden of the disease. Genetic variantsare key modulators of antidepressant efficacy, but previousGenome-Wide Association Studies (GWAS) have generallyfailed to identify the polymorphisms involved. Whole exome

sequencing and network analysis represent promising andinnovative strategies.Methods: 47 patients with diagnosis of MDD with currentepisode of at least moderate severity were selected if theysatisfied the definition of TRD or were optimal antidepres-sant responders. TRD was defined as lack of response to atleast two antidepressant trials while optimal responderssatisfied remission criteria after the first antidepressanttrial. Next generation exome sequencing was performedfrom whole blood. After quality control (fastqc) and align-ment to the reference human genome (ENSEMBL, release83), gene-based tests were performed by PlinkSeq andenrichment analysis was performed using the CytoscapeGeneMania plugin to identify networks involved in TRD.Replication of results in the STARnD study was attemptedusing a comparable phenotype (remission to the first anti-depressant trial (n=583) vs. non-remission to the fourthantidepressant trial (n=48)).Results: 24 TRD patients and 23 good responders wereincluded in the study. 967,208 variants were available. Initialpathway analysis based on known gene product interactionsidentified some networks that were associated with TRDstatus, including the neurotrophin signalling pathway andother pathways involved in cell growth. Particularly a groupof genes belonging to a network involved in metaphase-anaphase transition of mitotic cell cycle was replicated inSTARnD. Final analyses will be presented at the meeting.Discussion: Genes involved in cell growth and in meta-phase-anaphase transition of mitotic cell cycle may have arelevant role in the risk of TRD. Components of this network(the CDC20/APC complex) were demonstrated to have apivotal role in controlling dendrite growth in post-mitoticneurons, a process that is essential for antidepressantresponse. Future directions include whole exome sequen-cing in a larger sample to replicate these findings.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.274

SU86. VALIDATION STUDY IN TWO GENOME-WIDE SIG-NIFICANT RISK VARIANTS FOR ANTIPSYCHOTIC INDUCEDWEIGHT GAIN

Kazunari Yoshidan,1, Sarah Kanji2, Malgorzata Maciukiewicz2,

Arun K. Tiwari2, Ilona Gorbovskaya2, Vanessa F. Goncalves2,Clemet Zai2, Eva Brandl3, Natalie Freeman2,Jeffrey A. Lieberman4, Herbert Meltzer5,James L. Kennedy2, Daniel J. Müller2

1Pharmacogenetic Research Clinic, Campbell Family MentalHealth Research Institute, Centre for Addiction and MentalHealth2Centre for Addiction and Mental Health3Charite University Hospital4New York State Psychiatric Institute, Columbia University5Northwestern University

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M. Barbu et al.114

Background: Antipsychotic drugs are the primary inter-vention in the treatment of psychotic disorders, however,the use of antipsychotics is often accompanied by weightgain and metabolic syndrome. A recent Genome-WideAssociation Study (GWAS) investigating a Han Chinese sam-ple suggested a possible role of rs1097714 and rs10977154variants of the protein tyrosine phosphatase, receptor typeD (PTPRD) gene in antipsychotic induced weight gain(AIWG). Additionally, two upstream variants (rs1886243and rs6915627) of T-complex 11 (TCP11) were among the20 most significant SNPs in the original study. The purpose ofthis study was to replicate the association of the top 20variants from the aforementioned GWAS in two independentsamples to evaluate whether these associations are alsopresent in patients of European and African Americanancestry.Methods: The following two independent samples wereused: 1) schizophrenia or schizoaffective disorder patients(based on DSM III and DSM IV criteria) primary undergoingfirst exposure to atypical antipsychotic drugs and 2) patientsin the Clinical Antipsychotic Trials of Intervention Effective-ness (CATIE) sample. Samples 1 and 2 were genotyped usingIllumina Omni 2.5 Chip, Affymetrix 500 K “A” chipset, andthe Perlegen custom 164 K chip, respectively. In the mainanalyses in two replication samples. Analysis of Covariance(ANCOVA) was used to investigate the percentage of changein weight (Sample 1) or Body Mass Index (BMI) (Sample 2)from baseline to last observation carried forward (LOCF),where genotypes were coded as factors. Models in bothsamples were corrected for study duration, and additionallyfor age in Sample 1, and medications used in Sample 2.Results: In Sample 1 (122 men (65.9%), mean7SD age;36711 years, baseline body weight; 79.72715.9 kg % ofweight change (LOCF); 5.0877.11, weight gainer (47%);n=57 (31.0%), medication: clozapine, olanzapine, andrisperidone were mainly used), none of 14 genetic variantsshowed a significant association with % of weight change inthe European population. In African Americans, the nominalassociation was observed (F2,50=4.814; p=0.034) betweenrs3853114 variant of dynein axonemal heavy chain 5(DNAH5). In Sample 2 (118 men (78.1%), mean7SD age;40712 years, baseline BMI; 28.6375.43, % of BMI change(LOCF); 2.9577.79, weight gainer (47%); n=31 (20.5%),medication: olanzapine, risperidone, and quetiapine wereused), nominal associations with two TCP11 variantsrs1886243 (F2,148=3.14; p=0.046) and AIWG wereobserved. None of the variants described above survivedcorrection for multiple testing.Discussion: To the best of our knowledge, this is the firstgenetic association study evaluating PTPRD and TCP11 inEuropean and African American patients. However, theassociations between PTPRD variants and AIWG were notreplicated; whereas the effects of TCP11 remained nomin-ally significant. More studies across different ancestries areneeded to examine if PTPRD and TCP11 can be consideredsusceptibility genes for AIWG.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.275

SU87. GENETIC PREDICTORS OF ANTIPSYCHOTICRESPONSE TO LURASIDONE IDENTIFIED IN A GENOME-WIDE ASSOCIATION STUDYAND BY SCHIZOPHRENIA RISKGENES

Jiang Lin,1, Akane Yoshikawa2, Herbert Meltzer1

1Northwestern University2The University of Tokyo

Background: Schizophrenia (SCZ) is a heterogeneous dis-order with a complex genetic contribution to its etiologyand response to antipsychotic drugs (APDs). Biomarkerswhich predict response to APDs increase their benefit/riskratio. We sought to identify common variants in genes whichpredict response to lurasidone, an atypical APD, by asso-ciating Genome-Wide Association Study (GWAS) data andchange in Positive And Negative Syndrome Scale (PANSS)scores from two 6-week randomized, placebo-controlledtrials of lurasidone in schizophrenia (SCZ) patients.Methods: Population stratification was conducted basedon the genotyping data from Affymetrix 6.0 SNP array using1KG as reference genome. Only genetic-validated patientsof European (EUR) or African (AA) ancestries treated withlurasidone (n = 171/131) or placebo (n = 63/54) wereincluded. Treatment response was quantitatively evaluatedby change in PANSS-Total (ΔPANSS-T) between baseline andLast Observation Carried Forward (LOCF). Linear regressionwith an additive model for minor alleles, adjusted fordosage and genetic architecture (3 major PCs), was utilizedto test the association between the common geneticvariants (MAF > 0.05) and ΔPANSS-T. Both GCTA-GREMLand PLINK Polygenic Risk Scoring (PRS) implemented poly-genic risk modeling in the EUR group to determine if SCZ riskSNPs identified by PGC GWAS also contributed to thedetermination of treatment response.Results: No Genome-Wide Significant (GWS) findings werefound. However, the top genomic loci, with uncorrectedpo1×E-4, included: 1) synaptic adhesion and scaffoldinggenes, both essential for synaptic function; 2) other synap-tic plasticity-related genes (NRG1/3); 3) the neuron-specificRNA splicing regulator, RBFOX1; and 4) ion channel genes.Some genes predicted lurasidone response in both EUR andAA groups. We replicated some SNPs previously reported topredict response to other atypical APDs in other GWAS. Manyof the genes and associated pathways have previously beenlinked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated thatsome risk genes, together, contributed to prediction ofresponse. The top hits predicting response to lurasidonedid not predict improvement in placebo-treated patients. Inpost-mortem brain from SCZ patients, many of our top hitsshowing differential gene expression further supported thesignificance of our findings. The expression of some of thetop hits was significantly inversely correlated with the geneexpression of HTR7, an important high-affinity target forlurasidone.Discussion: This is the first evidence from clinical trialsthat SCZ risk SNPs (or genes) are related to clinical responseto an atypical APD. A non-hypothesis driven GWAS studyidentified genetic biomarkers which predicted treatment

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response to lurasidone. These results are currently repli-cated by an independent sample.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.276

SU88. AN OPRD1 VARIANT PREDICTS CONTINUEDOPIOID USE IN AFRICAN-AMERICANS UNDERGOINGBUPRENORPHINE TREATMENT

Richard Cristn,1, Alexander Zhang1, Glenn Doyle1,

Kenzie Preston2, Melody Furnari2, Landhing Moran2,Laura McNicholas3, Kyle Kampman1, James Cornish1,Karran Phillips2, Wade Berrettini1

1University of Pennsylvania2National Institutes of Health3Corporal Michael J. Crescenz VA Medical Center

Background: Opioid Use Disorder (OUD) is a significantpublic health issue in the United States and globally. FDA-approved treatment for OUD includes Opioid SubstitutionTherapy (OST) with medications such as methadone andbuprenorphine. While OST has been shown to be effective, ameta-analysis of outcome data from OST studies indicatedthat a significant percentage of opioid dependent patientstreated with OST do not sustain abstinence or reduce theirillicit opioid use. Understanding the factors that predictreductions in illicit opioid use during treatment would allowclinicians to make more informed therapeutic decisions,selecting medications that are most likely to benefitindividual patients.Methods: The START trial was a 24-week open-labelrandomized trial of methadone and buprenorphine for thetreatment of OUD. Weekly urine drug screens were per-formed. Treatment efficacy was defined by the proportionof opioid positive urine tests. A Generalized EstimatingEquation (GEE) was used to determine if variants in theOPRD1 gene were associated with treatment efficacy inAfrican-Americans (AA; n=77). A replication population(n=75) was collected from AA patients who had previouslyparticipated in OST trials in Baltimore. Urine drug screenswere performed three times per week. For a meta-analysis,weeks 21–24 were analyzed since they represent the lastmonth of data available for both data sets. Responders weredefined as patients who a) were retained in treatment untilat least week 21 and b) were opioid positive for less than50% of their urine drug screens in weeks 21–24. For in vitroanalysis, 15 bp regions surrounding the C or T allele ofrs678849 were cloned into luciferase vectors and trans-fected into neuroblastoma cells. Luciferase activity wasmeasured by dual-luciferase reporter assay system.Results: In the START trial, rs678849 was associated withthe efficacy of methadone (p=0.001) and buprenorphine(p=0.008) in treating OUD in AA patients. The pharmaco-genetic effect on buprenorphine (p=0.01), but not metha-done (p=0.23), was replicated in the independent AApopulation from Baltimore. In a meta-analysis of weeks

21–24 of both data sets, patients with the C/C genotype hada significantly higher proportion of opioid positive urine drugscreens (59%) than T allele carriers (26%, po0.0001).Patients with the C/C genotype were also significantly lesslikely to meet responder criteria (27%) than other patients(64%, p=0.007). The number needed to treat (NNT) was2.8 for the response analysis. Functional analysis in neuro-blastoma cells by luciferase assay found that the vectorcontaining the C allele had lower luciferase activity thanempty vector. In contrast, the T allele vector had signifi-cantly higher luciferase activity than the C allele or emptyvector.Discussion: These data suggest that a variant in theOPRD1 gene has a large pharmacogenetic effect on bupre-norphine efficacy in the AA population and that the variantmay have effects on expression. We hypothesize that the Callele of rs678849 functions as a silencer element, bindingtranscriptional repressors and downregulating OPRD1expression. We also hypothesize that the T allele of thevariant is an enhancer element and upregulates OPRD1expression through interactions with a unique group oftranscription factors. Further in vitro studies will be neededto dissect the complete mechanism and a prospectiveclinical trial that confirms this pharmacogenetic effect willbe necessary before rs678849 can be used to guide treat-ment decisions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.277

SU89. TRANSETHNIC ANALYSIS OF HIGH-RESOLUTIONHLA ALLELES AND COMPLEMENT 4 STRUCTURAL POLY-MORPHISMS IN SCHIZOPHRENIA

Hanna Ollilan,1, Ming Li2, Michael Mindrinos2, Chunlin Wang2,

Marcelo Fernandez-Vina3, Raquel Kuehn2,Sujatha Krishnakumar2, Julie Wilhelmy3, Ming T. Tsuang4,Stephen J. Glatt5, Emmanuel Mignot3, Douglas F. Levinson3

1Stanford University School of Medicine2Immucor3Stanford University4University of California, San Diego5SUNY Upstate Medical University

Background: Genome-Wide Association Studies (GWAS)have produced strong evidence for association of Schizo-phrenia (SCZ) in the extended Major HistocompatibilityComplex (chromosome 6q), including the Human LeukocyteAntigen (HLA) region. It has been reported that structuralpolymorphisms in the C4 gene can explain the signal in thisregion, but it has not been determined by direct high-resolution genotyping whether HLA alleles have indepen-dent effects. We have used a novel next-generation sequen-cing method to achieve HLA typing with 8-digit (4-field)resolution over classical HLA genes (A, B, C, DRB1, DRB3-5,DQA1, DQB1, DPA1 and DPB1) in cohorts of three ethnicities;and assayed C4 structural polymorphisms in a subset of the

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sample to permit imputation in the entire cohorts. Thesedata permit analysis of the association of SCZ with HLAalleles while accounting for C4 variants.Methods: Subjects included 21,592 individuals: SCZcases/controls from the MGS and GPC cohorts (European-ancestry: 5,762 cases, 5,558 controls; African-American:2,671 cases, 2,373 controls), and 1,670 Taiwan families(3,340 parents, 1,728 affected offspring). HLA genotypingwas carried out using the Mia Fora NGS Flex HLA Typing Kit(Immucor), which uses long-range PCR to capture 11 HLAloci (the entire gene in most cases) followed by high-depth,multiplexed Illumina sequencing. C4 polymorphisms wereassayed using ddPCR using published primers and callingalgorithms, in 940 individuals representing all ancestriesand genotyping platforms. Analyses are almost completed,including imputation of C4 structural alleles into all samples(HIBAG), followed by frequentist association tests of HLAalleles with and without conditioning on C4 alleles, takingancestry covariates into account (PLINK). It is expected thatimputation of HLA genotypes can also be improved for eachancestry based on the high-resolution genotyping of largecohorts.Results: All analyses are in progress and will be completedprior to the Congress. Missing data rates across loci are�1%, and Mendelian error rate in trios is low. C4 alleles canbe imputed with high accuracy in all combinations ofancestry and genotyping platform. Imputation accuracywas over 90% for all HLA genes.Discussion: The results of this study will provide impor-tant new information about whether HLA alleles haveeffects on SCZ risk, independent of their linkage disequili-brium with C4 structural polymorphisms. The study will alsoprovide improved resolution of imputation of both C4polymorphisms and of HLA alleles.

Disclosures: Jazz Pharmaceuticals - Consultant, SelfFacebook - Consultant, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.278

SU90. GENOME-WIDE ASSOCIATION STUDY (GWAS) ANDANALYSIS OF VIOLENCE IN SCHIZOPHRENIA

Vincenzo de Luca, Samia Tasmim, Ali Bani-Fatemi,Anvesh Roy

n

Centre for Addiction and Mental Health

Background: Schizophrenia patients are at higher risk ofengaging in violent behaviours than the general population.Schizophrenia is also regarded as a highly heritable disorder,and in 2014, a large genetic study by the SchizophreniaWorking Group (SWG) of the Psychiatric Genomics Consor-tium (PGC) identified 108 risk loci for SCZ. The relationshipbetween violence and these risk loci has not been studied,neither has there been any GWAS where Single-NucleotidePolymorphisms (SNPs) were correlated with violence. Thisstudy aims to analyze the specific effect of genome-widesignificant schizophrenia SNPs on violence in schizophrenia.

Methods: We recruited 87 subjects between the age of 18to 75 from the Centre for Addiction and Mental Health(CAMH), who had a diagnosis of schizophrenia or schizoaf-fective disorder. We recorded physical violence scoresindicating any violent actions to inflict pain, bodily harm,or death on another individual from the standardized scale,Modified Overt Aggression Scale (MOAS). We genotyped2.5 million SNPs for each participant, and the DNA wasanalyzed using the whole genome analysis tool-set, PLINK.Results: We found 13 SNPs which were associated withviolence, and the highest correlation was with the SNPkgp11155273 on chromosome 10 (p=2.051E-7).Discussion: This study found an association betweenviolence and the kgp11155273 SNP on chromosome 10.Further studies using larger subject pools are required toprobe further into the nature of this association, anddetermine the genetic basis of violence in schizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.279

SU91. COMMON AND RARE RISK VARIANTS MAP TOGENES WITH SIMILAR CHARACTERISTICS IN BOTH SCHI-ZOPHRENIA AND EDUCATIONAL ATTAINMENT

Laura Whitton, Mohamad Nor Azzimi Sohedein,Gary Donohoe, Derek Morris

n

Cognitive Genetics and Cognitive Therapy Group, Neuroi-maging and Cognitive Genomics (NICOG) Centre, School ofPsychology, National University of Ireland Galway

Background: Exome sequencing data are providing insightinto the contribution of rare protein-altering variants toneurodevelopmental disorders such as Schizophrenia (SZ) andto cognitive function in the general population. Disruptive,damaging Ultra-Rare Variants (dURVs) that alter proteins aremore abundant in schizophrenia patients than controls and aremore concentrated in brain expressed genes, specificallyneuronally expressed genes with synaptic functions (Genoveseet al., 2016, Nat Neurosci, 19:1433-41). dURVs in highlyconstrained genes influence Educational Attainment (EA; aproxy for cognition) in the general population (Ganna et al.,2016, Nat Neurosci, 19:1563-5). We used Gene Set Analysis(GSA) to investigate if signals from Genome-Wide AssociationStudy (GWAS) of SZ and EA similarly mapped to highlyconstrained genes and to neuronally expressed genes withsynaptic functions. We also investigated if SZ and EA GWASsignals were enriched in brain regions at different timepointsfrom early development through to adulthood.Methods: We performed competitive Gene Set Analysis(GSA) using MAGMA to test if genes within a gene-set weremore strongly associated with SZ or EA than other genes inthe genome. We applied GSA to the largest available SZ(n=150,064) and EA (n=405,072) GWAS. We used theprobability of being loss-of-function intolerant (pLI) metricto identify highly constrained genes. Sets of organ-expressed genes were from derived the Protein Atlas.

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Expression data for neurons, oligodendrocytes and astro-cytes were sourced from Zhang et al. (2014, J Neurosci,34:11929-47). Expression data for 14 different brain regionsat 5 different time points was sourced from the Allen BrainAtlas.Results: Highly constrained genes (pLI40.9; n=3,230) arestrongly enriched for association with SZ (p=3.14E-08) andEA (p=1.27E-09) in comparison to genes under less constraint(0.1opLIo0.9; n=4,621; p=0.40 for SZ and p=0.34 for EA)or weak constraint (pLIo0.1; n=10,374; p=0.99 for both SZand EA). Brain-specific genes are strongly enriched in SZ(p=1.87E-09) and EA (p=3.92E-08) in comparison to othertissues (e.g. kidney-specific, p=0.97 for SZ and p=0.93 forEA). Neuron-specific genes are strongly enriched in SZ(p=3.24E-09) and EA (p=1.33E-08) in comparison to oligo-dendrocyte-specific genes (p=0.0004 for SZ and p=0.03 forEA) or astrocyte-specific genes (p=0.32 for SZ and p=0.06for EA). For neuron-expressed genes, there is strong enrich-ment in the potentially synaptic gene set (p=4.53E-09 for SZand p=2.74E-09 for EA) but no enrichment in non-synapticgenes (p=0.24 for SZ and p=0.17 for EA). Results areconsistent across all brain regions with highly-expressedgenes showing enrichment for both phenotypes. Across time-points, the strongest enrichment for SZ and EA is in genesthat are highly expressed during trimester 2.Discussion: Our GSA indicates that common variantsassociated with either SZ or EA are more likely to map tohigh-constrained genes and neuronally expressed genes withsynaptic functions, in a pattern similar to that reported fordURVs. Our analysis supports the second trimester as animportant stage in the genetic aetiology of these twophenotypes. This was across all brain regions, likely reflect-ing correlated gene expressions across the brain. Commonand rare risk variants are mapping to genes with similarcharacteristics in SZ and EA but how they combine toinfluence an individual's risk of SZ or their cognitive functionremains to be elucidated.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.280

SU92. MODIFICATION OF THE ASSOCIATION BETWEENMMP9 GENE VARIANTS AND ANTIPSYCHOTIC TREAT-MENT RESPONSE BY CHILDHOOD ADVERSITY IN AFIRST-EPISODE SCHIZOPHRENIA COHORT

Nathaniel McGregor1, Nicole Thompson1, Kevin O'Connelln,1,

Robin Emsley1, Lize van der Merwe2, Louisa Warnich1

1Stellenbosch University2University of the Western Cape

Background: Antipsychotics remain the only effectiveoption for ameliorating the symptoms of schizophrenia. How-ever, inter-individual differences in treatment outcome arevast and suggest a role for genetic and environmental factorsin affording favourable outcomes. A notable epigenetic rela-tionship which has gained considerable traction in recent

literature is the way in which the severity of childhood traumacan modify associations seen between genetic variation andantipsychotic treatment response. A potential mechanism ofaction which may facilitate this relationship is synapticplasticity. This study investigated the role of variants in matrixmetallopeptidase 9 (MMP9), a gene involved in synapticplasticity, with treatment outcome considering the severityof childhood trauma as an interacting variable.Methods: The cohort comprised 103 South Africanfirst-episode schizophrenia patients treated with a singleinjectable antipsychotic, flupenthixol decanoate, moni-tored over 12 months. Positive And Negative SyndromeScale (PANSS) scores assessment were taken at nine timeintervals across the 12 month period and the ChildhoodTrauma Questionnaire (Berstein and Fink, 1998) was used toassess the severity of childhood trauma. Polymorphismswere selected using a Tag SNP approach (LD threshold=0.8,MAF 4/=0.1), as well as minding available exome andGWAS data for the aforementioned cohort.Results: Relationships between novel and previouslydescribed variants, and haplotypes, with antipsychotictreatment response were found to be modified when con-sidering the severity of childhood trauma as an interactingvariable. In some cases, directionality of initial associationswere reversed considering the severity of childhood adver-sity as measured by CTQ.Discussion: This study provides the first evidence for theinvolvement of polymorphisms within MMP9 and the severityof childhood trauma in antipsychotic treatment response,and warrants further investigation into the role gene-environment interactions may play in the betterment ofantipsychotic treatment strategies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.281

SU93. REPLICATION OF TWO INDEPENDENT LOCI INHLA-DQB1 AND HLA-B CONTRIBUTING TO THE RISK OFCLOZAPINE-INDUCED AGRANULOCYTOSIS

Bettina Konten,1, Ina Giegling1, Sophie Legge2, Dan Cohen3,

M. Pirmohamed4, Jari Tiihonen5, Annette Hartmann1,JP Bogers6, J. van der Weide7, K. van der Weide8,A. Putkonen9, Eila Repo-Tiihonen10, T. Hallikainen9,E. Silva4, O. Ingimarsson11, Engilbert Sigurdsson12,James L. Kennedy13, Gerome Breen14, Patrick Sullivan15,Marcella Rietschel16, Hreinn Stefansson17, DA Collier18,Michael O'Donovan2, Dan Rujescu1

1Martin Luther University Halle-Wittenberg2Cardiff University3Mental Health Care Organization North-Holland North4The University of Liverpool5Karolinska Institutet6Mental Health Services Rivierduinen7St. Jansdal Hospital, Psychiatric Hospital GGz Centraal,Dependance Meerkanten8St. Jansdal Hospital

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9University of Eastern Finland, Niuvanniemi Hospital10Niuvanniemi Hospital11School of Health Sciences, University of Iceland, Land-spitali University Hospital, Mental Health Services12Landspitalinn University Hospital13Centre for Addiction and Mental Health14King's College London15University of North Carolina at Chapel Hill16Central Institute of Mental Health17deCODE genetics18King's College London, SGDP Centre, Institute of Psychia-try, Psychology & Neuroscience

Background: The atypical antipsychotic drug clozapine isthe only effective drug for treatment-resistant schizophre-nia, but also bears the risk of inducing severe adverse drugresponses like neutropenia and agranulocytosis. Agranulo-cytosis and neutropenia occurs in about 1% and 3% oftreated individuals. The aetiology is largely unknown, butthere is evidence for contributing genetic factors. Identify-ing biomarkers could decrease blood monitoring effort andenable a more widespread use of clozapine. Several studiesidentified HLA variants contributing to the risk of agranulo-cytosis. The Clozapine-Induced Agranulocytosis Consortium(CIAC) identified two independent loci in the major histo-compatibility complex genome-wide associated with cloza-pine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E�14) and an amino acidchange in HLA-B (158 T) (OR=3.3, P=6.4E�10). Our studywas performed to replicate these interesting findings.Methods: The atypical antipsychotic drug clozapine is theonly effective drug for treatment-resistant schizophrenia,but also bears the risk of inducing severe adverse drugresponses like neutropenia and agranulocytosis. Agranulo-cytosis and neutropenia occurs in about 1% and 3% oftreated individuals. The aetiology is largely unknown, butthere is evidence for contributing genetic factors. Identify-ing biomarkers could decrease blood monitoring effort andenable a more widespread use of clozapine. Several studiesidentified HLA variants contributing to the risk of agranulo-cytosis. The Clozapine-Induced Agranulocytosis Consortium(CIAC) identified two independent loci in the major histo-compatibility complex genome-wide associated with cloza-pine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E�14) and an amino acidchange in HLA-B (158 T) (OR=3.3, P=6.4E�10). Our studywas performed to replicate these interesting findings.Results: HLA-DQB1 (126Q) was associated with agranulo-cytosis (OR=0.12, P=5.25E-05) and neutropenia (OR=0.18,P=7.34E-06), whereas HLA-B (158 T) was associated withneutropenia only (OR=2.45, P=1.32E-02). The HLA-DQB1signal was mainly driven by agranulocytosis cases.Discussion: We were able to replicate previous findings.Our study gives further evidence for the implication ofimmunological pathways and especially HLA-DQB1 in agra-nulocytosis and neutropenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.282

SU94. EXPLORING THE SOMATIC VARIATION INSCHIZOPHRENIA

Alexander Charneyn,1, John Fullard1, Mads Engel Hauberg2,

Vahram Haroutunian3, Panos Roussos1

1Icahn School of Medicine at Mount Sinai2Aarhus University3Icahn School of Medicine at Mount Sinai, Mental IllnessResearch, Education, and Clinical Center (VISN 3), James J.Peters VA Medical Center

Background: The presence of somatic variation in thehuman brain has been elucidated over the past severaldecades. Most recently, single-cell whole-genome sequen-cing studies have provided unequivocal evidence thatindividual human brain cells harbor unique genetic variants.The functional significance of this phenomenon is unclear,but some studies have suggested that it contributes to riskof neuropsychiatric disease. Currently, cost and laborrequirement render difficult the sequencing of individualgenomes at the scale that will likely be necessary to fullyuncover the extent and role of somatic variation in thebrain. A scalable alternative, however, has been developedin the field of cancer genomics wherein somatic variants areidentified by comparing the frequencies of variant alleles intumor and normal bulk tissue specimens from the sameindividual. Here, we apply this approach to investigate therole of somatic variation in schizophrenia in a pilot study of9 individuals (5 schizophrenia cases and 4 unaffectedcontrols).Methods: Specimens from the prefrontal cortex and tem-poral muscle of 5 schizophrenia cases and 4 controls wereobtained from the Mount Sinai NIH Brain and Tissue Repo-sitory. Deep whole-exome sequencing (250X coverage) wasperformed using DNA extracted from neuronal and non-neuronal nuclei, which were isolated from cortical speci-mens by fluorescent-activated nuclear sorting. We followedstandard protocols for mapping and filtering reads, thencalled somatic Single Nucleotide Variants (sSNVs) using asuite of 6 calling algorithms. For each individual, the callingalgorithms were utilized to call variants in the exomes ofboth the neuronal and non-neuronal cells of the brain bycomparing them to a matched “normal” sample from thesame individual (i.e., the temporal muscle). Variants werethen filtered using an in-house quality control pipeline, anda subset of the remaining calls were validated with digitalPCR (dPCR) and parallel sequencing of multiple clones(clone-seq).Results: We identified 26 sSNVs in neuronal and non-neuronal cells from the brains of 9 individuals. We chose10 of 26 for experimental validation using dPCR and clone-seq, observing a validation rate of 80%. We noted that 13 ofthe 26 sSNVs were found in a single schizophrenia case; assuch, 4 of the 10 sSNVs included in validation experimentswere from this individual, 3 of which were successfullyvalidated. For 5 sSNVs, only the neuronal exome of theindividual had the variant, for 17 only the non-neuronalexome and for 4 both the neuronal and non-neuronalexomes. At least 1 sSNV was observed in all 5 of the casesand in 2 of the 4 controls. We noted that 2 of the 23 somatic

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SNVs in cases fell within one of the 16 copy number variantsimplicated in schizophrenia by the largest study of copynumber variation in schizophrenia to date. Several of thesSNVs observed in our cohort fall within genes known tofunction in determining cellular fate and development,including WNT10B, SMAD1 and FGF1.Discussion: Here, we present a pipeline suitable for thelarge-scale investigation of somatic variation in the humanbrain. We show evidence that somatic variation occurs in acell-type specific manner in the human brain. Genesaffected by sSNVs in the brain have known roles indetermining cell fate. Greater number of sSNVs in schizo-phrenia cases compared to controls was observed, andmultiple case sSNVs fall within known schizophrenia CNVs.Larger sample sizes are needed so as to further elucidatethe extent and role of somatic variation in the human brain.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.283

SU95. GENOME-WIDE ANALYSES OF CLINICALFEATURES OF SCHIZOPHRENIA IN THEPSYCHIATRIC GENOMICS CONSORTIUM

Tim Bigdelin,1, Roseann Peterson2, Anna Docherty3,

Kenneth Kendler2, PGC SCZ workgroup, Ayman Fanous4

1SUNY Downstate Medical Center2Virginia Commonwealth University3University of Utah School of Medicine4SUNY Downstate Medical School

Background: Schizophrenia (SCZ) is a clinically hetero-geneous disorder. Individual patients may vary with respectto onset, course of illness, response to treatment, outcome,and the particular pattern of symptoms endorsed. Proposedrevisions to DSM-5 included dimensional measurement ofseveral different symptom domains. We sought to deter-mine whether common genetic variants influence clinicalheterogeneity including symptom severity, Age-Of-Onset(AOO), smoking behaviors, and suicide attempt.Methods: The Psychiatric Genomics Consortium (PGC)study of SZ comprised 8,000 cases of European ancestrywith available clinical phenotype data; 412,000 cases withavailable information on age-of-onset of illness; and45,000 cases with data on smoking behaviors or suicideattempt(s). Symptoms averaged over the course of illnesswere assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID,and CASH. Factor analyses of each constituent PGC studyidentified positive, negative, manic, and depressive symp-tom dimensions.Results: We examined the relationship between clinicalfeatures and aggregate polygenic risk scores constructedfrom the results of the primary PGC-SCZ GWAS, andestimate SNP-based heritabilities from genome-wide sum-mary-statistics methods. Of particular interest, we repli-cated our previous finding that polygenic risk explains atleast some of the variance in negative symptoms, a core

illness dimension, and demonstrate that AOO is influencedby the aggregate effects of common genetic variation. Weobserved and subsequently replicated the significantgenetic correlation of SCZ with smoking behaviors; compar-ing smoking behaviors among SCZ cases to the generalpopulation, we observe positive genetic correlations forboth smoking initiation and smoking quantity.Discussion: By compiling detailed clinical informationfrom over 20 constituent studies of the PGC, we havedemonstrated a polygenic basis for clinical features of SCZincluding AOO, negative symptom severity, and smokingbehaviors. The efforts described herein underscore theimportance of both detailed phenotyping and the collabora-tive efforts of large-scale research consortia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.284

SU96. INVESTIGATION OF THE RISPERIDONE TREAT-MENT RESPONSE: A PHARMACOGENETICS STUDY IN ACOHORT OF FIRST EPISODE OF PSYCHOSIS PATIENTS

Giovany Costa, Marcos Santoron

, Vanessa Ota,Carolina Carvalho, Fernanda Talarico, Leticia Spindola,Gabriela Xavier, Diogo Marques, Cristiano Noto,Eduardo Gouvea, Ary Gadelha, Quirino Cordeiro,Rodrigo Bressan, Sintia Belangero

Federal University of Sao Paulo

Background: Schizophrenia is a severe and disablingmental disorder, characterized by the psychotic symptoms.The delay in providing a proper treatment, the duration ofthe First Episode of Psychosis (FEP) and the low response tothe initial treatment are among the main factors of poorprognosis. In a previous study, our group evaluated thetranscriptome in blood of antipsychotic-naïve FEP patientsbefore and after risperidone treatment, identifying 15genes that may be directly related to this antipsychoticdrug. The aim of the present study is to identify geneticpolymorphisms related to risperidone response.Methods: A total of 53 FEP patients with genetic data andtwo clinical evaluations (baseline and 2 months follow-up)were included. At first, SNPs genotypes from genes differen-tially expressed between case and healthy controls found in aprevious study of our group, went through a quality controlstep in order to exclude SNPs and individuals below the cutofflimits. The remaining SNPs were extracted from microarrayInfinium PsychArray using Plink 1.9 and RStudio softwares.Subsequently we performed the analysis of associationbetween the groups of responders and non-responders tothe treatment and the SNPs most associated with theresponse were analyzed in silico by the GTEx database.Risperidone response was assessed using the Positive AndNegative Syndrome Scale (PANSS) total score from the twotimepoints, considering as responders those with a decreaseof at least 30% in PANSS. With this criterion, 27 patients wereconsidered responders and 26 were non-responders.

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Results: We analyzed a total of 69 independent SNPswithin 14 of the 15 differentially expressed gene andobserved a statistically significant association betweenrs1812923 SNP and risperidone response (χ2(2)=6.536,p=0.038). In addition, considering a dominant model,alternative A-allele carriers were associated with a betterresponse to treatment (χ2(1)= 4.775, p= 0.029). An insilico analysis in the GTEx database further showed that thisSNP is an eQTL of the SNCA gene in tissues of the tibialartery and left ventricle of the heart where the A allele isupregulated and an eQTL of the RP11-67M1.1 gene (locatedin the reverse strand) into the cerebellum, tissue in whichthe A allele is downregulated.Discussion: In this study, we found suggestive associationbetween the rs1812923 SNP (A/C) and the response totreatment. This SNP is located intronic region of the SNCAgene which has been associated with Parkinson disease andwas downregulated in FEP patients after risperidone treat-ment, the next step of this study will be to replicate theseresults in another cohort of FEP patients (N=60) and inchronic schizophrenia patients (N=254).

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.285

SU97. GENETICALLY INFORMED SUBTYPING OFSCHIZOPHRENIA

Xiangning Chenn

, Jain-Shin Wu, Travis Mize, Jingchun Chen

University of Nevada, Las Vegas

Background: Schizophrenia is a mental disorder withheterogeneous clinical presentation and genetic predisposi-tion. In DSM IV, schizophrenia was classified into five subtypesbased on clinical features. Due to its limited application inclinical practice and the lack of biological underpinning,these subtypes were removed in DSM V. In recent years, manylarge scale genome-wide association studies have beenconducted and numerous genetic factors have been identi-fied for various diseases and traits, including schizophrenia.This provides an opportunity to explore subtyping of complexdiseases into genetically homogeneous subgroups so thatmore effective treatments can be developed.Methods: We calculated polygenic scores for the cases ofthe Molecular Genetics of Schizophrenia (MGS) study(N=2,681) for a variety of diseases and traits, and eval-uated their potential as classifiers to subtype schizophreniausing k-means clustering algorithm. We verified the clusterstructure in the Sweden Study of Schizophrenia (SSS) study(N=2,895). We further validated the clusters with func-tional data from the Clinical Antipsychotic Trials of Inter-vention Effectiveness (CATIE) study (N=741).Results: Using k-means algorithm, we found that the poly-genic scores of neuroticism and blood creatinine level couldreliably classify MGS patients into two clusters (subtypes) andthe cluster structures had been verified in the patients ofSSCC and CATIE studies. Furthermore, using the rich data of

neurocognitive and lab tests in the CATIE study, we found thatthe cluster memberships were associated neurocognitivefunctions (Wide Range Achievement Test 3rd edition, Readingscore: P=0.0015) and lab tests (creatine phosphokinase test:P=7.2� 10-7; HDL: P=0.0003; triglycerides: P=0.0015;white blood cells: P=0.0022; Neutrophil cells: 0.0064).Furthermore, by the end of phase 1 trial, the minor subtype(84 out of 650 subjects) had improved positive symptoms(P=0.0479) comparing to the baseline at enrollment. Thenegative symptoms showed a trend (P=0.0843).Discussion: The results indicate that genetically informedsubtyping has functional and biological underpinning. Moreimportantly, our subtyping may be linked to treatmentoutcomes when measured by the symptom presentation.While our results need to be verified, the implication toclinical practice is clear and significant.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.286

SU98. THE DISTRIBUTION OF AMINO ACID CHANGESFROM CODING VARIANTS IS ALTERED IN SCHIZOPHRENIA

Loes Olde Loohuisn,1, Mudra Choudhury1, Roel Ophoff2

1University of California, Los Angeles2University of California, Los Angeles Center for Neurobe-havioral Genetics

Background: Schizophrenia is a highly heritable polygenicdisorder with a neurodevelopmental component. Despitethe recent success of genome-wide association studies inidentifying common risk loci, as well as the discovery of arole for rare and coding variants in disease risk, together,these variants explain only a portion of heritability.

Here, we investigate the hypothesis that coding variantsdisproportionately affect specific amino acid changes inschizophrenia. In particular, we hypothesize that schizo-phrenia patients have an increased burden of codingvariants that result in a higher need for specific essentialamino acids, i.e., amino acids that can only be obtainedfrom food intake.Methods: In a case-control cohort of 5,090 Swedish samples(2,546 cases and 2,544 controls) for which whole exomesequencing data are publically available, we tested thishypothesis by comparing case/control distributions of thenumber of coding variants for each possible amino acid change.Results: Interestingly, we observe two significant aminoacid changes affected by common variants that survivecorrection for multiple testing: threonine - proline (TP:mean(sd)=69.2 (7.0) in controls, 68.3(7.0) in cases, P=2.44� 10-5) and threonine - lysine (TK: 26.7(3.4) in controls,26.3(3.4) in cases, P=1.20� 10-4). This result is not drivenby outliers in the cohort. Both changes were observed lessfrequently in cases than controls. We do not observesignificant changes in overall common coding variants,variants altering essential versus non-essential amino acids,or rare variants.

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The genes that harbor these common coding variants arerelatively tolerant to variation and ubiquitously expressed.Moreover, preliminary gene set analysis highlight a glycosy-lation cluster as the most enriched cluster for both TP andTK changes (Enrichment score z=6.8, P=2.1 � 10-10 for TP,and z=2.3, P=1.2 � 10-3 for TK using DAVID 6.8 withstandard settings). Interestingly, glycans (the carbohydratethat attaches to proteins during glycosylation) do attach tothreonine, but not to proline and lysine.Discussion: Threonine is an essential amino acid, and thedecreased number of variants away from threonine, asobserved in schizophrenia cases, results in a higher needfor its intake. Threonine is transformed to glycine, whichworks in the brain to reduce unwanted muscle contractionsand has been used for treatment of ALS and multiplesclerosis. Recent evidence suggests that it also has antipsy-chotic effects. Given the hypothesized neurodevelopmentalcomponent of schizophrenia, it is noteworthy that reducedmaternal supply of threonine during development has beenlinked to limited fetal protein accretion and fetal growth.

Our results highlight an imbalance in amino-acid codingvariants in schizophrenia patients, resulting in a potentialincreased need for threonine (and glycine). While preliminaryin nature, these findings could potentially lead to a betterunderstanding of disease etiology and inform treatment plans.

However, these results need to be replicated in an indepen-dent cohort, and further scrutiny and additional analyses areneeded to determine the biological significance of our findings:we are currently performing these follow up analyses.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.287

SU99. EXPLORATORY FINDINGS MAY IMPLICATE GENE'SVARIANTS, RELATED TO ANTIPSYCHOTIC MECHANISMSOF ACTION, WITH SCHIZOPHRENIA PSYCHOPATHOLOGI-CAL FEATURES

Marco Calabròn,1, Stefano Porcelli2, Concetta Crisafulli1,

Sheng-Min Wang3, Soo-Jung Lee3, Chang-su Han4,Ashwin A. Patkar5, Prakash S. Masand6, Diego Albani7,Ilaria Raimondi7, Gianluigi Forloni7, Carlotta Cristalli8,Vilma Mantovani8, Chi-Un Pae3, Alessandro Serretti2

1University of Messina2University of Bologna3Catholic University of Korea College of Medicine4Korea University College of Medicine5Duke University Medical Center6Academic Medicine Education Institute, Duke-NUS MedicalSchool7IRCCS - Istituto di Ricerche Farmacologiche Mario Negri8Center for Applied Biomedical Research (CRBA), St. OrsolaUniversity Hospital

Background: Schizophrenia (SCZ) is a common and severemental disorder. The involvement of genetic factors in thedisease is well known. In the present paper, we investigated

the effects of several SNPs within 9 candidate genesinvolved with Antipsychotics (APs) mechanisms of actionand APs response in SCZ.Methods: Two independent samples were investigated in thepresent study. 176 subjects diagnosed with SCZ and 326 healthycontrols of Korean ancestry, and 83 SCZ subjects and 194healthy controls of Italian ancestry were used to test associa-tion with AP response (measured as PANSS scores). Secondaryanalyses were also performed on SCZ risk. Exploratory analyseswere also performed on symptoms clusters response (PANSSsubscales), Age of onset and other parameters.Results: Only nominal associations were found for APsresponse: the analyses showed associations for rs11071511,rs2337980(CHRNA7) and rs6740584(CREB1) in the Koreansample. Allelic analyses in the Italian sample evidenced anominal association of rs12144159(PLA2G4A). None of theabove associations survived to the FDR correction. Interest-ing data was found on exploratory analyses, which evi-denced a correlation of the genes under investigation withseveral parameters. In particular, fairly indicative data wasfound for rs11071511 (CHRNA7), rs10798069 (PLAG2G4A) inrelation to Positive symptoms (Korean Sample); rs10814130(SIGMAR1) in relation to Negative symptoms (Korean Sam-ple); rs1719895 and rs2037547 (GSK3B), rs2186358 andrs2839364 (S100B) in relation to Age of Onset (Koreansample); rs10737276 (PLA2G4A) in relation to Age of onset(Italian sample).Discussion: Our results did not support a primary role forthe genes investigated in APs response as a whole. However,our exploratory data suggests that these genes may beinvolved in symptoms clusters response. In particular, thesevariants may determine a higher genetic loading, resultingin an anticipation of the disorder onset (age of onset of thepathology).

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.288

SU100. SEQUENCE MOTIF AND PROTEIN DOMAINENRICHMENT ANALYSIS OF PSYCHIATRIC GWASFINDINGS

Joseph McClayn,1, Andrey Shabalin2

1Virginia Commonwealth University2Center for Biomarker Research and Personalized Medicine,School of Pharmacy, Virginia Commonwealth University

Background: Genome-Wide Association Studies (GWAS)have enabled the mapping of scores of genes for psychiatricdisorders. A commonly-used method to infer function for aset of associated genes is pathway analysis. Here, genes aretested for enrichment in biological pathways, with the goalto find functional links between them. However, a drawbackto pathway analysis is that many genes in the humangenome remain poorly characterized and they cannot beassigned to a pathway. Here, we propose a solution thatorganizes genes into functional categories on the basis of

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motifs extracted from sequence information alone. Motifsare short, recurring sequence patterns presumed to havebiological functions. DNA sequence motifs can give rise totranscription factor binding sites, while amino acidsequence motifs can specify functional protein domains.For example, a transcription factor binding motif couldindicate that a gene is part of a specific regulatory pathway.A domain in a protein could indicate if it is membranebound, or part of a signaling cascade. Hence sequencemotifs and domains provide elementary clues to function,even in the absence of experimental data.Methods: Here we present a pilot analysis to test forenrichment of Schizophrenia (SZ) GWAS findings among setsof genes encoding specific protein domains. We selectedprotein domains from the SMART (Simple Modular Architec-ture Research Tool) database in the subcategory of signalingdomains. We exported UniProt identifiers for proteinspossessing each domain, matched them to gene IDs andpruned for redundancy. We dropped domain-specific genelists with fewer than ten genes. We then took all genesimplicated by the 108 loci for SZ mapped by the PGC (2014).We tested for enrichment of GWAS hits in protein domaingene lists using Fisher's exact test. If significant, weobtained an empirical p-value using permutation to accountfor any dependency in the findings.Results: We examined ten candidate domains in this trialstudy. Genes encoding several signaling domain proteinswere not represented among the PGC findings at all, e.g.acidPPC, PI3Kc, PTB. Genes encoding some strong candi-dates, such as the PDZ domain, were enriched in PGCfindings but not significantly (odds ratio=1.73, Fisherp=0.26). However, genes encoding ankyrin domain proteinswere significantly enriched in PGC SZ findings (oddsratio=2.38, permutation p=0.04).Discussion: PDZ domains represent strong candidatesbecause they organize proteins into complexes at thePostsynaptic Density (PSD). Exome sequencing has linkedrare mutations at PSD proteins to SZ. However, we detectedno significant enrichment of genes encoding PDZ domains inSZ GWAS hits that involve common variants. Ankyrindomains link membrane proteins to the underlying cytoske-leton and many ankyrin proteins are expressed in neurons,so this preliminary association is plausible. We concludethat this pilot analysis yielded promising findings, so we areautomating our analysis pipeline to cover all human proteindomains and DNA sequence motifs. Our goal is to system-atically test these for enrichment with psychiatric GWASfindings. Motif/domain enrichment analysis could comple-ment existing pathway analysis methods to discern functionamong sets of risk genes.

Disclosure: ACCP – Honoraria, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.289

SU101. IDENTIFICATION OF KEY SNPS AND PATHWAYSUNDERLYING DIFFERENTIAL GENETIC CORRELATIONSBETWEEN EDUCATION AND COGNITION ONSCHIZOPHRENIA

Max Lamn,1, Todd Lencz2, Cognitive Genomics Consortium

(COGENT)

1Institute of Mental Health2Zucker Hillside Hospital

Background: Prior investigation of the genetic architec-ture of educational attainment and schizophrenia hasreported a counter-intuitive positive genetic correlationbetween these phenotypes. Yet, it has been widely reportedthat debilitating cognitive impairments are a primaryfeature of the illness, and schizophrenia has been shownto have an inverse genetic correlation with general cogni-tive ability. In this study, we sought to understand thedifferential genetic correlation that exists between those ofcognition and education on schizophrenia, despite theformer phenotypes having largely overlapping geneticarchitecture.Methods: LD-Score Regression (LDSC) was conducted toexamine the relationship between schizophrenia (PGC2-SczWGp, 2014, Nature, PMID: 25056061), and subsets ofSNPs derived from GWAS for education (Okbay et al., 2016,Nature, PMID: 27225129) and cognition. GWAS summarystatistics from Sniekers et al., 2017 (Nature Genetics, PMID:28530673) and independent cohorts reported in Trampushet al., 2017 (Molecular Psychiatry, PMID: 28093568) weremeta-analyzed resulting N=107,207 individuals for cogni-tion. SNPs related to either education or cognition, butwere completely unrelated to the other phenotype wereidentified. Thus, SNPs nominally significantly (po.05) asso-ciated with education, but demonstrated no association tocognition (p4.50) were selected; there were 294,319 suchSNPs. We also examined 386,664 SNPs nominally associatedwith cognition (po.05) but unrelated to education (p4.50).Follow-up pathway analysis was conducted to identifypotential biological pathways underlying each set ofmarkers.Results: We confirmed significant inverse genetic correla-tions between cognition and schizophrenia (rg=-.192,p=2.85e-10) and positive correlations between educationand schizophrenia (rg=.097, p=3.91e-5). LDSC results forfiltered markers demonstrated that the counter-intuitivepositive correlation between education and schizophreniawas entirely driven by SNPs unrelated to cognition (rg[scz]=.55, p=1.06e-7). Much of the inverse correlation betweencognition and schizophrenia was accounted for by thecognition-specific SNPs (rg[scz]=-.11, p=4.65e-2). By con-trast, SNPs nominally significant (po.05) in both theeducation and cognition GWAS were unrelated to schizo-phrenia (rg[scz]=-.039, p=.73). The top enriched pathwaysfor SNPs specific to cognition appeared to be ion transport

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and ion channel regulation, while those for educationpointed to cell adhesion and neuronal developmentalpathways.Discussion: While the genetic architecture betweencognition and education is largely concordant; the dis-cordant association with schizophrenia reveals a criticalset of SNPs and pathways that differentiate the two. Inschizophrenia, ion transport and ion channel regulationrelated pathways appear dysregulated, explaining thestrong negative genetic correlations with cognition.However, it was a subset of pathways related to celladhesion and neuronal development underlying educa-tion genetic architecture that appears to drive thecounter-intuitive positive genetic correlation with schi-zophrenia. These findings suggest that a subset of theneurodevelopmental anomalies implicated in schizophre-nia may be associated with educational success in thegeneral population, perhaps providing a mechanism ofbalancing selection for these seemingly deleteriousalleles.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.290

SU102. GENOME-WIDE ASSOCIATION OF TARDIVEDYSKINESIA

Keane Limn,1, Max Lam1, Jianjun Liu2, Jimmy Lee1

1Institute of Mental Health2Genome Institute of Singapore

Background: Tardive Dyskinesia (TD) is a persistent andpotentially irreversible condition associated with long termexposure to antipsychotics. Commonly observed in schizophre-nia, TD is a movement disorder characterised by involuntarymovements of orofacial muscles, trunk and limbs. TD appearsto represent a genetically complex phenotype, with candidategene and genome-wide studies identifying a collection of genes.The pathophysiology of TD is still unclear and the geneticfactors predisposing TD across ancestries remain relativelyunexplored. Here, we performed a GWAS of TD in a sampleof East Asians, European and African-American ancestries.Methods: Two available datasets were used: 780 schizo-phrenia patients of Chinese ethnicity from Singapore and626 schizophrenia patients of European and African ancestryfrom the CATIE cohort. Dyskinesia was rated on the Abnor-mal Involuntary Movement Scale (AIMS) and TD case ascer-tainment followed the Schooler and Kane criteria. StandardGWAS QC procedures were carried out. Imputation wascarried out on the Sanger imputation server; markers werephased via SHAPEITand imputed via Minimac3 (MACH) to the1000 Genomes Project Phase 3 reference panel (GRch37). Toaddress complex ancestry effects, linear mixed modelassociation was carried out via GEMMA. Fixed-effectsmeta-analysis was conducted via GWAMA.

Results: Meta-analysis revealed one locus on chr16(rs11639774), which met the GWAS significant threshold(Z=5.551, p=3.09e-8). Three other loci of interests wereat subthreshold significance; these were found on chromo-somes 1 (rs499646, p=8.48e-8), 6 (rs6926250, p=2.59e-7)and 12 (rs4237808, p=1.1e-7) respectively. Further investi-gation revealed that these four loci harboured i) down-stream gene variant (rs11639774) ii) intronic variants(rs499646, rs6926250) and iii) intergenic variant(rs4237808). Though MAGMA gene-set analysis did not revealsignificant gene-based results, one of the top gene-setsappeared to implicate immunoglobulin production. Furthergene prioritization of the top 200 associated genes revealedunique brain expression profiles. Notably, several pathwaysemerged that point to DNA damage and immune responses.Discussion: Here we report the largest TD GWAS study todate and evidence for a significant GWAS locus for TD and threeother candidate loci of interest. This suggests an inherentvulnerability to TD, which might be brought about by long termantipsychotic exposure. Of interest, the role of immune systemin the aetiopathogenesis of TD warrants further research.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.291

SU103. UBIQUITINATED PROTEINS ARE ELEVATED INTHE BLOOD AND BRAIN OF INDIVIDUALS WITHSCHIZOPHRENIA

Chad Bousmann,1, Sandra Luza2, Serafino Mancuso2,

Dali Kang2, Md Shaki Mostaid2, Vanessa Cropley3,Cynthia Shannon Weickert4, Carlos Opazo5,Christos Pantelis2, Ashley Bush5, Ian Paul Everall6

1University of Calgary2University of Melbourne3Melbourne Neuropsychiatry Centre, The University ofMelbourne and Melbourne Health4Neuroscience Research Australia5Florey Institute of Neuroscience and Mental Health6Institute of Psychiatry, Psychology and Neuroscience, King'sCollege

Background: Evidence from genome-wide association,microarray, and protein studies have indicated dysregula-tion of genes and proteins within the Ubiquitin ProteasomePathway (UPP) in the blood and brain of individuals withschizophrenia. However, it is not clear which components ofthe UPP, if any, are dysregulated in both blood and brain.Methods: We obtained frozen postmortem OrbitofrontalCortex (OFC) tissue from 76 (38 schizophrenia, 38 control)individuals and erythrocytes from 181 participants, compris-ing 30 individuals with recent onset schizophrenia (meanillness duration=1 year), 63 individuals with schizophreniatreated with clozapine and considered ‘treatment-resis-tant’ (mean illness duration=17 years), and 88 controlparticipants. Free ubiquitin and ubiquitinated protein levels

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as well as endogenous ubiquitination and proteasomeactivity were quantified in erythrocytes and postmortemOFC blind to diagnosis.Results: Individuals with schizophrenia had higher levelsof ubiquitinated proteins compared to those with recentonset schizophrenia (p o 0.001, Hedges’ g=0.81) andcontrols (p o 0.001, g=0.79). Likewise, in postmortemOFC we detected elevated ubiquitinated protein levels inthose with schizophrenia compared to controls (p=0.002,g=0.73). These findings could not be better explained bydemographic (age, sex), clinical (e.g. medication), or tissue(e.g. pH) factors.Discussion: Our results suggest that protein homeostasismay be abnormal in both the blood and brain of those withschizophrenia, particularly in the later stages or specificsub-groups of the illness. Follow-up studies to determinethe mechanism by which this abnormality in protein home-ostasis arises and whether its presence in blood has prog-nostic utility are warranted.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.292

SU104. EXPERIMENTAL MODEL OF DISRUPTED IN SCHI-ZOPHRENIA 1 GENE IN A STEM CELL BASED NEURONALMODEL

Edit Hathyn,1, Sára Kálmán2, László Homolya3, Ágota Apáti3,

Zsófia Nemoda4, János Réthelyi4

1MTA TKI - Office for Research Groups Attached to Universitiesand Other Institutions of the Hungarian Academy of Sciences2Szeged University3Institute of Enzymology, Hungarian Academy of Sciences4Semmelweis University

Background: Induced Pluripotent Stem Cells (IPSCs) havethe capability to differentiate into any kind of cell types,such as Neuronal Progenitor Cells (NPCs), and then tomature neurons. By this new approach we can investigateneuronal differentiation processes or the role of specificgenes using genome editing techniques (e.g., ZFN, TALEN,or CRISPR). For example, the neuron-specific roles of thedisrupted in schizophrenia 1 (DISC1) can be studied in asimple, Petri-dish based model. The DISC1gene has beenintensively studied over the last decades after the descrip-tion of a balanced translocation of t(1;11)(q42.1;q14.3) in amultigenerational Scottish family with several cases ofpsychosis and affective disorders, followed by the identifi-cation of a frameshift DISC1 mutation in an American familyaffected with schizophrenia. Previous molecular biologicalexperiments have shown that DISC1 scaffold protein canaffect neuronal proliferation and migration, and synapsemaintenance. Animal model findings also pointed to its rolein hippocampal neurogenesis, which is a crucial neuronalmechanism affected in several psychiatric disorders.Methods: We aimed to characterize the possible roles ofDISC1 in vitro neuronal cell culture. We applied an isogenic

IPSC line in a model of hippocampal dentate gyrus neuro-genesis, given that impaired hippocampal neurogenesis hasbeen implicated in the pathogenesis of both schizophreniaand affective disorders. IPSC line XCL1 was engineered usingzinc finger nuclease technology to produce an isogenic DISC1exon-2 biallelic knockout cell line (XCL1 DISC1 exon-2 KO/KO). The locus of the genetic engineering was selectedbecause of the frameshift mutation. The isogenic IPSC pairwas characterized in terms of pluripotency and spontaneousdifferentiation potential. Following this, IPSC lines weredifferentiated into neuronal lineages using established pro-tocols to generate hippocampal dentate gyrus granule cells.The dentate gyrus protocol is founded on dual SMADinhibition, Wnt- and SHH inhibition, after generating free-floated embryoid bodies from pluripotent stem cells, whichresults in forebrain NPCs.Results: We have successfully derived and characterizedNPCs and then matured neurons from human IPSC XCL1 anddeletion pair, which were differentiated according to the DGPROX1 protocol. There was no significant difference at thespontaneous differentiation potential between the isogenicIPSC XCL1 lines. The immunofluorescence staining showedthat NPCs express Nestin and Sox2. This intermediate celltype can be further differentiated into PROX1 and MAP2positive functional neurons which have dendritic spines. Tillnow we have not found significant differences between wildtype and knock out cell lines based on induced outgrowthmeasurement and structure of ICC. We have found somealteration in Ca-dynamics between the two cell lines, how-ever these measurements need further investigation.Discussion: The generated neuronal progenitor cells andmature neurons carrying biallelic knockout of the DISC1gene were amenable for assays comparing the isogenic pairsby immunofluorescence microscopy, and transcriptomics.Functional studies, such as calcium-imaging assays, singlecell patch-clamp electrophysiology and real-time live cellvisualization of induced neurite outgrowth are under way tofurther. These investigations may help to explore the role ofDISC1 in hippocampal neurogenesis and the etiology ofpsychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.293

SU105. MODELING SCHIZOPHRENIA IN VITRO BY THEGENERATION OF NEURONS FROM PATIENT-SPECIFICSTEM CELLS

Matthias Jungn,1, Anne Puls1, Jovita Schiller1, Nicole Flegel1,

Albrecht Klemenz1, Claudia Claus2, Bettina Konte1,Annette Hartmann1, Ina Giegling1, Dan Rujescu1

1Martin Luther University Halle-Wittenberg2University of Leipzig

Background: Schizophrenia is a neurodevelopmental dis-ease. Causes include environmental and genetic factors. Char-acteristics of schizophrenia include a deregulation of the

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glutamatergic and the GABAergic neurotransmission and thedegeneration of predominantly inhibitory interneurons.Recently, 108 loci referring to Single Nucleotide Polymorphisms(SNPs) and 8 loci containing Copy Number Variations (CNVs)have been associated with schizophrenia suggesting a strongimpact of genetic factors on the embryonic development ofhuman brain. Together with other research teams, we identifiedCNVs in the Neurexin 1 gene (NRXN1) in patients suffering fromschizophrenia, which highly recommends the detailed analysisof NRXN1-related disease mechanisms. Neurexins are presynap-tic transmembrane proteins. We established patient-specificinduced Pluripotent Stem (iPS) cells from schizophrenia patientsand healthy donors to differentiate neurons for the investiga-tion of disease mechanisms related to NRXN1 in schizophreniapatients. Patient-specific iPS cells carry the disease-associatedgenetic background of a patient, which is a CNVs affectingNRXN1.Methods: Human iPS cells were generated from B-Lympho-blastoid Cell Lines (B-LCLs) using episomal vectors. B-LCLs wereobtained from patients carrying CNVs in NRXN1 and healthydonors. The pluripotency of stem cells was verified by alkalinephosphatase staining, immunofluorescence analysis, transcriptanalysis, western blot analysis, and the induction of three germlayers. A neuronal screening protocol was applied to select iPScell clones with a high differentiation potential towardsneuronal cell lineages. Established lines were differentiatedinto Neural Stem Cells (NSCs) and further differentiated intofunctional and mature neurons. Terminal differentiated neuronswere characterized by morphology, transcript analysis, westernblot analysis, immunofluorescence analysis, electrophysiology,and mitochondrial respiration.Results: Transcript analysis and western blot analysis of iPScells verified permanent induction of pluripotency markergenes including OCT4. The spontaneous differentiation of iPScells into derivatives of the three germ layers was demon-strated. The induction of neural stem cells was characterizedby mRNA and protein analysis of neural stem cells markersincluding SOX2 and PAX6. Neural induction towards corticalneurons was monitored by a set of neurodevelopmentalmarker genes including NESTIN, GFAP, and NGN3. The effi-cient differentiation of mature neurons was shown by theexpression of marker genes including glutamate and GABAreceptors. Mitochondrial respiration was elevated in differ-entiated neurons. Patch clamp analysis verified the differ-entiation of functional GABAergic and glutamatergic neurons.Discussion: Human iPS cells provide a powerful tool forthe analysis of schizophrenia-associated and patient-specificDNA variations including CNVs. We successfully establishedmature and functional neuronal cultures suitable to studydisease mechanisms related to NRXN1. Accordingly, thisapproach is an excellent opportunity for the identificationof potential therapeutic targets.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.294

SU106. DIFFERENTIAL DISTRIBUTION OF SCHIZOPHRENIARISK GENES WITHIN GENE CO-EXPRESSION NETWORKSCONSTRUCTED FROM RNA-SEQ DATA (POSTMORTEMDLPFC) OF AFFECTED AND UNAFFECTED INDIVIDUALS

Eugenia Radulescun,1, Richard E. Straub1, Andrew E. Jaffe2,

Joo Heon Shin1, Qiang Chen1, Daniel R. Weinberger3

1Lieber Institute for Brain Development2Lieber Institute for Brain Development, Johns HopkinsBloomberg School of Public Health3Lieber Institute for Brain Development, Johns HopkinsSchool of Medicine

Background: Schizophrenia polygenic risk is plausiblymanifested by complex transcriptional dysregulation in thebrain, involving networks of co-expressed and functionallyrelated genes.Methods: 1. Samples: DLPFC gene expression (RNA-Seq)abundance was quantified (RPKM) in postmortem humanbrains from the LIBD Postmortem Human Brain Repository(90 controls- CTRL, 76 schizophrenia- SCZ, Caucasians, age:16–80, RINZ7). Common Mind Consortium (CMC) RNA-Seqpostmortem DLPFC (125 CTRL, 109 SCZ, Caucasians, age,RIN as above) was used for replication of LIBD co-expressionnetworks.

2. Expression measures/ quality control: only genes withmedian RPKMZ0.1 (N=23132 genes; LIBD samples) wereused. Expression data was normalized by log2 transforma-tion and adjusted for RNA quality measures (RIN, PMI, totalgene assignment, proportion of mitochondrial RNA) byempirical Bayesian models.

3. Data analysis: WGCNA was applied to the adjustedexpression data to construct co-expression networks, sepa-rately for LIBD- CTRL and LIBD- SCZ. Modules of co-expressed genes were detected by dynamic tree cuttingmethod and summarized as “module eigengenes” forfurther analyses.

4. Modules of LIBD (CTRL; SCZ) were tested for enrich-ment in PGC2 genes within the 108 loci associated with theschizophrenia risk in the latest GWAS.

5. Composite module preservation statistics- medianrank and Zsummary was used for assessing the preservationof LIBD SCZ modules in LIBD CTRL network and for replica-tion of LIBD co-expression modules in the CMC independentdata sets. Gene enrichment analyses for testing modules’enrichment in Gene Ontology (GO) biological processes (BP)was performed with AmiGO/ PANTHER.Results: 17 co-expression modules were identified in eachLIBD group. Module preservation analysis showed a goodpreservation of co-expression modules between LIBD CTRLand SCZ networks, with all but one SCZ module showingevidence for strong preservation (ZsummaryZ10).

PGC2 genes were overrepresented in two CTRL modules(p=0.001973, p=0.028297) enriched for GO-BP such astranslation, ATP synthesis, oxidative phosphorylation,homophilic cell adhesion via plasma membrane adhesionmolecules, chemical synaptic transmission, axonogenesis,and in one SCZ module (p=0.000519) enriched for RNA

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processing, nervous system development and modulation ofsynaptic transmission. 58 PGC2 genes overlapped with theSCZ module (e.g., DRD2, FURIN, TSNARE1), whereas 48 + 17PGC2 genes were overrepresented in the two CTRL modules(e.g., CACNA1C, CHRM4, CACNA1I, TCF20). Of note, only9 overrepresented PGC2 genes were shared by CTRL andSCZ: AMBRA1, ANKRD63, HSPA9, LRP1, PRR12, PTPRF, RERE,TOM1L2, ZDHHC5. Replication of co-expression LIBD net-works in CMC data set showed evidence of weak to strongpreservation (Zsummary42, respectively Z10) for 16/ 17modules for each LIBD group.Discussion: Our results illustrate the complexity of SCZrisk distribution within the DLPFC co-expression networks inpostmortem brains of affected and unaffected individuals.

Importantly, not the same PGC2 genes are members ofco-expression modules in CTRL and SCZ, nor do theyaggregate in similar modules. These observations may beexplained by differential transcriptional regulation due topleiotropy, epistasis, epigenetic dysregulation, or evenhidden RNA quality artifacts. Future studies are necessaryto elucidate the participation of SCZ risk genes in brain co-expression networks.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.295

SU107. INDICATION OF CELL AGING BASED ON DNA-METHYLATION IN EARLY STAGE OF SCHIZOPHRENIA

Sintia Belangeron,1, Fernanda Talarico1, Leticia Spindola1,

Pawan Maurya2, Gabriela Xavier1, Vanessa Ota1,Patricia Moretti3, Ary Gadelha1, Eduardo Gouvea1,Cristiano Noto1, Quirino Cordeiro1, Rodrigo Bressan1,Simone de Jong4, Marcos Santoro1, Gerome Breen4

1Federal University of Sao Paulo2University Uttar Pradesh3University of Brasilia4King's College London

Background: The exposure to biological abnormalitiesproper of the psychiatric conditions (e.g. inflammation,oxidative stress, poor sleep and nutrition, insufficient exer-cise, cigarette smoking) may lead to accelerated cellularaging. Telomere length has been used as an index of biologicalaging in psychiatric illnesses and, using the same rationale, anovel age acceleration predictor is emerging: DNA MethylationAge (DMA). We tested the hypothesis that DMA could beassociated with Schizophrenia (SCZ), its psychopathology andresponse to treatment in early stages of illness.Methods: We assayed 60 antipsychotic-naïve First Episodeof Psychosis patients (FEP), the same individuals after2-month risperidone-exclusive treatment and 59 HealthyControls (HC), totaling 119 participants. Psychiatric diag-nosis was assessed using the Semi-Structured Clinical Inter-view for DSM-IV Axis-I (SCID-I). We used the Positive AndNegative Syndrome Scale (PANSS) to assess positive andnegative symptoms and general psychopathology. We

considered as risperidone-responders those with a decreaseof at least 30% in PANSS. Telomere length was determinedusing a multiplex qPCR assay, whereas DNA methylation agewas estimated by methylation levels at 353 genomic sites(Horvath, 2013) from Illumina 450 K methylation microarray.Results: We found a correlation between chronological ageand DMA (r2=0.899; po0.001), but we found no correlationbetween TL and chronological age or TL and DMA. Inpatients, DMA was not correlated to total, negative, positive,and general psychopathology PANSS. On the other hand, ourdata demonstrate significant statistical difference betweenHC and antipsychotic-naïve FEP, with patients having anominally lower baseline DMA mean than HC (t=2.260;df=117, p=0.026), including after adjustment for chronolo-gical age. After risperidone treatment, no differences in DMAremained comparing HC and FEP. Moreover, there was nodifference in DMA between responders and non-responders torisperidone. Logistic regression modelling showed that DMA(with age as a co-variable) is nominally associated with casestatus (FEP and HC) (po0.022; df=1).Discussion: Our data shows that the DMA is highly corre-lated to chronological age but not to TL, suggesting DMAcould be a better aging measure than TL. In addition, weshowed that DMA does not associate with either symptomsor psychopathology, but may be associated with increasedrisk for schizophrenia in treatment naïve patients.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.296

SU108. ARE POLYGENIC RISK SCORES FOR MAJOR MEN-TAL DISORDERS ASSOCIATED WITH GENERAL OR SPECI-FIC PSYCHOSIS SYMPTOM DIMENSIONS?

Diego Quattrone1, Marta Di Forti1, Pak Sham2,Evangelos Vassos

n,1, Giada Tripoli3, Charlotte Gayer-Ander-son3, Laura Ferraro4, Paul O'Reilly1, Michael O'Donovan5,Alexander Richards5, Jim Van Os6, Craig Morgan3,Ulrich Reininghaus7, Robin Murray3, Cathryn Lewis1

1MRC Social, Genetic & Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience, King'sCollege London2The University of Hong Kong3Institute of Psychiatry, Psychology & Neuroscience, King'sCollege London4University of Palermo5University of Cardiff6Maastricht University Medical Centre7School of Mental Health and Neuroscience, MaastrichtUniversity

Background: Psychotic symptoms can be conceptualisedas dimensions of psychopathology cutting across diagnosticboundaries. Thus, they might be considered enhancedquantitative phenotypes to relate to genetic variants assummarised by Polygenic Risk Scores (PRSs) for Major MentalDisorders (MMDs), including Schizophrenia (SZ), Bipolar

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Disorder (BP), and Major Depressive Disorder (MDD).The objectives of this study were to: 1) identify the

dimensional structure of symptoms at First Episode Psycho-sis (FEP), testing whether a bi-factor model statistically fitsthe conceptualization of psychosis as a single commonconstruct (general psychosis factor) while also recognisingmultidimensionality (positive, negative, disorganized,manic, and depressive symptom factors); 2) examine theextent to which MMD PRSs indexed the phenotypic variancedue to the general psychosis construct and to the specificsymptom dimensions.Methods: The sample included 1182 FEP patientsrecruited as part of the EUGEI study. The MRC Sociodemo-graphic Schedule and the OPerational CRITeria (OPCRIT)were used to collect sociodemographic information andassess psychopathology. DNA was extracted from blood orsaliva samples collected from 940 participants.

The following analysis steps were performed:1) OPCRIT psychopathology items were analysed using multi-dimensional item response modelling in Mplus to estimateunidimensional, multidimensional, and bi-factor models ofpsychosis. Models’ fit statistics were compared using Log-Like-lihood, and Akaike and Bayesian Information Criteria.2) SZ, BP, and MDD PRSs were built using the results from largemega-analyses from Working Groups of the Psychiatric Geno-mics Consortium. In PRSice, individuals’ number of risk allelesin the target sample was weighted by the log odds ratio fromthe discovery samples, and summed into the three PRSs.3) For the best data fitting psychosis model, linear regressionswere estimated to predict symptom dimensions as a continuousoutcome from the three PRSs, accounting for populationstratification.Results: The best model fit statistics was observed for thebi-factor model including one general and five specificsymptom factors compared with the other models. Thisindicated that there was a broad latent structure underlyingthe whole range of psychosis symptoms among five latentspecific symptom dimensions.

PRSs for SZ, BP, and MDD were calculated at the bestmodel fitting P-value threshold. As expected, there was asubstantial difference in discrimination of case-controlstatus between SZ PRS and BP and MDD PRSs.

A significant positive linear regression equation wasobserved for BP PRS and mania dimension severity (t(864)=2.74, po0.01), explaining 5% of the variance; whereas asignificant negative linear regression equation was found forMDD PRS and the negative dimension severity (t(864)=-1.75, p=0.05), explaining 3% of the variance. No sig-nificant association was found for SZ, BP, or MDD PRSs andthe general psychosis trait score.Discussion: These results suggest that a) psychosis atillness onset can be conceptualised as being composed ofone general factor and five specific symptom dimensions, b)there is an association between mania dimension score andBP PRS. Despite the need to both replicate these findingsalso using PGC new released GWAS to build better poweredPRSs, psychosis symptom dimensions have clearly beenshown to be a valid and a useful continuous quantitativephenotype across categorical disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.297

SU109. SCHIZOPHRENIA AND ADULT HEIGHT SHOW ANINVERSE POLYGENIC CORRELATION WITHIN SPECIFICFUNCTIONAL DOMAINS OF THE GENOME

Anil Orin,1, Loes Olde Loohuis2, Roel Ophoff3

1University of California, Los Angeles2Center for Neurobehavioral Genetics, University of California,Los Angeles3David Geffen School of Medicine, University of California,Los Angeles

Background: Many epidemiological studies have reportedon an inverse relationship between Schizophrenia (SCZ) andadult human height (H), two highly heritable traits. Thelargest investigation, a study of 1.35 million Swedish males,found that tall subjects (4 182 cm) had an approximately15% reduction in risk of developing schizophrenia comparedwith short subjects (o 177 cm). Genome-wide analysis hasnot provided evidence of a genetic correlation between thetraits, however. Elucidating the mechanisms underlying thisinverse association can enhance our understanding ofschizophrenia. To address the shared genetic architecturemore systematically, we performed a genetic covarianceanalysis using advanced statistical methods and annotation-stratified domains across the genome.Methods: We applied GNOVA (GeNetic cOVariance Analy-zer), a novel statistical framework that estimates annota-tion-stratified genetic covariance using GWAS summarystatistics (Q. Lu et al., Biorxiv 2017). GNOVA models thegenetic covariance between two traits as a linear system ofequations using GWAS test-statistics and linkage disequili-brium (LD) across annotations. Annotation-stratified ana-lyses can identify genetic overlap that would otherwise bemissed across the whole genome. We used the most recentpublished GWAS summary statistics for both SCZ and H andestimated LD from 1000 Genome reference panel. Weanalyzed their genetic covariance (rho) stratified by MinorAllele Frequency (MAF) bins, the predicted functionalgenome, and transcriptomic and epigenomic annotationsfrom a broad range of tissues and cell types from the GTExand Roadmap Epigenomics consortia.Results: Across the whole genome, we identified a sig-nificant inverse genetic relationship (rho= -0.0036, r=-0.03, P= 0.03), which was not detectable using the LDscore regression method (LDSC; r= 0.00, P= 0.91). Wefound that the covariance is concentrated in variants oflower allele frequencies (MAF bin1: 5–18%, rho= -0.0044,P=0.003) that are predicted to be functional (rho=-0.0043, P=0.001). Across 53 tissues of GTEx, using onlythe subset of lower frequency variants, we observe the SCZand H covariance in 13 tissues (Po 9.4e-4). These include6 brain tissues, but also spleen, whole blood, and lung.

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Across 220 chromatin profiles, we find significant covariancein 11 profiles (P o 2.3e-4) that are mainly brain- and blood-specific cell types and tissues.Discussion: In summary, we are the first to report asignificant inverse genetic relationship between SCZ andH. We show that this genetic overlap is small but significantand concentrated in variants of lower allele frequencies andspecific functional domains of the genome. Current workinvolves Mendelian randomization analysis in a large SCZcohort with anthropometric data available to further dissecttheir pleiotropic relationship. Our work confirms observa-tions of decades of epidemiological studies and provides anintegrative framework to investigate the shared geneticarchitecture between any two complex traits.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.298

SU110. ROLE OF 108 SCHIZOPHRENIA-ASSOCIATEDLOCI IN MODULATING PSYCHOPATOLOGICAL DIMEN-SIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Chiara Fabbrin

, Alessandro Serretti

University of Bologna

Background: Schizophrenia is a highly heritable disorderand the Schizophrenia Working Group of the PsychiatricGenomics Consortium (PGC) identified 108 loci with gen-ome-wide association with broad schizophrenia diagnosis.Schizophrenia is a clinically complex entity and the role ofthese 108 loci in modulating specific clinical features of thedisease is still unknown. This study investigated whichsymptom dimensions may be affected by these loci inschizophrenia and bipolar disorder.Methods: Positive, negative and depressive symptoms,suicidal ideation, cognition, violent behaviors, quality oflife and early onset were investigated in the ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE)and Systematic Treatment Enhancement Program for BipolarDisorder (STEP-BD) samples. Only white subjects wereincluded to avoid possible confounding from ancestry stra-tification. Imputation of genotypes was carried out afterstandard quality control using the Haplotype ReferenceConsortium panel as reference. Individual loci were inves-tigated using linear or logistic regression, then genes within50 Kbp from polymorphisms with po0.10 were included inan enrichment analysis (Cytoscape GeneMania plugin) andPolygenic Risk Scores (PRS) were estimated. In both samplescovariates were center, age, gender, ancestry-informativepopulation principal components and years of education forcognitive measures only. Bonferroni correction or falsediscovery rate were applied to account for multiple testing.Results: 89 polymorphisms among the 108 of interestwere available in both samples, 479 and 810 white subjects

were included from CATIE and STEP-BD, respectively.rs75059851 (IGSF9B gene) was associated with negativesymptoms in CATIE (p=0.00048); no other variants survivedafter multiple-testing correction. rs1023500 (CENPM gene)showed a trend of association with early onset withconsistent direction in both samples (p=0.033 in STEP-BDand p=0.073 in CATIE). GeneMania analysis showed thatnegative symptoms and suicidal ideation had a relevantenrichment of Gene Ontology (GO) terms related to acet-ylcholine neurotransmission, monoamines and ion channelactivity while pyridoxal phosphate binding and fucosemetabolism showed enrichment for cognition. GO termsreferred to processes involved in extracellular matrixstructure were found enriched for early onset. PRS showednominal associations with violent behaviors (p=0.034,Nagelkerke's R2=0.014) and depressive symptoms (p=0.04,R2=0.009).Discussion: This study provided preliminary evidence thata schizophrenia-associated variant in the IGSF9B (immuno-globulin superfamily member 9B) gene may modulatenegative symptoms. IGSF9B is involved in GABAergic signal-ing and it may mediate negative symptoms by affectingdepression and cognition. A polymorphism in the CENPM(centromere protein M) gene showed an interesting trend ofassociation with early onset. CENPM encodes for an innerprotein of the kinetochore, the multi-protein complex thatbinds spindle microtubules to regulate chromosome segre-gation during cell division. Multi-locus models may provideinteresting insights about the biological mechanisms thatmedicate specific symptom domains and the genetic overlapbetween schizophrenia and bipolar disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.299

SU111. EFFECT OF DINUCLEOTIDE POLYMORPHISM(RS67175440) OF DAT1 GENE: INCREASED RISK OFCLONINGER TYPE II ALCOHOLISM IN SEX-SPECIFICMANNER

Anton Nikolishinn

, Vadim Brodyansky, Natalia Chuprova,Maria Solovieva, Alexander Kibitov

V. P. Serbsky Federal Medical Research Centre of Psychiatryand Narcology, Laboratory of Molecular Genetics

Background: The role of dopamine in the addictions’development, including alcoholism, is well shown. TheDopamine Transporter (DAT) regulates the dopamine levelsin the synapse. In some studies, using autoradiography, a DATdensity was higher in patients with Cloninger type II alcohol-ism, which may be due to genetic influence (Tupala E. et’al2006, Kärkkäinen O. et’al 2013). The dinucleotide poly-morphism RS67175440 (A allele - AG, B allele - GA) is locatedin intron 1 of the SLC6A3 gene and can be within the

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regulatory region of the gene, which is interesting forstudying its effect on the alcoholism risk. This locus ispresumably involved in cocaine dependence risk (Zhou Y.et’al 2014). We attempted to assess the influence ofRS67175440 on the probability of development of alcoholism,including patients with the presence of Cloninger type II.Methods: Our sample consisted of 1200 patients withalcoholism (mean age 42.94711.001 years, 277 females)and 536 controls (mean age 43.6574.318 years, 165females), all ethnic Russians. The clinical variables (age atfirst alcohol use, age of onset and term of formation ofalcohol abuse, age and term of alcohol withdrawal syn-drome, age of first hospitalization, family history (FH) ofalcoholism) were assessed by a clinical interview patientand close relative (more often mother). For each individual,RS67175440 was genotyped by PCR-RFLP method usingBseRI. The observed genotype distributions didn’t deviatefrom Hardy-Weinberg equilibrium (Patients: 330AA, 596AB,274BB, P=0.88, Control: 146AA, 253AB, 137BB, P=0.20).For comparison of groups the chi-squared test with Bonfer-roni correction for multiple comparisons, logistic regressionand Mann-Whitney U-test were used.Results: According to the logistic regression, the generalgroup of patients has the influence of the combinationGenderxGenotype in relation to the alcoholism risk, but thiseffect was provided by a group of patients with Cloningertype II alcoholism (age of onset of abuse r 25 years) withthe presence of FH (TypeII+FH) for other patients thiseffect is not revealed. In men, the AA genotype increasesthe risk of AD by 41.3% in the overall comparison (95%CI1.07–1.866, P=0.015), and by 48.7% for the group Type II+FH (1.223–2.402; P=0.002); the AB genotype increases therisk by 47.6% in the overall comparison (1.173–1.857,P=0.001) and 71.4% for the group TypeII+FH (1.418–2.486; P=0.000). In women, the AA genotype reduces therisk by 71.3% for the group TypeII+FH (0.164–0.539;P=0.000); the AB genotype reduces the risk by 31.2% inthe overall comparison (0.51–0.927, P=0.014), and by 52%for the group TypeII+FH (0.321–0.717; P=0.000). Theindependent effect of gender was identical: for men, therisk was 48.2% higher than for women in the overallcomparison (1.181–1.86; P=0.001); and 48.7% higher forthe group TypeII+FH (0.808–2.738; P=0.000).Discussion: There were no differences in genotype orallele frequencies between patients and control usingthe dominant and recessive models. It can be assumedthat the differences in the general group are provided bythe influence of Cloninger type II, in particular, heredi-tary factors. Our results indicate that the locusRS67175440 in the DAT gene in men with the presenceof Cloninger type II alcoholism with family historyincreases, while in women reduces alcoholism risk withan early onset, but doesn’t effect on the dynamics ofalcoholism and clinical variables.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.300

SU112. EVALUATION OF THE IMPACT OF ULTRA-RAREVARIANTS IN CANNABIS USE DISORDER USING EXOMESEQUENCING

Jinjie Duann,1, Francesco Lescai1, Kyle Satterstrom2,

Carsten Rygaard Hjorthøj3, Thomas Werge4,Preben Bo Mortensen1, Ole Mors1, David Hougaard5,Mark Daly6, Merete Nordentoft7, Benjamin Neale8,The iPSYCH-Broad Consortium, Anders Børglum1,Ditte Demontis1

1Aarhus University2Broad Institute of MIT and Harvard3Copenhagen University Hospital4Institute of Biological Psychiatry, MHC Sct. Hans, MentalHealth Services – Copenhagen5Statens Serum Institut6Centre for Human Genetics Research, Harvard MedicalSchool7Mental Health Centre Copenhagen, Universityof Copenhagen8Massachusetts General Hospital

Background: Cannabis is the most widely used illicit drugin the world. Cannabis Use Disorder (CUD) is associated withadverse consequences, including psychiatric symptoms,cognitive decline, anxiety disorder and poor quality of life.35–40% of adults in Denmark and the United States arereported with life-time use of cannabis. The prevalence ofdiagnosed CUD in Europeans and Americans is estimated to1–1.5% and the heritability of CUD is estimated to 51–70%.With respect to the amount of risk explained by commonvariants, the SNP heritability has been estimated to 0.06–0.2. The difference between total heritability and SNPheritability suggests that rare variants might contribute tothe risk of CUD, which require sequencing to find them.Methods: We performed whole-exome sequencing of�7,366 Danish individuals identified in the Danish NewbornScreening Biobank (DNSB), including 1,236 affected withCUD, and �6,100 unaffected controls. We aligned exomesequence data against GRCh37 human genome referencewith bwa and identified variants using GATK. We performedquality control of variants and individuals (including princi-pal component analysis for exclusion of non-Europeans),annotated variants with respect to gene, functional impactand presence in the ExAC non-psych database using Hail.Subsequently various burden tests were performed.Results: Here we will present results from analysis of theimpact of Ultra-Rare Variants (URVs) in CUD. We willespecially focus on the burden of these variants in CUDcases compared to controls in highly evolutionary con-strained genes as well as specific gene-sets relevant toCUD. Furthermore, we will assess whether CUD risk genesidentified based on the common variant analysis also carryan increased burden of URVs. In addition, we will conductgene-based association analysis to identify top-rankinggenes most frequently hit by rare deleterious variants inCUD cases compared with controls.

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Discussion: We will discuss our comprehensive analyses ofthe role of URVs in CUD, which will further contribute to theunderstanding of the genetic architecture underlying thedisorder, and help elucidating relevant biological mechan-ism contributing to disease risk.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.301

SU113. POLYGENIC RISK BURDEN AND CANNABIS USECOMORBIDITY IN PATIENTS WITH SCHIZOPHRENIA ANDBIPOLAR DISORDER

Kristina Adorjann,1, Sergi Papiol1, Katrin Gade1,

Dörthe Malzahn1, Richard Sherva2, Monika Budde1,Fanny Aldinger1, Janos Kalman1, Urs Heilbronner1,Heike Anderson-Schmidt3, Oliver Pogarell4, Peter Falkai4,Joel Gelernter2, Thomas Schulze1

1Institute of Psychiatric Phenomics and Genomics2Yale School of Medicine3University Medical Centre Goettingen4Ludwig- Maximilian University of Munich

Background: Cannabis is the most widely used illicit drugin the world. It is well established that substance abusecomorbidity i.a. cannabis use is much higher among patientswith Schizophrenia (SCZ) and Bipolar Disorders (BD) than inthe general population. However, the relationship betweenrisk of SCZ, BD and cannabis use has not been completelyunderstood so far. Previous studies have revealed that agenetic predisposition to SCZ might be associated withincreased use of cannabis in healthy individuals. Given thisrelationship, we intended to study whether polygenic riskscores (PRS) for SCZ predict cannabis use in patients withSCZ and BD. In addition, we want to test whether BD PRS orCannabis (CAN) PRS have an impact on cannabis use in thesetwo subgroups.Methods: The present study included the USA GAIN/TGENsample (1.150 BD patients) and the German KFO/PsyCoursecohort (433 SCZ and 327 BD patients) (www.kfo241.de;www.PsyCourse.de). Information on ever/never use ofcannabis was available in these samples. PRS were calcu-lated as follows: For each SNP contributing to the PRS, thenumber of risk variants carried by an individual was multi-plied by the logarithm of the odds ratio for that particularvariant. The resulting values were summed up in an additivefashion obtaining a weighted individual estimate of the SCZgenetic burden in each individual at different p-valuethresholds. The most recent summary statistics on SCZGWAS (Ripke et al., 2014), BD GWAS (Hou et al., 2016)and Cannabis use (Sherva et al., 2016) were used toascertain risk variants, their P-values, and associated oddsratios for the respective disorders.Results: SCZ PRS were associated (Po0.05) with cannabisuse in the GAIN/TGEN sample of BD patients in all P-valuethresholds tested ranging from P=0.04 until P=1. A largergenetic burden was associated with a higher risk to use

cannabis. The R2 change explained by PRS ranged from 0.5%to 1.15%. These effects of SCZ PRS were replicated in the BDpatients from the KFO/PsyCourse cohort (P-value threshold0.0001, R2 change=1.94%, P-value=0.020). No effects wereobserved in the SCZ patients from this replication cohort.Likewise, no associations were observed between BD PRSand CAN PRS in any of the subsamples in this study.Discussion: First results suggest that individuals with BDand an increased polygenic risk for SCZ are more likely touse cannabis. The association between BD and cannabis usemight be not simply one of an environmental risk factor, butrather involves gene–environment interaction, as individualschoose and shape their own environment according on theirown innate preferences.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.302

SU114. EARLY SEXUAL ASSAULTIVE TRAUMA, POLY-GENIC RISK FOR AUD/CUD, AND NEURAL RESPONSEINHIBITION IN ADOLESCENCE AND YOUNG ADULTS:TRAJECTORIES OF FRONTAL OSCILLATIONS DURING AGO/NOGO TASK

Jacquelyn Meyersn,1, Vivia McCutheon2, Ashwini Pandey1,

David Chorlian1, Chella Kamarajan1, Michael Seay1,Stacey Subbie1, Jian Zhang1, Arpana Agrawal2,Samuel Kuperman3, John Kramer3, Andrey Anokhin2,Victor Hesselbrock4, Kathleen Bucholz2, Bernice Porjesz1

1State University of New York Downstate Medical Center2Washington University School of Medicine3University of Iowa4University of Connecticut

Background: Trauma, particularly when experiencedearly in life, may alter brain and concurrent cognitive,affective and behavioral development, thereby increasingrisk for substance use disorders and related psychopathol-ogy. While research indicates that genetic factors mayexacerbate these vulnerabilities, few studies have empiri-cally examined these effects using relatively large long-itudinal and genetically informative developmental sampleswith dense phenotyping in multiple domains.Methods: The association of early assaultive, non-assaul-tive, and sexual-assaultive experiences prior to age 10 withdevelopmental trajectories of neurophysiological functioningduring response inhibition (frontal theta and posterior deltaactivity during an equal probability Go/NoGo task) wereexamined, using data from the Collaborative Study of theGenetics of Alcoholism (COGA) prospective cohort, comprisingoffspring from high-risk and comparison families who wereaged 12–22 at enrollment and who have been sought forinterview every 2 years (only those with 3+ interviews wereincluded in the present analyses, N: 3,030). Interactions withearly trauma exposures and polygenic risk for Alcohol andCannabis Use Disorders (AUD, CUD) based on recently pub-lished GWAS data, were examined. Additionally, associations

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of neurophysiological functioning with AUD, CUD, Externaliz-ing (EXT) and Internalizing (INT) psychopathology measured ateach individual's last assessment were examined. Models wereadjusted for age, gender, self-reported race/ethnicity, par-ental alcohol use disorders, and participants' own alcohol andcannabis use.Results: Individuals exposed to sexual assaultive traumaprior to age 10 had altered developmental trajectories ofNoGo frontal theta; the typical developmental change infrontal theta activity observed throughout adolescence andyoung adulthood occurred at a slower rate among those whohad been exposed to early sexual assault, but not othertypes of trauma, compared to those who were not exposed(controlling for other types of assaultive and non-assaultivetrauma exposure). Importantly, effects remained significantafter accounting for parental history of AUD and partici-pants’ own alcohol and cannabis use. Associations weremore robust for participants with greater polygenic risk forAUD, but not CUD. Further, changes in NoGo frontal thetadevelopment was associated with increased risk for AUD andINT (mood disorders and suicidal ideation), but not CUD orEXT (conduct disorder, oppositional defiant disorder). Post-hoc analyses showed that early sexual assault was asso-ciated with higher rates of impulsivity (Barrett ImpulsivityScale) and sensation seeking (Zuckerman's Sensation SeekingScale).Discussion: Findings support the hypothesis that child-hood sexual assault may influence young adult AUD and INTvia alterations in genetic, brain and behavioral develop-ment in adolescence and young adulthood. However, futurestudies are needed to disentangle complex interactionsamong genetic and psycho-social influences on neurobiolo-gical development.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.303

SU115. GENETIC EFFECTS ON MU-OPIOID RECEPTORLIGAND BIASED SIGNALING

Xiao Zhangn

, Eric Vallender

University of Mississippi Medical Center

Background: The mu-opioid receptor, a G Protein-Coupled Receptor (GPCR), has been shown to be associatedwith alcohol and substance use disorders. Specific geneticmutations have been shown, in our studies and those ofothers, to affect propensity towards addiction and pharma-ceutical response; however, the mechanism responsibleremains largely unknown. A better understanding couldassist the development of personalized therapeutics.Recently, the role of ligand-biased downstream cellularsignaling in mu receptors has become an active area ofinterest, but the role of genetic variation in this context hasnot been considered. In this study, we explore whetherligand-induced downstream signaling pathways are biasedacross mu-opioid receptor polymorphisms.

Methods: We are testing two Single Nucleotide Poly-morphisms (SNPs) that change protein sequence, C17T andA118G, which exist on the N-terminal domain of the mureceptor and are common in human populations. Addition-ally, we are testing a rhesus macaque SNP, C77G, whichappears to be functionally and behaviorally parallel. Here,we first transduce transcriptional response element induci-ble luciferase reporters from four pathways (NFkB, cAMP,MAPK/ERK, and MAPK/JNK) into multiple cell lines (SK-N-MC, CHO and HEK 293). We then transfect in a plasmidcontaining the specific variation of the mu opioid receptorand generate a concentration response curve with DAMGO,beta-endorphin, or morphine.Results: Our previous work has demonstrated the effectsof both human and rhesus polymorphisms on cAMP signalingpathways for morphine, DAMGO and beta-endorphin. Forthe NFkB signaling pathway, in both humans and rhesusmacaques, significant differences in potency of morphine,beta-endorphin have been observed, but not DAMGO. Bothhuman C17:G118 and T17:A118 have higher potencies forthese ligands. A similar pattern is seen in the derived G77allele in rhesus macaques.Discussion: Preliminary data suggests that a mechanismby which polymorphisms in the mu opioid receptor exerttheir effects is through differential downstream signaling inaddition to differential potencies. This has implications notonly for understandings of the means by which the muopioid receptor affects behaviors, but also for how geneticdifferences are likely to affect novel biased ligands.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.304

SU116. ASSOCIATION BETWEEN THE NEURONAL CELLADHESION MOLECULE (NrCAM) GENE VARIANTS, WORK-ING MEMORY AND COGNITION IN METHAMPHETAMINEABUSE

GiOk Kimn

, Byung Dae Lee

Pusan National University Hospital

Background: The recent development of molecular genetictechniques is promoting the study of the genetic basis of drugabuse. It is possible that personality factor mediates interme-diately in the genetic contributions to drug abuse. Classicalgenetic studies document strong complex genetic contributionsto abuse of multiple addictive substances, to mnemonicprocesses that are likely to include those involved in substancedependence, and to the volumes of brain gray matter in regionsthat are likely to contribute to mnemonic/cognitive and toaddictive processes. [1] Several lines of evidence support a roleof the neuronal cell adhesion molecule (NrCAM) in polysub-stance abuse vulnerability in humans, as well as in therewarding effects of abused drugs in animals. [2] This gene,which encodes a receptor involved in nervous system develop-ment, is expressed in the central nervous system and located inthe 7q region. Polymorphisms in NrCAM have been reported to

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be associated with addiction susceptibility and with substanceabuse, implicating NrCAM in reward circuitry.Methods: Thirty-seven male methamphetamine abusers(age=43.377.8) and thirty unrelated controls (16 males,14 females; age=59.8710.4) were enrolled into the studyfrom the Bugok National Hospital drug abuse clinic for oneyear. They underwent a blood sample collection for NRCAMgene variants genotyping. Wizard Genomic DNA PurificationKit was used for extracting DNA from patient's blood col-lected in EDTA tubes. 10 single nucleotide polymorphisms(SNPs) in NrCAM gene were selected for variant analysis. Weevaluated working memory dimensions with Hinting Task(HT), Eye Task (ET), Picture Sequencing (PS), EmotionAttribution Task (EAT), Emotion Recognition 40 (ER40),Wisconsin Card Sorting Test (WCST). We assessed cognitivedimensions with Iowa Gambling Task (IGT) and Game of DiceTast (GDT).Results: The distribution of one NRCAM gene SNP genotypesand alleles significantly differed between patients and con-trols.(rs1990162; p=0.0418) Five NRCAM gene SNP genotypesand alleles were associated with some working memorydimensions in the patients.(rs2142325, rs381318, rs1269621,rs2072546, rs1269634) Of those SNP rs1269634 was associatedwith three working memory dimensions comprehensively.(PS-M, EAT, WCST-PE) Two NRCAM gene SNP genotypes and alleleswere associated with some cognitive dimensions in thepatients.(rs2142325, rs722519) Both SNPs were associatedwith four cognitive dimensions comprehensively.(IGT-A, B, C,D, B3, B5) Only one SNPs(rs2142325) was associated with bothworking memory and cognitive dimensions.Discussion: These findings support the idea that NRCAMgene polymorphisms could play a part in the geneticsusceptibility to methamphetamine abuse, and it seems tobe involved in predisposing addictive patients to a moredisturbed addictive behavior influencing on each workingmemory and cognitive factor. Considering the importantrole of the NRCAM gene in brain development, our resultstherefore replicate that the NRCAM gene is one of thestrong candidate genes for drug abuse.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.305

SU117. NEW AND META-ANALYTIC GENOME-WIDE STU-DIES OF HEAVY ALCOHOL CONSUMPTION WITH REDUC-TION TO A CLINICALLY TRANSLATABLE DIGITAL PCRASSAY

Robert Philibertn,1, Meeshanthinin Dogan2, Amanda Noel3,

Emma Papworth1, Papworth Black1

1University of Iowa2CardioDiagnostics3Behavioral Diagnostics

Background: The detection and quantification of heavyalcohol consumption is a challenge for researchers andclinicians alike. Unfortunately, its quantification and

treatment are stymied by the lack of clinically employablebiomarkers. In 2014, using the Illumina 450K platform, wepublished a preliminary DNA methylation signature of heavyalcohol consumption in otherwise healthy individuals thatremits as a function of abstinence. Herein, we present newgenome wide methylation findings and a meta-analysis of allresults.Methods: Heavy alcohol consuming subjects were ascer-tained through local treatment centers using protocols andprocedures approved by the Western IRB. After writtenconsent, subjects were interviewed with a version of theSemi-Structured Assessment for the Genetics of Alcoholismand a series of instruments designed to assess alcoholconsumption. Blood specimens were processed to provideDNA as previously described while serum was tested usingAbNova ELISA kits to determine tobacco and cannabisconsumption status.

Genome-wide DNA methylation from peripheral bloodDNA was assessed using Illumina Epic and 450K arrays. Theresulting array data was processed and cleaned via standardpublished procedures. The resulting clinical methylationdata was analyzed using MethLAB and JMP as indicated.Droplet digital PCR was performed using instruments andreagents from BioRad and a series of custom designedassays. Bisulfite conversion of DNA was conducted usingmaterials from Qiagen. Methylation status was them deter-mined using proprietary Bio Rad software.Results: Using the new Epic methylation array and DNAfrom consecutive heavy drinkers, we replicate the 2014results and show that 17429 CpG residues are differentiallymethylated in heavy drinkers. Meta-analysis of all datafrom the 448,059 probes common to both Illumina platformsshow a similarly profound signature with confirmation offindings from other groups. Principal components analysesshow that genome-wide methylation changes in response toalcohol consumption load on two major factors with onecomponent accounting for over 60% of the variance. Weadditionally show that a five marker panel of methylationprobes accurately classifies use status with an AUC of 0.97.Finally, using droplet digital PCR, we convert these array-based findings to clinically translatable assay and show thatthey accurately assess alcohol use status in third indepen-dent cohort.Discussion: We conclude that DNA methylation assess-ments are capable of quantifying alcohol use status andsuggest that that these epigenetic approaches will findwidespread use in both clinical research and patient care.

Disclosure: Behavioral Diagnostics - Stock / Equity, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.306

SU118. THE EFFECT OF PARENTAL KNOWLEDGE ONTHEIR CONSENT FOR THEIR CHILD'S PARTICIPATION INGENETIC RESEARCH

Smita Deshpande1, Sunita Kumari1,Nagendra Narayan Mishra2, Vishwajit L. Nimgaonkar3,Triptish Bhatia

n,4

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133PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

1PGIMER, Dr. R.M.L. Hospital2L.S. College, B.R.A. Bihar University3University of Pittsburgh4Indo-US Projects, PGIMER, Dr. R.M.L. Hospital

Background: In pediatric genetic research, parents need toprovide permission for their child's participation. Parents mayview these decisions differently from their own participation.This paper focuses on a qualitative analysis of interviewsconducted with parents whose children (autistic or intellec-tually disabled) were requested to participate in a geneticresearch study. Understanding how parents make decisionsabout enrolling their children in genetic research and whatthey think about receiving their children's individual geneticresearch results is important for developing effective andappropriate approaches for primary research recruitment.Methods: All participants were parents of prospectiveparticipants of a genetic study. During the enrollmentprocess, they were asked to participate in a genetic studyfor their children and informed consent was obtained.Irrespective of whether they agreed or refused to partici-pate, they were asked to record an interview regardingtheir attitude towards their children's participation ingenetic studies. A total of 70 parents were interviewed.The recorded interviews were based on an interview guide,were transcribed and translated into English. We used aniterative approach to the qualitative content analysis of thetranscripts and thematic analysis was performed.Results: On most of the structured questions, majority ofthe participants understood the elements of the informedconsent. But in spite of written statement in the consentform to the contrary, many felt that refusal to participatemight affect their treatment. While majority agreed thatresearch data should be confidential, a substantial numberopined that confidentiality of research data is not impor-tant. On qualitative analyses, significant themes regardingtheir attitudes towards research participation were:Research was a part of Government policies; Participationfor self-interest; Pro-social interest; Expectation of preven-tion of illness for next generation; Consent is for trust only.The themes were further elaborated. Other themes were:understanding of genetic research, confidentiality and com-prehension of informed consent.Discussion: The study revealed different attitudes ofparents with regard to genetic research participation. Thereasons of participation ranged from prosocial interests toself-interests. Confidentiality and comprehension of informedconsent were also predictors of participation in such studies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.307

Monday, October 16, 2017

Poster Session III4:30 p.m. - 6:30 p.m.

M1. FIVE NOVEL LOCI ASSOCIATED WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ARE REVEALED BYLEVERAGING POLYGENIC OVERLAP WITH EDUCATIONALATTAINMENT

Alexey Shadrin2, Olav Smelandn,1, Tetyana Zayats3,

Francesco Bettella2, Andrew Schork4, Oleksandr Frei2,Florian Krull2, Srdjan Djurovic1, Stephen Faraone5,Ted Reichborn-Kjennerud6, Stefan Johansson3, Jan Haavik3,Anders Dale7, Yunpeng Wang8, Ole Andreassen2

1Oslo University Hospital2University of Oslo3University of Bergen4Institute of Biological Psychiatry5SUNY Upstate Medical University6Norwegian Institute of Public Health7University of California, San Diego8NORMENT, University of Oslo and Institute of BiologicalPsychiatry, St. Hans Hospital

Background: Attention-Deficit Hyperactivity Disorder (ADHD)is a common neurodevelopmental condition that affects about5% of children and adolescents worldwide. Despite its highheritability little is known about underlying genetic factors.Among other things ADHD is tightly associated with educationalfailure. However, potential genetic overlap between ADHD andeducational attainment has not been examined in detail so far.Exploiting epidemiological similarity between ADHD and educa-tional attainment we aimed to improve discovery of ADHD-associated genetic factors and investigated genetic overlapbetween these phenotypes.Methods: We used ADHD data from the PGC (2064 trios,896 cases, 2455 controls) and educational attainment datafrom the SSGAC (N=328917).

To investigate polygenic overlap between ADHD andeducational attainment we constructed fold-enrichmentplots and conditional QQ plots in both directions: condition-ing ADHD on educational attainment and vice versa. Toexplore the nature of the polygenic overlap and test ahypothesis that investigated traits correlate genetically wecalculated correlations between z-scores of ADHD andeducational attainment variants for nested strata of var-iants, representing subsets of SNPs with increasing signifi-cance of p-values in one of the traits. Additionally wesupported this hypothesis by estimating genetic correlationbetween ADHD and educational attainment using LD scoreregression.

We applied condFDR/conjFDR method to identify specificloci associated with ADHD and loci associated with bothADHD and educational attainment simultaneously.

Consistency of effect directions for top associationsignals detected in our condFDR/conjFDR analyses wastested in the independent GWAS of ADHD symptoms fromEAGLE consortium (N=17666).Results: Using condFDR/conjFDR method we identifiedfive novel loci associated with ADHD, three of these beingshared between ADHD and educational attainment. Leadingvariants for four of five identified regions are located in

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introns of protein coding genes: KDM4A, MEF2C, PINK1,RUNX1T1, while the remaining one is an intergenic SNP onchromosome 2 at 2p24. Four of five loci have oppositedirections of effect in ADHD and educational attainment andconsistent directions of effect in the independent GWAS ofADHD symptoms from the EAGLE consortium.

A hypothesis of polygenic overlap between ADHD andeducational attainment was supported by significant geneticcorrelation (rg=-0.403, p=7.90E-8), consistent pleiotropicenrichment in conditional QQ plots, 410-fold mutualenrichment of SNPs associated with both traits and growingnegative correlation of association z-scores for the nestedSNP strata with increasing significance in both phenotypes.Discussion: We found five novel loci associated with ADHDand provided evidence for a shared genetic basis betweenADHD and educational attainment, implicating three geneticloci in this overlap. Four of five identified loci showedconsistent effects in the independent data set of ADHDsymptoms, and inverse correlation with educational attain-ment. The latter is in line with prior epidemiological andgenetic studies.

We belive that altogether these findings provide newinsights into the relationship between ADHD and educationalattainment, suggesting shared molecular genetic mechanisms.Further research is required to clarify the biological effects ofthe identified genetic variants and how these may influenceeducational attainment and ADHD pathogenesis.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.308

M2. ANALYZING THE ROLE OF COMMON EXOMIC VAR-IANTS ON MODULATING ADHD BEHAVIORS USING ABEHAVIORAL DYNAMIC APPROACH

Shaza Mokhtar1, Sarojini Sengupta2, Natalie Grizenko2,Ridha Joober2, Weam Fageera

n,1

1McGill University2Douglas Institute, McGill University

Background: Attention-Deficit/Hyperactivity Disorder(ADHD) is the most common behavioural disorder inschool-aged children (3–6%). ADHD is characterized bydevelopmentally inappropriate levels of attention, motorhyperactivity/impulsivity, or both. ADHD is a multifactorialhighly heritable disorder, but its genetic underpinningsremain very difficult to unravel. This is mainly due to itsmultilayered phenotypic presentations (combination of sev-eral cognitive, emotional and motor traits), multiple envir-onmental determinants and its complex geneticarchitecture. Our research group has been dissecting thesevarious dimensions through a pharmaco-behavioural geneticstudy of ADHD while systematically collecting highly rele-vant environmental factors.Methods: This unbiased and systematic approach will bedeployed in two phases. First, we are using 179 childrendiagnosed with ADHD aged between 6–12 years and their

parents to identify common exomic SNPs that are associatedwith ADHD or behavioural traits that are relevant for ADHD.This genotyping has already been completed through colla-boration with the international ADHD genetic consortium.Preliminary results of this genotyping and its quality controlindicate that there are over 20 000 eligible SNPs that can beanalysed. In the second phase, 100 SNPs were selectedaccording to a specific algorithm being developed (includingcriteria such as consistent association with ADHD acrossvarious behavioural relevant traits, functional relevancebased on the role of the SNP in gene function or expression,the role of the gene in functional neural networks…) to bereplicated in an independent sample of over 500 patients andtheir parents which are currently available in our laboratory.Results: Preliminary results of this genotyping and its qualitycontrol indicate that there are over 20,000 eligible SNPs thatcan be analysed. In the second phase, 100 SNPs were selectedaccording to a specific algorithm being developed (includingcriteria such as consistent association with ADHD across variousbehavioural relevant traits, functional relevance based on therole of the SNP in gene function or expression, the role of thegene in functional neural networks…).Discussion: To our knowledge, this is the largest studyattempting to unravel the genetic architecture of ADHDcombining highly enriched behavioural dimensions of ADHD,pharmacological probes and a two-pronged whole exomicexploratory and a confirmatory steps. It is expected that thishighly sophisticated approach will enable us to better under-stand the genetic of ADHD and its phenotypic variability.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.309

M3. GENE-GENE INTERACTION BETWEEN COMT ANDNET IN MODULATING ADHD BEHAVIORS

Weam Fageeran,1, Sarojini M. Sengupta2, Natalie Grizenko2,

Ridha Joober2

1McGill University2Douglas Mental Health University Institute,McGill University

Background: Cortico-subcortical circuit dysfunction playsan important role in the manifestation of ADHD symptoms.Dopamine (DA) and Norepinephrine (NE) are major playersin the fine regulation of these circuits. Both of theseneurotransmitters are major players in maintaining alert-ness, increasing focus, sustaining thoughts, and facilitatingmany cognitive functions. Thus, perturbation of either NE,DA (or both) signaling could be implicated in the pathogen-esis of ADHD.Hypothesis: Given the dynamic nature of the brain neuro-modulation, where any action on one system may reverbe-rate in the other systems, we hypothesize that NEtransporter gene could interact with a gene that is essentialfor the metabolism of DA (COMT Val108/158Met) on mod-ulating ADHD behaviors.

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135PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

Methods: 481 children with ADHD (9–12 years old) wereincluded in a 2-week double blind placebo controlled studywith methylphenidate. Teachers and parents were asked toevaluate the child's behavior at baseline, placebo, and MPHweeks. Repeated measure ANOVA with between-subjectfactor of both genes and within-subject factor of experi-mental conditions (EC) was used.Results: A highly significant 3-way interaction (NETnCOMT-nEC) was revealed in three SNPs of the NET gene (rs41154p= 0.002, rs187714 p= 0.001, and rs2242447 p= 0.006)according to the parents’ evaluation. By stratifying thechildren according to their COMT genotypes, we observethat all children behave in a similar fashion at baseline butrespond differently to placebo and MPH. In the Met/Met andVal/Val genotype groups, children who are carrying the AGgenotype of rs41154, CT genotype of rs41154, and CTgenotype of rs41154 tend to respond poorly compared topatients with the GG, CC, and CT genotypes respectively onplacebo and MPH.Discussion: Taken together, the current results suggestthe epistatic interaction between COMT and NET geneticpolymorphisms on response to pharmacological probes.Suggesting that complex gene-by-gene interactions may beimportant.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.310

M4. A CASE-CONTROL GENOME WIDE ASSOCIATIONSTUDY OF CHILDHOOD ATTENTION DEFICIT HYPERAC-TIVITY DISORDER (ADHD)

Ziarih Hawin,1, Hannah Yates1, Lindsey Kent2, Michael Gill3,

Mark Bellgrove1

1Monash University2University of St. Andrews3Trinity College Dublin

Background: Attention Deficit/Hyperactivity Disorder (ADHD)is the most prevalent mental disorder of childhood. Geneticinfluences are recognised as a major predisposing factor forADHD with heritability estimated between 75–90% which iscomparable to that of major psychiatric mental illnesses, suchas autism and schizophrenia. Identifying the individual DNAvariations that confer risk to ADHD has been a major scientificchallenge over the last 20 years. In this investigation, weconducted a Genome-Wide Association Study (GWAS) involving480 ADHD-DSM-IV diagnosed samples compared to 1207 ethni-cally notched controls.Methods: Genotyping was conducted using Psych-Chipplatform (Illumina, 2015). This array has been developedby Illumina in tandem with the Psychiatric Genomics Con-sortium for the purpose of large-scale genetic studies inpsychiatry. The Psych-Chip contains a GWAS backbone of588,628 markers enriched with 50,000 single nucleotidepolymorphisms (SNPs) which have been implicated in psy-chiatric conditions and/or neurodevelopmental disorders.

Quality control of the genotypic data was conducted asdescribed in Anderson et al. [2010].Results: Although no significant SNP association wasobserved at the GWAS level (5.0 E�8, several SNPs exhib-ited strong trends toward association. For example, associa-tion with rs6659350 which was mapped 22.8 kbp upstreamof the Tenascin-R gene (TNR), was tantalizingly close toGWAS significance (p=8.49E�08). In addition, rs2410116(mapped 300.2kbp upstream of DLC1 Rho GTPase ActivatingProtein (DLC1)) also showed a strong trend toward associa-tion with ADHD (p= 2.3E�07). Further, seven other SNPs(rs10006479, rs7007897, rs10835019, rs17772064,rs11788670, rs415300, rs2295135) showed strong trends (p-values ranged between 1.01E�05 and 2.98E�06).Discussion: Although our sample has limited power todetect reliable genome wide association with ADHD, itrepresents a contribution of never before analysed (pre-dominantly Australian) samples to the international GWASeffort. Although our analysis shows promising trendstowards association, ultimately these results will need tobe verified in the context of current international ADHDGWAS consortia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.311

M5. GENETIC OVERLAP BETWEEN ADHD AND ASD INSHANK GENES IN CHINESE POPULATION

Lu Hua Chenn,1, Chi-chiu Lee2, Ting-pong Ho3,

Se-fong Hung1, Chun-pan Tang2, Merce Garcia-Barcelo3,Yee Ching Kelly Lai1, Suk Ling Ma1, Yi Man Flora Mo1,Ming Chung Marshall Lee1, Ka Sin Caroline Shea4,Pak Chung Sham5, Patrick Wing-Leung Leung1

1The Chinese University of Hong Kong2Kwai Chung Hospital, Hospital Authority3University of Hong Kong4Alice Ho Miu Ling Nethersole Hospital, Hospital Authority5Centre for Genomic Sciences, University of Hong Kong

Background: Attention Deficit/Hyperactivity Disorder(ADHD) is characterized with inattention, hyperactivityand impulsivity, while Autism Spectrum Disorder (ASD) ischaracterized with impaired social communication andinteraction, restricted and repetitive patterns of behaviorand activities. Phenotypically, both appear to be quitedifferent. However, clinically it has been found that 20–50% ADHD children meet diagnostic criteria for ASD, while30–80% ASD children meet diagnostic criteria for ADHD.These rates of comorbidity between the two disorders implythat they may share underlying etiologies. Although recentevidence has suggested a genetic overlap between ADHDand ASD, little progress has been made so far to identify thespecific genes involved. The shank synaptic scaffold pro-teins, which are encoded by SHANK genes and located at thepost-synaptic density of glutamatergic synapses, have beenreported to be associated with a number of psychiatric

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disorders, including ADHD and ASD, separately. The aim ofthe current study is to investigate whether there is agenetic overlap between ADHD and ASD in SHANK genes.Methods: In the present study, only male children withChinese ethnicity, aged between 6 to 12 years, wereincluded. 298 ADHD family trios (including ADHD childrenwithout ASD and their biological fathers and mothers), 134ASD children without ADHD, and 109 children with both ASDand ADHD were recruited from public hospitals in HongKong. 232 normal control children were recruited from localprimary schools. A number of single-nucleotide polymorph-isms (SNPs) from SHANK2 and SHANK3 were selected forgenotyping. After quality control, 14 SNPs from SHANK2 and7 SNPs from SHANK3 were included for data analyses. ForADHD family trios’ data, we constructed ADHD cases andmatched pseudo-control, which were based on transmittedand un-transmitted parental alleles using the Haplotype-Relative-Risk (HRR) principle. The pseudo-control supple-mented the normal control to increase the statistical power.Likewise, ASD children with or without ADHD were alsopaired with samples of normal control and pseudo-controlfor association analysis. PLINK and KGG were used forstatistical association analyses at SNP-level and gene-level,respectively.Results: When association analysis was done betweenADHD children without ASD and samples of normal controland pseudo-control, the T allele of rs7106631 of SHANK2significantly decreased the ADHD risk (p=0.001, OR=0.70).When allele frequencies’ comparisons were conductedbetween ASD children with or without ADHD and samplesof normal control and pseudo-control, the same protectiveeffect of rs7106631 T allele was identified with OR=0.74(p=0.011). Further association analysis conducted betweenall clinical children (i.e., ADHD children without ASD & ASDchildren with or without ADHD) and samples of normalcontrol and pseudo-control yielded more significant resultsfor rs7106631 (p=0.0003, OR=0.72). Additionally, signifi-cant associations were found for other SHANK2 SNPs,namely, rs7113016 (p=0.027), rs1073294 (p=0.008),rs11236616 (p=0.003), rs10899158 (p=0.048), andrs9888288 (p=0.004). However, no significant result wasdetected for SNPs of SHANK3. Subsequent gene-level ana-lysis based on whole dataset suggested the significant roleof SHANK2 in both ADHD and ASD (gene-level p=0.003).Discussion: Consistent with previous findings in Westernpopulations, this current study provides additional evidencefor the significant association of SHANK2 with ASD from aChinese population. A new finding rarely reported in pre-vious studies is the association of SHANK2 with ADHD. Thisimplies a shared genetic susceptibility between ADHD andASD. Both disorders do share a number of characteristics,including male preponderance, increased level of oxidativestress, and abnormal neuronal connectivity, reflectingpotentially common underlying neurodevelopmentalabnormality. Speculatively, the identification of SHANK2from this current candidate gene study as associating toboth ADHD and ASD may provide the common geneticetiology to explain their shared characteristics and higher-than-chance comorbidity. Further studies examining thefunctional abnormalities of the identified gene, SHANK2,are warranted in the future.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.312

M6. PHARMACOGENETICS PREDICTORS OF METHYLPHE-NIDATE EFFICACY RESPONSE IN CHILDHOOD ADHD

Nicole Myer1, Joseph Boland1, Stephen Faraone2,David Krause

n1

1Genomind2SUNY Upstate Medical University

Background: Stimulant medication has long been effec-tive in treating Attention-Deficit Hyperactivity Disorder(ADHD) and is currently the first line pharmacologicaltreatment for children. Both methylphenidate and amphe-tamine modulate extracellular catecholamine levelsthrough interactions with dopaminergic, adrenergic, andserotonergic system components; it is therefore likely thatcatecholaminergic molecular components influence theeffects of ADHD treatment.Methods: We conducted a PubMed search to identify allpeer-reviewed publications examining efficacy response tomethylphenidate in the treatment of childhood ADHD. Usingmeta-analysis, we sought to identify predictors of pharma-cotherapy to further the clinical implementation of perso-nalized medicine. We used meta-regression to examine theeffects of gender ratios, cohort ethnicity, study quality, andmean participant age. Egger's test and Duval and Tweedie's'trim and fill' were used to examine and correct forpublication bias.Results: We identified 35 studies (3,698 children) linkingthe efficacy of methylphenidate treatment with DNA var-iants. Pooled-data revealed a statistically significant asso-ciation between Single Nucleotide Polymorphisms (SNPs)rs1800544 ADRA2A (odds ratio: 1.69; confidence interval1.12–2.55), rs4680 COMT (odds ratio: 1.40; confidenceinterval: 1.04–1.87), rs5569 SLC6A2 (odds ratio: 1.71; con-fidence interval 1.22–2.38), and, repeat variants VNTR4 DRD4 (odds ratio: 1.64; confidence interval: 1.15–2.33),VNTR 7 DRD4 (odds ratio: 1.47; confidence interval: 1.00–2.15), and VNTR 10 SLC6A3 (odds ratio: 1.26; confidenceinterval: 1.11–1.67), whereas the following variants werenot statistically significant: rs1947274 LPHN3 (odds ratio:0.95; confidence interval: 0.71–1.26) and rs5661665 LPHN3(odds ratio: 1.07; confidence interval: 0.84–1.37). Funnelplot asymmetry amongst SLC6A3 studies was identified andattributed largely to small study effects.Discussion: This meta-analysis supports an associationbetween genetic variants - within the ADRA2A, COMT,SLC6A2, and DRD4 genes - and efficacy response to methyl-phenidate for the treatment of childhood ADHD. Thesefindings have major implications for advancing our thera-peutic approach to childhood ADHD treatment.

Disclosure: Genomind - Employee, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.313

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M7. GENOME-WIDE ANALYSIS IN UK BIOBANK IDENTI-FIES FOUR LOCI ASSOCIATED WITH MOOD INSTABILITYAND GENETIC CORRELATION WITH MDD, ANXIETY DIS-ORDER AND SCHIZOPHRENIA

Daniel Smithn

University of Glasgow

Background: Mood instability is a core clinical feature ofaffective and psychotic disorders. In keeping with theResearch Domain Criteria (RDoC) approach, it may be auseful construct for identifying biology that cuts acrosspsychiatric categories.Methods: We aimed to investigate the biological validityof a simple measure of mood instability and evaluate itsgenetic relationship with several psychiatric disorders,including Major Depressive Disorder (MDD), Bipolar Disorder(BD), schizophrenia, Attention Deficit/Hyperactivity Disor-der (ADHD), anxiety disorder and Post-Traumatic StressDisorder (PTSD). We conducted a Genome-Wide AssociationStudy (GWAS) of mood instability in 53,525 cases and 60,443controls from UK Biobank.Results: We identified four independently-associated loci(on chromosomes eight, nine, 14 and 18), and a commonSingle Nucleotide Polymorphism (SNP)-based heritabilityestimate of approximately 8%. There was a strong geneticcorrelation between mood instability and MDD (rg=0.60,SE=0.07, p=8.95� 10–17) and a small but significantgenetic correlation with both schizophrenia (rg=0.11,SE=0.04, p=0.01) and anxiety disorders (rg=0.28,SE=0.14, p=0.04), although no genetic correlation withBD, ADHD or PTSD. Several genes at the associated loci mayhave a role in mood instability, including the deleted incolorectal cancer (DCC) gene, eukaryotic initiation factor2B (eIF2B2), placental growth factor (PGF), and proteintyrosine phosphatase, receptor type D (PTPRD). Strengths ofthis study include the very large sample size but ourmeasure of mood instability may be limited by the use ofa single question.Discussion: Overall, this work suggests a polygenic basisfor mood instability. This simple measure can be obtained invery large samples; our findings suggest that doing so mayoffer the opportunity to illuminate the fundamental biologyof mood regulation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.314

M8. ASSOCIATION OF POLYMORPHISM RS2278749 GENEARNTL WITH SOME COMPONENTS OF AFFECTIVE DIS-ORDERS AND SLEEP DISTURBANCES IN MALE POPULA-TION 25–44 YEARS IN RUSSIA / SIBERIA

Valery Gafarov2, Elena Gromova1, Igor Gagulin1,Dmitriy Panov

n,1, Almira Gafarova1, Eldar Krymov1

1FSBI Institute of Internal and Preventive Medicine SB RAMS

2Collaborative Laboratory of Cardiovascular Diseases Epi-demiology SB RAMS

Background: To study the association of polymorphismrs2278749 gene ARNTL with some components of affectivedisorders and sleep disorders in the male population 25–44years in Russia / Siberia (Novosibirsk).Methods: In 2014–2016 GG It surveyed a random repre-sentative sample of the male population 25–44 years, one ofthe districts of Novosibirsk. Randomly selected 200 men hada mean age of 35.5 years, who underwent psychosocialtesting. Testing conducted by questionnaire "4-item JenkinsSleep Questionnaire». Test anxiety and depression con-ducted modified questionnaires of the Welsh Depressionsubscale of the MMPI and Bendig Anxiety subscale of theMMPI, the study of the life of exhaustion conducted ques-tionnaires The Maastricht Questionnaire (MQ). Question-naire "Knowledge and attitude towards their health" wasalso proposed. The men included in the study, studied thefrequency distribution of genotypes of rs2278749 ARNTLgene. Differences in the frequency distribution of genotypesof rs2278749 ARNTL gene were evaluated by Chi square (X2)test between groups. The values of p r 0,05 wereconsidered statistically significant.Results: It was found that the most common genotypers2278749 ARNTL gene was homozygous C / C genotype -74,9%, C / T genotype was at - 22.3%, 2.8% - genotype T / T.It was revealed that carriers of the genotype C / T morelikely to experience serious conflicts in the family, moreexperienced their frustration, they often have disturbingdreams, and they wake up tired and exhausted, in addition,they often met the high level of the life of exhaustion, andthey soon became frustrated. Carriers of genotype T / Toften took the trouble "to heart" and were more punctual.On the other hand, the carriers C / C genotype were morehostile, were inclined not to trust anyone, almost "never"accept negative situations "close to the heart" and much lessexperienced disturbing dreams.Discussion: It was determined that the genotype C / TARNTL gene associated with sleep disorders in the Siberianpopulation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.315

M9. INVESTIGATING THE IMPACT OF DEPRESSION ANDSCHIZOPHRENIA POLYGENIC RISK SCORES ON EMO-TIONAL PROBLEMS FROM CHILDHOOD TO MID-LIFE

Lucy Riglinn,1, Stephan Collishaw1, Ajay K. Thapar1,

Barbara Maughan2, Michael O'Donovan1, Anita Thapar1

1Cardiff University2King's College London

Background: Previous studies find that both schizophre-nia and mood disorder risk alleles contribute to adultanxiety and depression. Emotional problems (depression or

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anxiety) begin in childhood and show strong continuitiesinto adult-life; this suggests that symptoms are the mani-festation of the same underlying liability across differentages. However, other findings suggest there are develop-mental differences in the etiology of emotional problems atdifferent ages. These include (a) differences in treatmentresponsiveness and gender ratios in child/adolescence com-pared to adulthood, (b) recent genetic findings that schizo-phrenia risk alleles were specifically associated with“earlier-onset” (o27 years) rather than “later-onset”depression. To our knowledge, no study has prospectivelyexamined the impact of psychiatric risk alleles on emotionalproblems at different ages in the same individuals.Methods: Data were analyzed using regression-based ana-lyses in two UK, prospective, population-based cohorts(NCDS and ALSPAC). Schizophrenia and Major DepressiveDisorder (MDD) Polygenic Risk Scores (PRS), were derivedfrom published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessedprospectively from age 7 to 44 years in NCDS and from age7 to 18 years in ALSPAC.Results: Schizophrenia PRS were associated with emotionalproblems from childhood (β=0.044, p=0.005) to mid-life(β=0.033, p=0.023), while MDD PRS were associated withemotional problems only in adulthood (β=0.035, p=0.011;childhood β=0.014, p=0.372). Associations between schizo-phrenia PRS and early emotional problems appear to be drivenby anxiety rather than depression.Discussion: Our prospective investigations suggests thatearly (childhood) emotional problems in the general populationshare more genetic risk with schizophrenia, while later (adultlife) emotional problems also shared genetic risk with MDD. Thisis consistent with findings from cross-sectional clinical studies ofMDD. The results suggest that the genetic architecture ofdepression/anxiety is not static across development.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.316

M10. ALLELIC VARIATION IN GLRB PREDISPOSES TOAGORAPHOBIA BY INCREASING STARTLE RESPONSEAND MODULATING DEFENSIVE REACTIVITY

Heike Webern,1, Jürgen Deckert1, Ulrike Lueken1,

Manuel Kuhn2, Carmen Villmann3, Jan Richter4,Benjamin Straube5, Agnes Gajewska1, Marta Andreatta1,Alejandro Arias-Vasquez6, Leif Hommers1, Lindsey Kent7,Tina Lonsdorf2, Paul Pauli1, Andreas Reif8

1University of Würzburg2University Medical Center Hamburg-Eppendorf3University Hospital of Würzburg4University of Greifswald5Phillips-University Marburg6Radboud University Nijmegen Medical Centre7School of Medicine, University of St. Andrews8University of Frankfurt

Background: The molecular genetics of Panic Disorder(PD) with and without agoraphobia (AG) are still largelyunknown and linkage, candidate gene and Genome-WideAssociation Studies (GWAS) of PD/AG were mostly negativeor inconsistent due to phenotypic diversity, genetic hetero-geneity and underpowered sample sizes.Methods: Assuming a dimension from agoraphobic cognitionsto full PD/AG, we (1) conducted a GWAS on a dimensionalanxiety phenotype (ACQ) in 1,370 healthy volunteers, (2) eval-uated the found Glycine Receptor Beta (GLRB) locus in anextended sample of healthy 2,547 volunteers, (3) validated it ina population based sample (N=3,845) with another measure ofAG symptoms [SCL-90], (4) assessed it relevance for thecategorical phenotype PD/AG in 506 case-control pairs, (5) mea-sured mRNA expression in vitro and post mortem (N=76),(6) examined the effect of GLRB risk polymorphisms on startlehabituation, potentiation, and generalization (N=101 healthyvolunteers), complemented by a behavior avoidance test(N=115 PD/AG patients) and fMRI analysis (N=76 healthyvolunteers; N=86 patients with PD/AG) of fear network andgeneral sensory activation and (7) performed analyses ofagoraphobic behavior in partial Glrb knock-out mice.Results: (1) GWAS on the ACQ phenotype resulted in twogenome-wide significant (po5� 10-8) SNPs rs78726293 andrs191260602, both located in an intronic region of the GLRBgene. (2) Evaluation of the GLRB locus in an extended sample,(3) validation in a second, independent cohort with a dichot-omous SLC-90 based agoraphobia phenotype and (4) in a PD/AGcase-control control sample revealed in two further highlysignificant p-values for GLRB variants rs17035816 (p=3.8� 10-4) and rs7688285 (p=7.6� 10-5). (5) GLRB gene expression wasfound to be significantly reduced in presence of the SNPrs7688285´s risk allele in vitro and post mortem midbraintissue. (6) Functional assessment on startle response demon-strated that GRLB risk alleles go along with impaired startlehabituation and increased startle potentiation and general-ization. Further fMRI analysis demonstrated that rs7688285 riskallele carrier show an increased neurofunctional activation inthe anterior insular cortex and altered fear conditioning as afunction of genotype. Finally (7) demonstrated partial Glrbknockout-mice an agoraphobic phenotype.Discussion: Present results provide translational evidencethat genetic variation within the GLRB gene predisposes toagoraphobia by modulation of the intermediate phenotypestartle reflex. GWAS on the ACQ phenotype providedgenome-wide significance for the GLRB locus, that we henceconfirmed by validation in an independent cohort and byassociation with PD/AG. Results from behavioral studies inGlrb knockdown mice further supported that this gene isinvolved in agoraphobic behavior.

As GLRB mutations are causal in hyperekpleksia, weprobed whether the startle reflex as an intermediatephenotype is modulated by genetic variation in GLRB anddemonstrated that risk alleles go along with impairedstartle habituation and increased startle potentiation andgeneralization. Further fMRI analysis showed that GLRB riskalleles are associated with increased fear-induced activa-tion of the fear network, but also with a general fear-independent activation of the sensory network.

Our data propose how a genetic risk factor might via anintermediate neurobiological phenotype lead to development

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of a mental disorder, thus opening perspectives for noveltherapeutic approaches.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.317

M11. ASSESSING THE ROLE OF LONG NONCODING RNAS(LNCRNAS) IN AUTISM SPECTRUM DISORDERS

Nancy Francoeur1, Michael Gandal2, Xiao Xu1,Kwadwo Sarpong1, Jessica Johnson1, Pamela Sklar1,Harm van Bakel1, Daniel Geschwind2, Dalila Pinto

n,1

1Icahn School of Medicine at Mount Sinai2David Geffen School of Medicine at UCLA

Background: The contribution of non-coding genomic ele-ments remains largely unexplored in Autism Spectrum Dis-orders (ASD). Long non-coding RNAs (lncRNAs) areincreasingly recognized for their role in transcription regula-tion, and likely contribute to transcriptome dysregulation inASD.Methods: We are applying a combination of short-readand long-read RNA-Seq, with and without lncRNA capture tounveil the role of lncRNAs in ASD. As lncRNAs are poorlyrepresented in standard RNA-Seq experiments, we usedcapture RNA-Seq (Capture-Seq) to quantify lncRNA expres-sion in postmortem prefrontal cortex and cerebellum tissuesin a cohort of 40 ASD and controls. We additionallycombined full-length (PacBio) isoform sequencing (Iso-Seq)with capture (Capture-IsoSeq) to build a comprehensivemap of brain-expressed lncRNAs.Results: The enrichment by Capture-Seq increased thelncRNA fraction of our RNA-Seq datasets from 5% to 57%. Weidentified 28 differentially expressed (false discovery rate(FDR) o 0.05) lncRNAs and Transcripts of Unknown CodingPotential (TUCPs) in ASD samples compared to controls. A“guilt-by-association” analysis further revealed genes underputative cis-regulation of Differentially Expressed (DE)lncRNAs that are implicated in pathways dysregulated inASD. Finally, Capture-IsoSeq profiling identified �3,600novel multi-exonic lncRNA/TUCP isoforms expressed inprefrontal cortex.Discussion: Our Capture enriched sequencing approachessubstantially improved our ability to profile lncRNA expres-sion and reconstruct poorly annotated lncRNA isoforms. Wehave identified many DE lncRNA/TUCP transcripts in acohort of 40 ASD and controls from two different brainregions as a key step towards understanding the role oflncRNAs in ASD etiology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.318

M12. PAVING THE WAY FOR PRECISION MEDICINE INPSYCHIATRY – DESIGN AND IMPLEMENTATION OF AUNIFIED RARE GENETICS CURRICULUM

Daniel Moreno De Lucan,1, David Ross2

1Brown University2Yale University

Background: This is an exciting time in psychiatry. Forthe last few years, we have been witnessing an acceler-ated pace of genetic discoveries that are redefining ourunderstanding of mental health disorders spanning fromautism to schizophrenia. Insights have come from com-mon and rare genetics alike, fueled by techniques thathave a higher resolution and a lower cost. However, mostpsychiatrists were trained in an era that preceded thiscutting-edge work, and psychiatry residency and fellow-ship programs have not yet integrated this new informa-tion into their curricula. Current challenges includedetermining unified content areas that should be knownby psychiatrists, as well as implementing the deliveryand teaching of these concepts using principles of adultlearning. Here, we describe joint efforts to address thispractice gap, using rare genetics as a vehicle.Methods: Multiple stakeholders have gotten together toaddress this issue. The Education Taskforce of the Interna-tional Society of Psychiatric Genetics (ISPG) was formed toidentify and standardize key content areas that should becovered in psychiatry training programs across the globe,while the National Neuroscience Curriculum Initiative(NNCI) has focused on implementing the delivery of thiscontent. As a joint effort, we have developed an interactivecase conference tailored towards teaching principles andapplications of rare genetics in psychiatry, using autism asan example to provide clinical correlation and applicabilityof this knowledge. We designed the module using the NNCIstandards, and included supporting media and guidance forfacilitators to allow for this material to be free-standing andindependent from local expertise for its delivery. Weadministered this exercise to 300 psychiatry residents,fellows, and psychiatry program directors at diverse set-tings, and obtained pre and post knowledge assessments, aswell as qualitative data on impressions and utility of themodule.Results: Our preliminary results showed an overall lowgenetic literacy among all surveyed groups in the pre-assessments, followed by a high retention of contentafter the exercise, with detailed analyses underway. Wealso obtained positive qualitative feedback, whichincluded an increased appreciation for the clinicalrelevance of this knowledge and satisfaction with themethod of delivery.Discussion: Our results were in agreement with ourhypothesis of low genetic literacy across psychiatry,which justifies the need for increased efforts to stan-dardize and deliver this knowledge. We showed that themodule was well received and feasibly applied with local

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resources within diverse settings, and led to increasedgenetics knowledge in participants. This highlights theimportance of blending key content with sound pedago-gical methods and maintaining the clinical grounding ofexercises, and underscores the relevance of modest andattainable learning objectives. The approach used here,for which collaborations between the ISPG EducationTaskforce and the NNCI were key, could easily beadapted and broadly generalized for other core compe-tencies in genetics.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.319

M13. BEHAVIOR PHENOTYPING OF A MOUSE MODEL OFPHELAN MCDERMID SYNDROME WITH A FULL DELETIONOF SHANK3 GENE

Elodie Drapeaun

, Mohammed Riad, Yuji Kajiwara,Joseph Buxbaum

Icahn School of Medicine at Mount Sinai

Background: Phelan-McDermid Syndrome (PMS) is a raregenetic syndrome in which one copy of the q13 portion ofchromosome 22 is missing or mutated leading to a globaldevelopmental delay, hypotonia, delayed or absent speech,intellectual disability, and autistic behaviors. SHANK3, a genecoding for a key structural part of the post-synaptic density, isthe critical gene for the core neurological and behavioralsymptoms in this syndrome, and the loss of one copy ofSHANK3, occurring through intragenic deletion or pointmutation, is sufficient to cause Phelan-McDermid syndrome.However, the size of the region affected can be highlyvariable, from point mutation to up to 8 Mb deletions andthe deletion size seems to be correlated with the syndromeseverity. Due to multiple intragenic promoters and alterna-tively spliced coding exons within the gene, several Shank3isoforms have been identified in human and mouse brains.Methods: Numerous mouse models have been generated butmost target only some of those isoforms while the vast majorityof SHANK3 mutations found in PMS patients are deletions of theentire gene. Our aim is based on a novel mouse model, in whichall Shank3 isoforms are disrupted and which more closelymirrors the most common genetic mutations found in PMSand our goal was to investigate the behavioral consequences ofa disruption of all isoforms of Shank3.Results: Our laboratory had previously created a mousemodel with a deletion of exons 4 to 9 leading to thedisruption of the full length Shank3 protein. We used aCre-LoxP strategy to add an additional LoxP site flankingexon 22 and disrupt all isoforms. We carried an extensivebehavioral phenotyping of neonate, young and adultwild-type, heterozygote and homozygote mice with abattery of test designed to assess the main feature ofPMS including neurodevelopmental milestones, sensoryand motor functions, sociability, stereotypies and cogni-tive functioning.

Discussion: Mice with a full deletion of Shank3 are moreseverely affected than previously published mouse modelwith a partial deletion. Abnormal Mendelian ratios at thetime of weaning were observed showing a significant deficitfor homozygote mice that can be partially explained by anincrease of early postnatal lethality. Both sensory and motordisabilities were detected in neonate and adult mice. Whilesocial performances and interest for social stimuli were notimpaired, the homozygote mice displayed a strong objectavoidance and escape behavior. Additionally, we observed adeficit in both initial training and reversal of Barnes maze, aspatial memory task involving hippocampal-prefrontal cir-cuits. Electrophysiological recording showed that both long-term potentiation and long-term depression are impaired inShank3 deficient mice.

Our new mouse model of PMS recapitulates the coresymptoms of PMS providing an improvement of both con-struction and face validity compared to previous model.Ongoing experiments will identify neural mechanisms andbrain circuitry involved in PMS and will use this model toscreen potential treatments for Shank3-haploinsufficiency.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.320

M14. COMBINED ANALYSIS OF THE ORAL MICROBIOMEAND MICROTRANSCRIPTOME OF AUTISM SPECTRUMDISORDER

Steven Hicks2, Neil Khurana1, Daria LaRocca1, Sarah Barns3,Jeremy Williams3, Angela Savage3, Kayla Wagner3,Richard Uhlig3, Frank Middleton

n,1

1SUNY Upstate Medical University2Penn State College of Medicine3Quadrant Biosciences

Background: Autism Spectrum Disorder (ASD) affects 1 in45 children aged 3–17 and is characterized by a wide arrayof deficits in social interaction, communication, and beha-vior. Despite significant evidence for genetic contributionsto ASD risk, single gene variants as a group do not explainthe vast majority of cases. Consequently, considerableinterest has turned to the study of epigenetic mechanismsas potential contributing factors. miRNAs are now well-recognized epigenetic regulators of gene expression thatinfluence biological processes in all cell types and arereleased from the cells in which they are synthesized andcirculate throughout the body in extracellular fluids. Wepreviously identified significant alterations in miRNA levelsin the saliva of ASD subjects (average age 9) compared withmatched typically developing control children. We alsoobserved (but did not report) that the salivary microbiomeof ASD children was significantly different than that of thecontrol children. In the present study, we sought toreplicate and extend these observations on the oral micro-transcriptome and microbiome of ASD children in a largerand younger cohort.

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Methods: Parental consent was obtained for all subjects.More than 350 samples were collected from children aged 2–6, with either a confirmed diagnosis of ASD, DevelopmentalDelay, or healthy controls. Comprehensive medical anddemographic information was obtained using detailed ques-tionnaires, the Vineland Adaptive Behavior Scales (2ndEdition), and the Autism Diagnostic Observation Schedule(2nd Edition). Identification and quantification of salivamiRNA and microbiome abundance were performed usingNGS on a NextSeq. 500 instrument at the SUNY MolecularAnalysis Core (SUNYMAC) at Upstate Medical University.Alignment of NGS reads was performed to the miRbase21database using the Shrimp2 algorithm in Partek Flow soft-ware to identify mature and precursor miRNAs and align-ment of metatranscriptome reads was performed to theHuman Microbiome Database, using K-SLAM and Krakensoftware. Data were subjected to quantile normalization,filtered for quality control, and examined for their diag-nostic utility using machine learning algorithms. The mostpromising variables were also examined to identify salientpatterns and subjected to functional analysis.Results: Saliva miRNA and microbiome taxon variablesdemonstrated the ability to distinguish children with ASDfrom typically developing controls, with accuracy approx-imating 75–80% based on Monte-Carlo Cross Validation.When combined, the best miRNA and taxon classifiers fromthe learning algorithm performed at an overall accuracylevel exceeding 86%, including more than 90% accuracy forASD children. Notably, the top miRNA classifiers dispropor-tionately targeted mRNAs that were enriched in several keybiological pathways of interest for ASD, including Amphe-tamine Addiction, Axon Guidance, and Oxytocin Signaling.Notably, many miRNAs and taxon classifiers exhibited robustcorrelations, suggesting possible host-microbiome signaling.Discussion: This is the first report of correlated miRNAand microbiome elements in saliva. Our results indicate ahigh degree of potential diagnostic utility in using thesesaliva-based data for ASD and Developmental Delay. Ongoingwork is establishing the quantitative relationship betweenthese variables and functional measures of ASD symptomsand severity, as well as co-morbid medical conditionsincluding sleep disorders and GI disturbances.

Disclosure: Quadrant Biosciences - Board Member, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.321

M15. SPECTRUM OF COMMON AND RARE MUTATIONSCONTRIBUTING TO AUTISM RISK IN FAMILIES

Rachel Kembern,1, Xiao Ji1, Jing Zhang1, Christopher Brown1,

Daniel Rader1, Laura Almasy2, Maja Bucan1

1University of Pennsylvania2University of Pennsylvania, Children's Hospital ofPhiladelphia

Background: Autism Spectrum Disorder (ASD) is a hetero-geneous, highly heritable neurodevelopmental syndrome

characterized by impaired social interaction, communicationand repetitive behavior. ASD-associated variants range fromchanges to a Single Base Pair (SNPs), to the loss or gain ofmultiple base pairs (Copy Number Variants, CNVs). In addition,ASD-associated variants can be either inherited or de-novo,and either common, with a small increase to risk, or rare, witha strong causal effect. Identifying a set of individuals withgreater phenotypic homogeneity may help us reduce geneticheterogeneity, and pinpoint mutations that give us greaterinsight into the genetic roots of the entire autism spectrum.Under this hypothesis, the Perelman School of Medicine at theUniversity of Pennsylvania established ASPE, the AspergerSyndrome/Autism Spectrum (AS/ASD) Program of Excellence,in 2017, to significantly improve the understanding of thegenetic causes of AS/ASD. A major focus of ASPE will be on theNRXN1 gene, which codes for the protein neurexin 1 and hasbeen associated with Autism Spectrum Disorder and otherpsychiatric and neurodevelopmental disorders.Methods: The team will compare the genomes of indivi-duals with and without mutations in the NRXN1 gene andindividuals with AS and their family members who may or maynot have been diagnosed with AS. We hypothesized that riskfor ASD is the result of a cumulative effect of common, smalleffect variants with additional strong contributions to riskarising from rare, severe effect mutations in genes such asNRXN1. As an initial exploration of this hypothesis, we utilizedpublically available genotype and exome sequence data(Autism Genetic Resource Exchange, Simons Simplex Collec-tion) and summary statistics from a recent autism GWAS(Psychiatric Genomics Consortium: ASD) to generate polygenicrisk scores for all individuals within a family, and establish thecontribution of common variants to ASD risk. In addition, weidentified rare damaging mutations (both SNPs and CNVs) ingenes previously associated with ASD, including NRXN1.Results: Common polygenic risk for ASD varies betweenfamilies with an ASD proband, with some families carryinghigh risk for ASD, and others carrying low risk. Risk scores inthe ASD probands are significantly higher than unaffectedfamily members. We identified several families with low riskfor ASD that carry a mutation in NRXN1, suggesting thatsome individuals will develop ASD as a result of commonvariation, whereas others with low common polygenic riskmay develop ASD as a result of a severe effect variant.Discussion: Overall, our findings show that it is necessaryto explore the mutational spectrum of variants in familiesby including both common and rare SNPs and CNVs, to fullycapture the genetic basis of risk for ASD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.322

M16. PATHVIEW WEB: USER FRIENDLY PATHWAYVISUALIZATION AND DATA INTEGRATION

Weijun Luon

, Cory Brouwer

University of North Carolina at Charlotte

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Background: Pathway analysis is widely used in omicsstudies. Pathway-based data integration and visualization isa critical component of the analysis. To address this need,we recently developed a novel R package called Pathview.Pathview maps, integrates and renders a large variety ofbiological data onto molecular pathway graphs. Pathviewquickly became a leading tool in pathway visualization, andhas been widely adopted by tens of thousands of scientistsand dozens of dependent applications worldwide.Methods: Here we developed the Pathview Web server, asto make pathway visualization and data integration acces-sible to all scientists, including those without the specialcomputing skills or resources. Pathview Web features anintuitive graphical web interface and a user centereddesign. We also provide a comprehensive online help systemand multiple quick-start example analyses. Even with nospecial computing training and resources, users may stillaccomplish pathway based data visualization and integra-tion independently.Results: The server not only expands the core functions ofPathview, but also provides many useful features notavailable in the offline R package: 1) The results graphsare interactive and hyperlinked to abundant external anno-tation data online; 2) The server provides the latest, mostcomplete and accurate pathway definitions and graphs byregular synchronization with KEGG source databases; 3)Users can review, replicate and share their analyses easilywith free registered user accounts, which enable collabora-tive research and reproducible science; 4) Useful userengagement features allow users make comments andsuggestions, or ask for help in designated pages. Impor-tantly, the server presents a comprehensive workflow forboth regular and integrated pathway analysis of multipleomics data. In addition, the server also provides a RESTfulAPI for programmatic access and conveniently integration inthird-party software or workflows.Discussion: Pathview Web is openly and freely accessibleat https://pathview.uncc.edu/.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.323

M17. NOVEL QUANTITATIVE METHOD FOR GENETICASSOCIATION TESTING

Gido Schoenmackern

, Tom Claassen, Tom Heskes,Barbara Franke, Jan Buitelaar, Alejandro Arias-Vásquez

Radboud University Nijmegen Medical Centre

Background: Traditional genome-wide association studiesperform a per-SNP association test, resulting in millions oftests. To subsequently examine effects at higher levels,gene-based, pathway-based, or polygenic risk approachesare used to aggregate the SNP-level association results.These methods result in a high multiple-testing burden, arevulnerable to inflation due to effects of Linkage Disequili-brium (LD) and gene size, and require time-expensive

computing per phenotype. We propose a quantitative scor-ing method that operates directly on SNP-level data and canbe used for any arbitrary genetic region of interest. Wehypothesize that (a) our method can robustly identifygenetic regions of interest, that (b) our method can beused to explain variance in a similar manner to polygenicrisk approaches, and that (c) our method is robust againsteffects of LD and gene size. These properties ensure thatour novel method can be used for genetic associationtesting.Methods: Our primary data set consists of the NijmegenBiomedical Study: 4452 genome-wide genotyped subjectsusing the Illumina HumanOmniExpress-12 and -24 BeadChipplatforms with available Body Mass Index (BMI) measure-ments. In this data set, we tested the effects of LD byincremental pruning, the effects of gene size by Kolmo-gorov-Smirnov distribution comparison, and we comparedour association results to results obtained using existinggenetic association applications (Plink 1.9, Magma 1.04, andPRSice 1.25). Secondly, we compare variance explained fordifferent methods in an Attention Deficit HyperactivityDisorder (ADHD) discovery (n=2947) and replication(n=785) cohort.Results: Using our novel method and fewer than 4500individuals, we find one significantly associated gene for BMI(SNRPC) and several other suggestive genes which areconfirmed in literature to be associated with BMI and werenot picked up by the other methods tested. Secondly, wefind a similar variance explained for ADHD across cohortscompared to the existing method. Lastly, our method isinvariant to gene sizes and shows robust results against theeffects of LD.Discussion: Our results show that our novel method canidentify true genetic regions of interest for BMI, can explainvariance across cohorts for ADHD, and proves robust againstthe effects of gene size and LD. We identified genes ofinterest that were missed by existing methods, suggestingthat our method could add to existing genetic associationtests. More work in larger cohorts is needed to identify inwhich precise conditions our method can increase power todetect genetic regions of interest, however these firstresults in both a physical and a psychiatric/behavioralphenotype show promise.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.324

M18. ALLELIC HETEROGENEITY ACROSS PSYCHOTICDISORDERS AND RELATED PHENOTYPES

Tatiana Polushinan,1, Vidar Steen1, Ole Andreassen2,

Stephanie Le Hellard1

1University of Bergen2University of Oslo

Background: Major mental illnesses have been shown tooverlap at the clinical and genetic levels. The genetic

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overlaps have been so far explored at the single geneticvariants level, but very few studies have explored howindependent variants within a locus could contribute to thegenetic overlaps. In our study, we intend to increase theinformation captured from GWASs by focusing on allelicheterogeneity, i.e. the contribution of several independentmarkers within one genetic locus, within a trait and acrossrelated traits.Methods: Using summary statistics from GWASs of traitsrelated to mental illnesses: psychotic disorders, cognitivetraits and brain volumes, we first selected independentgenomic regions associated in each traits after conditionalregression (Yang et al.[1]). All the genetic variants in LDwith the associated signal were included in the genomicregions. We then first explored the overlaps in the regionswithin traits and across traits. We also scored eachgenomic region in each of the traits, using the Brown scorefor each bin, and explored the overlap in the significantregions.Results: We observed allelic heterogeneity within andacross traits. 147 genomic regions were associated withindependent markers (not in LD) across several traits. Wehave established a map of genetic overlaps for these clustersacross psychiatric disorders and relevant phenotypes (brainvolumes, cognitive and personality traits). The strongestoverlaps were observed in pairs: schizophrenia - educationalattainment and schizophrenia – bipolar disorder.

We have established a pipeline for identification of allelicheterogeneity across different phenotypes.

Several of the GWAS included were too limited in power toprovide significant hits yet, and will need bigger samples toyield more significant results.Discussion: We identify allelic heterogeneity acrosstraits, demonstrating that some genetic regions harborindependent associations with related phenotypes. Ourapproach is complementary to studies that explore geneticoverlap at the single marker level. This improves ourunderstanding of the impact of genetic factors in mainpsychotic disorders and related phenotypes, and could helpto direct functional studies later.

Disclosure: Nothing to disclose.

Reference

[1] Yang J. et al. Nat. Genet. 2012.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.325

M19. ESTIMATE SPATIOTEMPORAL IMPACT OF BRAINVARIANTS

Kevin Verviern

, Jacob Michaelson

University of Iowa

Background: Functional characterization for genetic var-iants is a major challenge in whole-genome sequencing-based studies. Recent approaches, such as TiSAn (Vervier

et al., 2017) or GenoSkyline (Lu et al., 2016), estimatetissue-specific impact of variations, in particular in humanbrain tissues. However, such annotations do not provideinsights on which brain regions or development time pointsmight be especially vulnerable to a given variant.Methods: In this work, we propose to integrate spatio-temporal gene expression from BrainSpan (BrainSpan, 2014)to estimate what the 'context matrix' of a variant is.Variants found in non-coding regions are represented as acombination of gene expression matrices, where weightsare based on associations demonstrated in SLINGER models(Vervier et al., 2016).Results: We validate our approach on psychiatric disorderdatasets, and use temporal patterns to discriminate early-and late-onset damaging variants. Brain region-specificvariants also help to identify combined mechanisms ofaction, in complex traits.Discussion: Spatio-temporal profiles could also be com-bined with polygenic risk score approaches, and providenew dimensions to study psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.326

M20. COMBINING POLYGENIC RISK SCORES ACROSSSEVERAL TRAITS CAN IMPROVE SCHIZOPHRENIA RISKPREDICTION

John Hubertn

, James T.R. Walters, Antonio Pardiñas,Peter Holmans, Andrew Pocklington, Michael O'Donovan,Valentina Escott-Price

MRC Centre for Neuropsychiatric Genetics & Genomics,Cardiff University

Background: Schizophrenia is a highly heritable disorderand is known to have a substantial common polygeneticcomponent [1]. The polygenic risk score approach [1] allowscommon genetic liability to the disorder to be directlyestimated in individuals regardless of their affected status.In addition to weakly predicting schizophrenia affectedstatus in independent case-control datasets, polygenic riskscore approaches have revealed significant shared SNPheritability between schizophrenia and multiple psychiatricand behavioural traits [2,3]. We therefore postulated thatcombining risk score profiles derived from several traitsmight improve the prediction of schizophrenia risk.Methods: Polygenic risk score profiles were calculated forthe CLOZUK schizophrenia GWAS study [4] (11260 cases, 24542controls) by training on six recent GWAS datasets: schizophrenia(independent of the CLOZUK set), bipolar disorder, bipolar vsschizophrenia [5], major depression disorder, educationalattainment [6] and neuroticism [7]. Principal componentanalysis (PCA) was employed to generate factor loadings forthe six polygenic risk score profiles. The advantage of PCA isthat it converts a set of possibly correlated variables (e.g. dueto shared genetic liability) into a set of uncorrelated variables,with the first principal component accounting for the greatest

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degree of variance in the dataset outcome. We investigated theprediction accuracy of the first principal component comparedto the schizophrenia polygenic risk score by means of areaunder the curve (AUC) analysis.Results: Our analysis indicates that schizophrenia caseprediction accuracy of the combined schizophrenia andneuropsychiatric-related first principal component isincreased as compared to the AUC of schizophrenia poly-genic risk scores alone. The first principal component alsovisually separates cases and controls in the CLOZUK indivi-duals based upon their combined (schizophrenia and neu-ropsychiatric-related traits) profiles.Discussion: We have proposed an approach to combinegenetic evidence for schizophrenia and neuropsychiatric-related traits into one score and tested its predictionaccuracy. This approach takes advantage of the sharedgenetic risk between schizophrenia, psychiatric disordersand behavioural traits, and at present, can improve theprediction of schizophrenia risk.

Disclosure: Nothing to disclose.

References

[1] International Schizophrenia Consortium. 2009 Nature460(7256), 748-52

[2] Cross-Disorder Group of the Psychiatric Genomics Con-sortium. 2013 Lancet 381(9875), 1371-9

[3] Power, R.A. et al. 2015 Nat Neurosci. 18(7), 953-5[4] Pardiñas, A. et al. 2016 Biorxiv 068593[5] Ruderfer, D.M. et al. 2014 Mol Psychiatry 19(9), 1017-24[6] Okbay, A. et al. 2016 Nature 533(7604), 539-42[7] Smith, D.J. et al. 2016 Mol Psychiatry 21(6), 749-57

http://dx.doi.org/10.1016/j.euroneuro.2017.08.327

M21. VARIANTS IN THE PROMOTER OF TRKB ARE ASSO-CIATED WITH A GOOD RESPONSE TO LITHIUM IN BIPO-LAR DISORDER

Nathaniel Millern,1, Seth Ament2, Tatyana Shekhtman1,

Jared Roach2, John R. Kelsoe1

1University of California San Diego2Institute for Systems Biology

Background: BDNF and its receptor TrkB have repeatedlybeen associated with bipolar disorder and lithium response.Lithium induces release of BDNF which is essential for itsfunction. We have previously shown that genetic variants inthe TrkB gene are associated with lithium response andbipolar disorder. The goal of this study was to identify noveland common sequence variants in these two genes thataffect the action of lithium in bipolar disorder.Methods: Retrospective samples were collected in regardto lithium responsiveness. 73 good responders, (LiR), 49moderate responders (Mod), and 47 poor responders (NR)individuals were used for a sequencing study of these twogenes. We targeted exons, non-coding regions with putative

regulatory functions, 5’ and 3’ untranslated regions, andnumerous DNase hypersensitive regions. Samples werecombined into pools of 23 to 37 individuals. Paired-endsequencing was done using Custom Amplicons (Illumina).Variants were called with Genome Analysis Toolkit. PLINKwas used to calculate a chi-square statistic between indivi-dual groups. Annotation of identified variants was doneusing SIFT and PolyPhen-2.Results: For BDNF, 35 variants were called, and 159 variantswere called for TrkB. Using a conservative Bonferroni correc-tion for 174 comparisons, a statistically significant p-valuewould be o2.8� 10-4. Comparing good responders to poor,two suggestive variants were found for BDNF. In the promoterof TrkB, a minor allele variant was found more frequently thanexpected in the LiR samples compared to the NR, having ap-value of 2.93� 10-6. RegulomeDB predicts this variant isimportant for transcription factor binding.Discussion: Targeted sequencing revealed the over abun-dance of a minor allele of a common SNP in the promoter ofTrkB for LiR but not in NR. Lithium efficacy for thetreatment of bipolar disorder is likely to involve theBDNF/TrkB pathway. This study provides a likely candidateregion to further investigate the function of lithium inbipolar individuals.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.328

M22. GENOME-WIDE METHYLOME AND TRANSCRIPTOMEPROFILES OF MANIC EPISODE IN BIPOLAR DISORDER

Ya-Chin Leen,1, Pao-Yang Chen2, Ming-Chyi Huang3,

Wen-Yin Chen3, Hsi-Chung Chen4, Ming-Hsien Hsieh4,Tzu-Pin Lu1, Po-Hsiu Kuo1

1Institute of Epidemiology and Preventive Medicine,College of Public Health, National Taiwan University2Institute of Plant and Microbial Biology, Academia Sinica3Taipei City Psychiatric Center, Taipei City Hospital4National Taiwan University Hospital

Background: Bipolar Disorder (BD) is a highly heritablepsychiatric disorder. More than two thirds of BD patients haverecurrent episodes throughout lifetime. To explore theunderlying biological mechanisms of manic episode in BD,the current study adopted two experimental platforms tocapture the episodic dynamic feature. We compared thedifferences of methylome and transcriptome between acutemanic episode and remission, which were influenced by bothinheritant genetic sequence and environmental stimuli.Methods: We enrolled 12 BD patients with collectedbiological samples and clinical data at two time points,the acute manic state and remission in at least two-monthsfollow-up for intra-individual comparisons. Young ManiaRating Scale (YMRS) score and Hamilton Depression RatingScale (HAMD-21) were used to evaluate symptom severity.The manic state was defined as having YMRS score Z21 andHAM-D r8; the remission was defined as having YMRS score

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o12 and HAM-D r8. We applied reduced representationbisulfite sequencing (RRBS) and RNA-Sequencing (RNA-Seq)for methylomic and transcriptomic analyses using IlluminaHiSeq. 2000. After quality controls and gene annotation,Differential Methylated Genes (DMGs) and differentialexpressed genes (DEGs) were identified with statisticalmethods for paired data. We also applied CLOVER algorithmwith JASPAR database to identify potential targets ofTranscription Factors (TFs) on the DEGs/DMGs. Analyses ofthe molecular pathways and networks were visualized withIngenuity Pathway Analysis (IPA) tool.Results: The average reads number for RRBS and RNA-Seqwere 38 and 30 millions, respectively. No significant globalmethylation changes were found across the whole-genomewith adjustment of multiple testing, while 337 DMGs hadnominal p-valueso0.05 with gene annotation, including 181hyper-methylated and 156 hypo-methylated genes compar-ing mania to remission status. In transcriptome analysis,there were 438 significant DEGs with p-values less than 0.05after multiple testing. Combining information from methy-lation and gene expression patterns, we found the followinggenes with methylation changes at promoter region alongwith differential gene expressions, PAX8, KREMEN1, FOXD2,PRR5 and PAPD4. A number of molecular networks werederived specifically by either gene expression or methyla-tion analyses. The common pathways between DEGs andDMGs included nervous system development, cell signaling,and post-translational modification.Discussion: With comprehensive genomic data obtained byhigh-throughput technologies at the genome-wide level, weidentify potential biomarkers underlying BD manic state. Theoverlapping results of DEGs and DMGs are relevant to tran-scriptional regulation, such as PAX8 and FOXD2. Their func-tions are found to be related to mitochondrial dysfunction andbrain development through transcriptional regulation. Furtherexperimental studies are needed to validate these results. Inconclusion, methylomic and transcriptomic biomarkers areidentified for regulating BD manic episode, which couldprovide novel insights for the pathogenesis of manic illness,and facilitating to allocate better therapeutic targets for BD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.329

M23. GENETIC ASSOCIATION AND FUNCTIONAL CHAR-ACTERIZATION OF A VARIANT IN THE MCPH1 GENE INBIPOLAR DISORDER AND SCHIZOPHRENIA

Mariam Aleissan

, Sally Sharp, Alessia Fiorentino,Niamh O'Brien, Nicholas Bass, David Curtis,Andrew McQuillin

University College London

Background: Both Schizophrenia (SCZ) and Bipolar Dis-order (BPD) disorder are serious psychiatric conditions thatcan give rise to debilitating symptoms that can severelyimpact the life of the affected individual, and their

families. We have previously reported that the MCPH1 genevariant rs61749465 A4G (p.Asp61Gly) showed suggestiveevidence for association with schizophrenia (SCZ; Leonenkoet al. 2017). The MCPH1 gene has multiple roles in cellularfunctions including, DNA damage/repair pathways; centro-somal localization; E2F transcription factor 1-mediatedapoptosis; transcriptional activation of cell cycle check-point, DNA stability; and telomere structure. A secondMCPH1 point mutation (rs199422124 C4G; p.Thr27Arg) isan autosomal recessive cause of microcephaly.Methods: The schizophrenia associated MCPH1 variantrs61749465 was tested for association in 2,300 BipolarDisorder (BPD) subjects, and 1,820 normal comparisonsubjects. We also analysed the microcephaly causing muta-tion rs199422124 in the BPD and control subjects and in ourSCZ cohort of 1,930 subjects. Next, we conducted analysisof the in vitro effects of the rs6174965 and rs199422124variants on cell survival/proliferation using cell counts, andthe MTT assay; their effect on DNA damage using the cometassay; their effect on mRNA stability using a combination ofActinomycin D treatment followed by Q-PCR; and theireffect on gene expression using RNA-Seq analysis combinedwith pathway analysis and gene network analyses.Results: After genotyping we report evidence for associa-tion with BPD (P=0.0009). Notably the variant allele ofrs61749465 was absent in the 1,820 comparison subjectstested. rs61749465 is located in the N-terminal of the BRCT1domain of MCPH1. Bioinformatic analysis predicted theAsp61Gly substitution to be damaging to MCPH1 proteinfunction. rs199422124 was not detected in any of theparticipants. We sought to characterize the functionaleffects of these variants on MCPH1 function. Cell viabilityand cell count assays indicated that the variant allele ofrs199422124 had a larger impact on cell survival comparedto the variant allele of rs61749465, however neither of thevariant alleles significantly altered DNA damage or mRNAstability. Gene expression analysis for rs61749465 using RNA-seq shows that the expression of a number of heat shockprotein have been affected. Gene network and pathwayanalysis indicated that the variant alleles may impactcellular aging and protein translation.Discussion: Further in vitro and in vivo characterizationof the rs61749465 variant in MCPH1 may provide insight intothe molecular pathogenesis of psychosis.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.330

M24. EFFECTS OF SCHIZOPHRENIA AND BIPOLAR POLY-GENIC RISK SCORES ON AGE AT ONSET IN BIPOLARDISORDER

Janos Kalmann,1, Sergi Papiol1, Urs Heilbronner1,

Till F.M. Andlauer2, Heike Anderson-Schmidt3,Monika Budde1, Katrin Gade4, Stefan Herms5,Andreas J. Forstner6, Josef Frank7, Franziska Degenhardt8,Markus Nöthen8, Marcella Rietschel7, Peter Falkai9,Thomas Schulze10

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1Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich2Max Planck Institute of Psychiatry3University Medical Centre Goettingen4Georg August University Goettingen5Human Genomics Research Group, University of Basel,University of Bonn6University of Bonn7Central Institute of Mental Health8Institute of Human Genetics, University of Bonn9Molecular and Behavioral Neurobiology, Ludwig Maximil-lian University10Institute of Psychiatric Phenomics and Genomics; Ludwig-Maximilians-University of Munich

Background: Patients with early age at onset (AAO)Bipolar Disorder (BD) are characterized by a higher recur-rence rate of mood episodes, higher number of suicideattempts, more severe psychotic symptoms and neurocog-nitive impairments and a poor long-term prognosis (Aminoffet al. 2013). Results of previous studies investigating thegenetic background of AAO in BD provide some evidencethat early AAO might be, to a certain degree, geneticallydetermined. (Lin et al. 2006, Craddock et al. 2014) The aimof this study was to investigate whether earlier diseaseonset in BD might be a consequence of a higher cumulativeBD or Schizophrenia (SCZ) genetic risk.Methods: Data of DSM-III or IV BD patients (N=1980) waspooled from three large, international studies: from theConsortium of Lithium Genetics (ConLiGen) dataset, fromthe PsyCourse study and from the BoMa sample. AAO wasdefined as the age at the first mood episode. Different AAOsubgroups were identified with admixture analysis and thelikelihood of AAO-group membership was expressed withposterior probability values. All individuals were genotypedon whole-genome SNP arrays and their SCZ- and BD-polygenic risk scores (PRS) at 11 different p-value thresholds(pTs) (pT1=0.00000005, pT11=1) were calculated usingdata from SCZ PGC2 and BD-PGC as training data sets. Theassociations between the SCZ- and BD-PRSs and AAO wereevaluated with linear regression, whereas the AAO scores ofthe identified AAO-groups were compared with ANOVA.Results: The cumulative polygenic risk for bipolar disorderwas significantly associated with age of onset (R2 change) atmore liberal p-value thresholds. No association was foundbetween AAO and SCZ-PRS. Three different BD-AAO sub-groups (mean: 17.42, 22.07, 39.49) were identified withadmixture analysis. The identified groups did not differ interms of their SCZ-PRS and BD-PRS.Discussion: Our results suggest that the accumulation ofbipolar disorder-associated alleles in individuals with earlierdisease onset could be a possible explanation for theobserved genetic determination of age of onset in bipolardisorder. However, this explains only a small proportion ofthe phenotype implying that other factors may be of greaterrelevance. Similar to previous studies, we could identifythree different age of onset subgroups in bipolar disorderusing admixture analysis. These groups were previouslyvalidated based on phenotypic differences, however nodata has been available on their genetic and molecularcharacteristics. Nevertheless, we found no group difference

in terms of genetic risk for schizophrenia and bipolardisorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.331

M25. GENETICS OF COGNITIVE FUNCTION IN SCHIZO-PHRENIA AND BIPOLAR DISORDER

Philip Harveyn,1, Ning Sun2, Qiongshi Lu3, Yiming Hu3,

Boyang Li3, Quan Chen2, Mihaela Aslan2,Krishnan Radhakrishnan2, Kei-Hoi Cheung2, Yuli Li2,Frederick Sayward2, Nallakkandi Rajeevan2, Hongyu Zhao3,Michael Gaziano4, John Concato2

1Research Service, Bruce W. Carter VA Medical Center2Connecticut Epidemiology Research Center3Yale University4Massachusetts Veterans Epidemiology Research and Infor-mation Center

Background: Cognitive impairment is a frequent andserious problem in patients with various forms of severemental illnesses, including Schizophrenia (SZ) and BipolarDisorder (BP). Cognitive performance in patients withbipolar disorder or schizophrenia has been found to be verysimilar in underlying structure, and recent research hassuggested genomic linkage to several different cognitivephenotypes. In addition, recent evidence from the CognitiveGenomics Consortium (COGENT) study, focusing on a pooledpopulation of more than 35,000 healthy European ancestrypatients from 24 studies, reported an estimated SNP herit-ability of 21.5%. The current study examined the genomiccorrelates of cognitive and functional skills performance in8,051 U.S. veterans with either SZ or BP.Methods: Veterans Affairs (VA) Cooperative Studies Pro-gram (CSP) Study #572 evaluated cognitive and FunctionalCapacity (FC) measures among BPI and SZ patients, using asubset of tests from the MATRICS Consensus cognitivebattery (MCCB) and the UCSD Performance based skillsassessment brief version (UPSAB). In conjunction with theVA Million Veteran Program, and using a customized Affyme-trix Axiom genotyping array for samples from 3,388 SZ and4,663 BP CSP #572 patients (N=8,051 total), we conductedgenome-wide association analyses for European Americans(3,952) and African Americans (2,598) separately.Results: There are no SNPs with genome-wide statisticallysignificant results for either EA or AA samples. We alsoapplied MetaXcan to calculate gene-level test statisticsacross 44 tissues and did not identify any associated genes.However, based on the comparison between summarystatistics from this study and those from published GWASof 55 diseases/traits, there is statistically significant evi-dence of genetic correlation between cognitive functionand schizophrenia (1.7E09), but not bipolar illness.Discussion: No SNPs with strong evidence of associationwith cognitive performance were identified in this study, butgenetic correlation analysis between this study and published

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GWAS on schizophrenia from other studies suggests sharedfactors between cognitive functions and schizophrenia. Lateranalyses will perform targeted examination of the linkage ofpreviously identified genes and SNPs to overall performanceand specific cognitive phenotypes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.332

M26. THE IMPACT OF BIPOLAR AND SCHIZOPHRENIAPOLYGENIC RISK SCORES ON FAMILIAL FEATURES OFBIPOLAR DISORDER

Katrin Gaden,1, Sergi Papiol2, Urs Heilbronner2,

Monika Budde2, Kristina Adorjan3,Heike Anderson-Schmidt4, Janos Kalman2, Fanny Aldinger2,Till F.M. Andlauer5, Thomas Schulze6

1Georg-August-University Goettingen2Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich3Institute of Psychiatric Phenomics and Genomics4University Medical Centre Goettingen5Max Planck Institute of Psychiatry Munich6Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich

Background: In Bipolar Disorder (BD), some endopheno-types such as the occurrence of psychotic symptoms orsuicide attempts, the level of psychosocial functioning,disorder subphenotypes like type I/II disorder and comor-bidities like alcohol or drug abuse are highly familial. Weexplored whether polygenic risk scores for bipolar disorder(BD-PRS) or schizophrenia (SZ-PRS) can predict these phe-notypes in a sample of German and Austrian patientsdiagnosed with BD according to DSM-IV-criteria.Methods: The present study included 326 BD patientsbelonging to the German KFO/PsyCourse cohort (www.kfo241.de; www.PsyCourse.de). The study protocol wasapproved by the local ethics committees and is in accor-dance with the 1964 Declaration of Helsinki. Sociodemo-graphic and clinical information on patients was assessedusing a comprehensive inventory for phenotype character-ization. Association of BD- and SZ-PRS with target variableswas tested via logistic regression analyses at several inclu-sion p-value thresholds (0.00000005 to 1). Polygenic riskscores were calculated using imputed, quality-controlledgenome-wide patient genotypes (Illumina Infinium PsychAr-ray) and summary statistics of two large case-controlgenome-wide association studies (Hou et al., 2016; PGC-Schizophrenia-Working-Group, 2014). Results were cor-rected for age, sex, recruitment center, duration of illnessand population stratification.Results: A higher SZ polygenic burden was significantlyassociated with lifetime use of illicit drugs at severalp-value thresholds (strongest association at threshold0.0001, R2 change 2.7%, p-value=0.005). Only with onethreshold a slightly positive association of SZ-PRS with

alcohol abuse was observed (0.0000001, R2change 3.1%,p=0.026). Patients diagnosed with bipolar I disorder hadhigher SZ-PRS compared to patients with bipolar II disorderat several thresholds (strongest association at 0.05 thresh-old, R2 change= 2.4%, p=0.020, OR=1,6). We found nosignificant association of SZ-PRS with other target variables.Higher BD-PRS were significantly associated with higherlevels of psychosocial functioning in our patient sample(measured by Global-Assessment-of-Functioning-scores,strongest effect at threshold 0.001, R2 change= 2.6%,p=0.014,), but not with any other target variable.Discussion: Our results suggest that a higher polygenic SZburden plays a bigger role for lifetime occurrence ofsubstance abuse in BD patients than the polygenic BDburden. Also, there may be a stronger genetic overlapbetween schizophrenia and BD I disorder subtype thanbetween schizophrenia and BD II disorder subtype. Interest-ingly, a higher polygenic BD burden may even have positiveeffects on overall psychosocial functioning in BD patients.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.333

M27. GENETIC VALIDATION OF BIPOLAR DISORDERIDENTIFIED BY AUTOMATED PHENOTYPING USING ELEC-TRONIC HEALTH RECORDS

Chia-Yen Chenn,1, Phil Lee1, Victor Castro2, Jessica Minnier3,

Shawn Murphy1, Vivian Gainer2, Tianxi Cai4, Pamela Sklar5,Roy Perlis1, Jordan Smoller6

1Massachusetts General Hospital2Partners Healthcare3Oregon Health & Sciences University4Harvard T.H. Chan School of Public Health5Icahn School of Medicine at Mount Sinai6Harvard Medical School

Background: Bipolar Disorder (BD) is a heritable mooddisorder with about 1% lifetime prevalence in generalpopulation. Many BD-associated loci have been identifiedthrough Genome-Wide Association Studies (GWAS). How-ever, larger sample size and more detailed clinical/pheno-typic information are needed to further understand theetiology of BD. To expand to research resources for BDgenetics, we seek to leverage the Electronic Health Records(EHR) database, combined with genome-wide genetic data.As part of the International Cohort Collection for BipolarDisorder (ICCBD), we developed automated phenotypingalgorithms that can identify BD patients using codified dataand concepts extracted by Natural Language Processing(NLP) from clinical narratives. Using these algorithms, weidentified BD cases and healthy controls in the PartnersHealthCare the Research Patient Data Registry (RPDR) andgenome-wide genotyped these BD cases and controls. Wedemonstrated that these algorithms have high positivepredictive value using a gold standard of in-person struc-tured interviews (Castro et al. Am J Psychiatry, 2015).

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Methods: Here, we attempted to genetically validatethese algorithm-identified BD cases and controls by 1)quantifying the contribution of genetic components toalgorithm-identified BD and 2) estimating the genome-widegenetic similarity between algorithm-identified BD and BDascertained by psychiatrist diagnosis or systematic inter-view. We evaluated BD cases identified with 4 differentalgorithms: an algorithm using narrative note with NLP andLASSO procedure (NLP) and 3 rule-based algorithms usingcodified data of patient's diagnostic and treatment historywith decreasing levels of stringency – “coded-strict”,“coded-broad”, coded-broad based on a single clinicalencounter (coded-SV). We used LD score regression toestimate SNP-based heritability (h2g) and genetic correla-tion (rg) between 4 EHR-based BD and between BD ascer-tained conventionally by diagnosis or interview in thePsychiatric Genomics Consortium (PGC) and ICCBD GWAS.Results: We identified and genotyped 862 NLP, 1968 coded-strict, 2581 coded-broad and 408 coded-SV BD cases, and a setof 3952 controls of European ancestry. The estimated h2g were0.24 (p=0.015), 0.09 (p=0.064), 0.13 (p=0.003), 0 (p=0.591)for NLP, coded-strict, coded-broad and coded-SV BD, respec-tively. These h2g were lower than those observed by the PGC+ICCBD (0.23, p=3.17E-80, total N=33181). However, the rgbetween conventionally ascertained BD and the EHR-basedcases were high for NLP (0.66, p=3.69E-5), coded-strict(1.00, p=2.40E-4), and coded-broad (0.74, p=8.11E-7). Theh2g for EHR-based cases combined was 0.11 (p=0.006) and therg with PGC BD was 0.83 (p=2.88E-6). The rg between EHR-based BDs ranged from 0.90 to 0.98.Discussion: These results provide the first genetic valida-tion of automated EHR-based phenotyping for BD andsuggest that this approach identifies cases that are highlygenetically correlated with those ascertained through con-ventional methods. High throughput phenotyping using thelarge data resources available in EHRs represents a viablemethod for accelerating psychiatric genetic research.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.334

M28. MATERNAL AGE AT BIRTH IS ASSOCIATED WITHOFFSPRING LEUKOCYTE TELOMERE LENGTH INFAMILIES WITH BIPOLAR DISORDER

Daniela Martinezn,1, Vincent Millischer2, Leandro Michelon3,

Nubia Esteban4, Alexandre Pereira4, Catharina Lavebratt5,Martin Schalling5, Homero Vallada3

1University of São Paulo Medical School2Karolinska Institutet, Center for Molecular Medicine3University of São Paulo4Laboratory of Genetics and Molecular Cardiology, HeartInstitute, University of São Paulo Medical School5Karolinska Institutet

Background: There is already a number of reports correlat-ing the effect of parents’ ages with the risk of schizophrenia,

but studies looking for an association between parental age andBipolar Disorder (BD) are scarce and with inconsistent findings.BD has recently been related to a process of accelerated aging,with studies showing association with Leukocyte TelomereLength (LTL) in this population. However, little is knownregarding the inheritance of telomere length, with some studiesestimating the heritability between 36–86%. About the effect ofa parent' age determining LTL, just a few studies have notedlonger telomere lengths among offspring of older mothers, andnone have shown an interaction or association with a psychia-tric disorder. The present investigation assessed the impact ofmaternal and paternal age at birth as a determinant for theoffspring's LTL with and without BD diagnosis within familieswith several members affected by this disease.Methods: Telomere length (T) was estimated in a sampleof 144 individuals, including 60 BD patients from 18 Brazilianfamilies, which was measured in relation to the single copygene (S) – β-globin gene (HBB) – using a singleplex real timePCR, providing a ratio of number of copies of T by S (T/S).The analysis were obtained by a linear mixed model (LMM).Results: We found a positive association between mater-nal age at childbirth and offspring early life telomere length(β=0.012; p=0.015), whereas there was no association ofpaternal age on offspring telomere length (β=0.008;p=0.232). The LMM analysis also showed a significantpositive relationship on interaction between bipolarity andmaternal age demonstrates a strong influence on telomerelength (β=0.022; p=0.024). The same analysis showed noassociation on interaction between bipolarity and paternalage (β=0.009; p=0.223).Discussion: An association between maternal age and off-spring LTL and the interaction with BD was observed. It couldbe speculated that an influence of oxidative stress duringfirst pregnancy, changes in mitochondrial DNA or even otherparent-specific imprinting mechanism, such as DNA methyla-tion, relevant to the neurodevelopment of the brain. To ourknowledge, this is the first study evaluating association ofmaternal age and telomere length in the offspring of familieswith several members affected by BD. Additional studies areneeded to confirm these preliminary findings.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.335

M29. INFLUENCE OF SINGLE NUCLEOTIDE POLYMORPH-ISMS IN ALZHEIMER'S SUSCEPTIBILITY-LOCI ON COGNI-TIVE PHENOTYPES

Lisa Endlichn,1, Bettina Konte2, Ina Giegling1,

Annette Hartmann3, Dan Rujescu1

1University of Halle2Martin Luther University Halle-Wittenberg, University ofMunich3University of Munich

Background: Late Onset Alzheimer's Disease (LOAD) is achronic and progressive neurodegenerative disorder

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affecting elderly people and is accompanied by severecognitive decline. Genetics is supposed to be one of thekey factors for the susceptibility to the disease. Several locihave been associated with an increased risk of developingAlzheimer's disease via Genome-Wide Association Studies(GWAS). The aim of this study was to investigate whether 33susceptibility loci recently associated with LOAD in a largemeta-analysis affect cognition in a healthy population.Methods: Therefore, 2147 unrelated healthy subjects ofGerman descent were recruited. The Structured ClinicalInterview for DSM-IV (SCID 1 and SCID 2) was conducted toexclude psychotic diseases, a family history was recorded toexclude subjects with a positive family history for psychoticdisorders and the Mini Mental Status Examination (MMSE)was conducted for every subject being older than 60 years,to exclude possible cognitive impairments. Cognitive per-formance was assessed via the German version of the'Wechsler Adult Intelligence Scale, Revision 1991' (WAIS-R).Genotype data was obtained using chip technology andimputation. After stringent quality controls 31 singlenucleotide polymorphisms (SNPs) were analyzed. SNPs hav-ing mismatches between reported and estimated genderand callrate differences Z 0.02 between cases and controlswere not considered. The analysis was calculated throughan additive linear regression model.Results: Nominal association could be detected for 18SNPs affecting at least one phenotype. The most signifi-cant SNP rs983392 was associated with the subscale digitspan. This polymorphism is in linkage disequilibrium withthe membrane spanning 4-domains A6A-gene (MS4A6A),belonging to the MS4A gene family on Chromosome 11q12.This gene was associated with a smaller right middletemporal volume, which hosts the hippocampus. Adecreasing hippocampus is known to be a symptom inAlzheimer's disease.

Another notable finding was the association ofrs6733839 with performance, verbal and general IQ. ThisSNP is located near the bridging integrator 1-gene (BIN1),located on chromosome 2q14.3. It is thought to beinvolved in synaptic vesicle endocytosis and modulationof tau pathology, one of the key symptoms of Alzheimer'sdementia.Discussion: Results of this study indicate an influence ofLOAD associated variations on cognitive performance inhealthy controls. Both verbal and performance subtestsshow significant associations. These findings could help toimprove the knowledge of pathophysiology and genetics ofcognitive decline as observed LOAD. However, furtherresearch is needed to validate these associations and detectthe functional relevance of the affected genes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.336

M30. NEXT-GENERATION RNA SEQUENCING OF POST-MORTEM ANTERIOR CINGULATE AND DORSOLATERALPREFRONTAL CORTICES TO IDENTIFY DIFFERENTIALLYEXPRESSED GENES IN PATHOLOGY-VERIFIED LEWYBODY DEMENTIA

Anto Praveen Rajkumar Rajamanin

, Emily Bell, Paul Francis,Dag Aarsland

King's College London

Background: Lewy Body Dementias (LBD) includeDementia with Lewy Bodies (DLB) and Parkinson's DiseaseDementia (PDD). DLB is the second most common neuro-degenerative dementia, and it is associated withincreased mortality, earlier nursing home admissions,higher risk of falls, poorer quality-of-life, more healthresource utilisation, higher costs, and more caregivers’burden than Alzheimer's disease. There are no disease-modifying treatments for LBD, and reliable cost-effec-tive biomarkers that can aid early diagnosis of LBDremain elusive. Identifying Differentially ExpressedGenes (DEG) in LBD brains can reveal underlying func-tionally disrupted molecular pathways, and it may leadto novel biomarkers and potential RNA drugs for LBD.However, relevant studies investigating transcriptomicsof LBD remain sparse.Methods: We studied anterior cingulate and dorsolateralprefrontal cortices of post-mortem pathology-verified brainsfrom the following three groups, (i) DLB (n=7), (ii) PDD(n=7), and (iii) non-demented older people (n=6). TotalRNA was extracted, and their quality was assessed byAgilent 2100 Bioanalyzer (N=40). Next-generation RNA-sequencing (RNA-seq) (75 bp; paired-end; minimum 30million clean reads/ sample) was completed using IlluminaHiSeq-4000. After appropriate quality control, reads werealigned to the human genome by HISAT2. Aligned reads werecounted by featureCounts, and DEG were identified byedgeR 3.18.1 with Benjamini-Hochberg false discoverycorrection (5%). Functional analyses of identified DEGs wereperformed using Ingenuity Pathway Analysis. Subgroupanalyses were performed between LBD with and withoutpathogenic GBA (Glucosidase, Beta Acid) mutations.Results: We have identified specific significantly upre-gulated and downregulated DEGs in LBD, while compar-ing with non-demented older people. DownregulatedDEGs in LBD include Oxytocin Receptor (OXTR), Myelo-peroxidase (MPO), Selectin E (SELE), Cathepsin G(CTSG), and Somatostatin (SST), and upregulated DEGsin LBD include X-Inactive Specific Transcript (XIST),Polypeptide N-acetyl galactosaminyl transferase 6(GALNT6), and mitochondrial Proline dehydrogenase(PRODH). DEGs in LBD are significantly enriched for priondiseases, cytokine-cytokine receptor interaction, phago-some, and glycerophospholipid metabolism pathways.We have also identified the DEGs that significantly differ

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between DLB and PDD, and the transcriptomic differ-ences between the two cortical regions.Discussion: Although this has been an explorative study,this is the hitherto largest RNA-seq study investigating thetranscriptomics of pathology-verified LBD brains. In additionto enhancing our understanding of LBD neurobiology atmolecular level, this study has identified specific RNAtargets that may be novel biomarkers and therapeutictargets for DLB and PDD. Further replication experiments,and more bioinformatic analyses of our data are on-going.We are currently investigating serum exosomal RNA cargo ofpeople with LBD for evaluating the peripheral biomarkerpotential of identified DEGs. Translational relevance andtherapeutic potential of identified DEGs will be evaluatedby in-vitro experiments.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.337

M31. GENOME-WIDE ASSOCIATION STUDY OF COMOR-BID ALCOHOL DEPENDENCE AND MAJOR DEPRESSION

Hang Zhoun,1, Renato Polimanti1, Bao-Zhu Yang2,

Qian Wang2, Shizhong Han3, Richard Sherva4, Yaira Nunez2,Hongyu Zhao2, Lindsay Farrer4, Henry Kranzler5,Joel Gelernter1

1Yale School of Medicine2Yale University3University of Iowa4Boston University5University of Pennsylvania

Background: Alcohol Dependence (AD) and Major Depres-sion (MD) are leading causes of disability, and they often co-occur. Genetic epidemiologic data have shown that they share,at least to some extent, a common genetic etiology. Themolecular nature of this shared genetic basis is poorly under-stood. To detect genetic risk variants for comorbid AD and MDand to determine whether polygenic risk alleles are sharedwith neuropsychiatric traits or subcortical brain volumes.Methods: This Genome-Wide Association Study (GWAS)analyzed criterion counts of comorbid AD and MD in datasets of African Americans (AA) and European Americans (EA)that were collected as part of the Yale-Penn study of thegenetics of drug and alcohol dependence from 2000–2013.After excluding subjects who were never exposed to alcoholor had missing information for any diagnostic criterion, weperformed GWAS on two samples (“Yale-Penn-1” and “Yale-Penn-2”) totaling 4,653 AAs and 3,169 EAs. AAs and EAswere analyzed separately. We then tested whether Poly-genic Risk Scores (PRS) derived from potentially relatedtraits in EAs could be used to predict comorbid AD and MD.Comorbid criterion counts (ranging from 0–14) comprised forDSM-IV AD (7 criteria) and MD (9 criteria, scaled to 7).Results: Of the 7,882 participants, 42.7% were female.The median comorbid criterion count was 6.2 (interquartilerange [IQR], 2.3–10.9). Under the linear regression model,

rs139438618 at the Semaphorin 3A (SEMA3A) locus wassignificantly associated with AD-MD comorbidity in AAs inthe Yale-Penn-1 sample (beta coefficient [β]=0.89,P=2.76� 10-8). In the Yale-Penn-2 sample, the associationwas also significant (β=0.83, P=2.06� 10-4). Meta-analysisof the two samples yielded a more robust association(β=0.87 [95% CI, 0.61–1.12], P=2.41� 10–11). There wasno significant association identified in EAs. PRS analysesshowed that individuals with a higher risk of neuroticism(β=1.01 [95% CI, 0.50–1.52]) or depressive symptoms(β=0.87 [95% CI, 0.32–1.42]) and a lower level of subjectivewell-being (β=-0.94 [95% CI, -1.46 to -0.42]) and educa-tional attainment (β=-1.00 [95% CI, -1.57 to -0.44]) were athigher level of AD+MD; while larger intracranial (β=1.07[95% CI, 0.50–1.64]) and smaller putamen volumes (β=-1.16[95% CI, -1.86 to -0.46]) predicted higher risks of AD+MD.Discussion: SEMA3A variation is significantly associatedwith comorbid AD and MD in AAs. Using PRS analyses, weidentified pleiotropy with neuropsychiatric traits and brainvolumes. Further studies are warranted to understand thebiological and genetic mechanisms of this comorbidity,which could facilitate medications development and othertreatments for comorbid AD and MD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.338

M32. PER3 POLYMORPHISMS, MORNINGNESS-EVENING-NESS AND DEPRESSION: PRELIMINARY EVIDENCE IN ABRAZILIAN FAMILY-BASED COHORT, THE BAEPENDIHEART STUDY

Francieli Ruizn,1, Tâmara P. Taporoski5, Daniela Martinez5,

Andrew Beale2, Felipe Beijamini3,José E. Krieger1, Kristen L. Knutson4, Alexandre Pereira1,Mario Pedrazzoli1, Homero Vallada5, Malcolm Von Schantz2

1University of São Paulo2University of Surrey3Federal University of Fronteira Sul4Northwestern University5Univesity of São Paulo Medical School

Background: There is a significant interest in the con-tribution of the circadian timing system to individualdifferences in a wider range of behaviour. This is in partbecause sleep complaints and disturbances of the circadiantiming system are common in psychiatric disorders. Basedon diurnal preference, people can be divided into chron-otypes with demonstrated differences in sleep-wake pat-terns and a variety of circadian rhythms, behavioralrhythms, and diurnal variation in mood. Specifically, greatereveningness has been related to greater depression. Thehuman PER3 gene contains a variable number tandemrepeat (VNTR) which is associated with diurnal preference:the longer allele (five tandem repeats) has been reported toassociate with greater morningness, and the shorter allele(four tandem repeats) with greater eveningness. We have

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investigated the PER3 polymorphism and its relationship tosleep, circadian and depression characteristics in a Brazilianfamily-based cohort.Methods: Baependi is a small rural town in Brazil thatprovides a window of opportunity to study the influence ofsleep circadian patterns in a highly admixed rural populationwith a conservative lifestyle. Here, we studied 786 subjects(mean age7SD 46.5716.2, 42% female). Blood samples werecollected from all participants. The Per3 length polymorphismwas genotyped using PCR followed by gel electrophoresis. Wetested for associations between the PER3 polymorphism andsleep characteristics, daytime sleepiness, and chronotype usingthe Pittsburgh Sleep Quality Index, Epworth SleepinessScale and Morningness-Eveningness Questionnaire, respectively.Depressive symptoms were assessed using the Beck DepressionInventory [BDI-II]).Results: Our genotyping data showed that 36% of thesubjects were homozygous for the shorter allele (4/4), 51% ofthe participants were heterozygous (4/5) and 12% of thesubjects were homozygous for the longer allele (5/5). Allelefrequency was 0.62 for the 4-repeat and a 0.38 for the5-repeat. The percentages of the chronotypes Morning type(M-type), Neither type (N-type) and Evening type (E-type) were5%, 46% and 7%, respectively. We observed an increase of thedepression symptoms in evening types [F(2, 1014)=4.8,p=0.007]. On the other hand, no such associations wereobserved the PER3 genotype. There were no significant differ-ences in the MEQ score [F(2, 317)=0.46, p=0.63], daytimesleepiness [(F(2, 317)=0.23, p=0.79)], sleep efficiency [(F(2,317)=2.59, p=0.07)] and sleep characteristics [(F(2, 317)=1.92, p=0.14)] between the PER3 genotypes.Discussion: We observed an association between even-ingness and depression. Identifying factors contributing toindividual differences in sleep and to describe how thesefactors are associated with physiological and psychologicalprofiles may aid our understanding of the role of sleep andthe circadian system in mental health. On the other hand,we were not able to replicate the association between thePER3 VNTR polymorphism and chronotype, which has beenconfirmed independently in multiple populations worldwide(including in Brazil). Neither did we observe any associationwith depression. CNPq – PVE 400791/2014-5.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.339

M33. DEPRESSION PROBLEMS AMONG TURKISH TWINS

Fazil Alievn,1, Sevgi Yurt Oncel2

1Virginia Commonwealth University, Karabuk University2Kirikkale University

Background: In this study, we investigate factors affect-ing depressive behavior among adult Turkish twins living inthe Kırıkkale and Ankara regions of Turkey. Twins adminis-tered a health and lifestyle interview which includedquestions about smoking, alcohol and drug use, depression,

demographics and factors possibly affecting behavior pro-blems. Main focus was on binary variable pointing todepressive problems.Methods: We assessed 309 twin pairs (339 males and 279females) aged between 15 and 45 years living in theKırıkkale and Ankara regions of Turkey. We analyzed thedata using descriptive statistics, t-tests, chi-square tests,and bivariate and multivariate clustered logistic regression.In addition, we fit Structural Equation Models (SEM) todetermine contributions of latent genetic and environmen-tal factors to depression in this sample.Results: 256 participants (43.9%) were identified as havingdepressive problems, of which 45.3% were males and 54.7%were females. Mean for depression was significantly higherin males than in females (p=0.0001). Our study showed thatgender, presence of a twin with depression in the family,age, marital status, and daily sports activities all played asignificant role in depressive behavior among twins. Thetwin analysis suggested that genetic factors play significantrole on the liability to depressive problems.Discussion: Significant differences in the presence ofdepression in women versus men are observed for theTurkish population. We find that having a twin with depres-sion plays a significant role in depression problems amongTurkish twins. This study will enable us to better understandgenetic and environmental influences on behavioral out-comes across diverse cultures.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.340

M34. A GENETIC RISK SCORE, DEPRESSION AND OBE-SITY: EVIDENCE FROM THE SPANISH POPULATIONSTUDY PISMA-EP

Margarita Riveran,1, Blanca Gutierrez2, Paula Rovira3,

Esther Molina4, Maria Victoria Martín-Laguna2,Inmaculada Ibanez-Casas2, Kathryn McKenney2,Ana Ching-López2, Isabel Ruiz-Pérez5,Miguel Rodríguez-Barranco6, Jorge Cervilla2

1King's College London2University of Granada3Vall d’Hebron Research Institute, Universitat Autònoma deBarcelona, Mental Health and Addictions, Hospital UniversitariVall d’Hebron4University of Seville5CIBER de Epidemiología y Salud Pública6Andalusian School of Public Health

Background: Depression and obesity are highly prevalentdiseases in the general population, responsible of disabilityburden worldwide. Both conditions are major risk factors forchronic physical diseases such as type 2 diabetes, cardio-vascular disease and hypertension among others. The reasonwhy obesity and depression cluster together is not totallyunderstood and several mechanisms have been proposed.There are many factors driving this observation, such as

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individual lifestyle choices, socioeconomic factors, psycho-social stress, disparities in health care, medication, as wellas biological and genetic factors. The aim of this study is toinvestigate whether a Genetic Risk Score (GRS) combining85 candidate SNPs for depression and other major psychia-tric disorders is associated with depression and predictsdepression in individuals with obesity.Methods: The sample consists of 743 community-basedindividuals from the PISMA-ep study. The PISMA-ep is across-sectional epidemiological study of mental disordersbased on a representative sample of the adult population ofAndalusia, Spain. A DSM-IV diagnosis of major depressionwas ascertained using the MINI interview. Height and weightdata reported from each individual was used to calculateBody Mass Index (BMI), as a measure of obesity, using theformula: weight(kg)/height(m)2. All individuals have beengenotyped for the 85 candidate polymorphisms using Taq-Mans OpenArrayTM Genotyping System. These markerswere selected according to genome location, function andprevious evidence. Logistic regression models will be con-ducted to predict depression. We will calculate anunweighted GRS by summation of the number of risk alleles,and a weighted GRS as the sum of risk alleles at each locusmultiplied by their effect sizes. Receiver Operating Char-acteristic (ROC) analysis will be used to compare thediscriminatory ability of predictors of depression.Results: We hope that both unweighted and weighted GRSwill be associated with depression and explain a modestamount of variance. We also hope that adding ‘traditional’risk factors to GRS will significantly improve the predictiveability with the area under the curve (AUC) in the ROCanalysis. We further expect that the GRS will discriminatedepression better in obese individuals compare to normal-weight subjects.Discussion: The association between depression and obe-sity has repeatedly been reported in many studies. Giventhe high prevalence of both disorders, we expect thatincorporating genetic information, traditional risk factorsand obesity status may largely improve the predictingability for depression. Addressing obesity in people withdepression or vice versa is highly important as both dis-orders are associated with substantial personal and societaleconomic costs worldwide.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.341

M35. GENOME-WIDE ASSOCIATION STUDY OF COMOR-BID DEPRESSION AND ANXIETY SYMPTOMS IN ANEXTENDED PEDIGREE COHORT

Andre Brooking Negraon,1, Tamara Taporoski1,

Nubia Esteban2, Malcolm von Schantz3, Homero Vallada1,Alexandre Costa Pereira4

1University of São Paulo Medical School2National University of Colombia3University of Surrey

4Laboratory of Genetics and Molecular Cardiology, HeartInstitute, University of São Paulo Medical School

Background: Genetic markers of susceptibility for anxi-ety and depression have been elusive. Increased samplesize, utilizing symptoms rather than disorders and, explor-ing genetic covariability between pairs of traits are knownapproaches to increase the power of GWAS and have beenused isolatedly. We have previously demonstrated a stronggenetic covariability between depression and anxiety symp-toms in a family based cohort, The Baependi Heart Project.Combining two strategies, symptoms approach and geneticcovariability in a GWAS can result in greater detectionpower of genetic markers associated with those traits.Methods: We investigated depression and anxiety symp-toms, quantified using the Hospital and Depression Scale(HADS) in 1,375 individuals from 93 nuclear familiesrecruited from an admixed population in Brazil. GWAS wasperformed for anxiety and depression scores both indepen-dently (univariate analysis), and using bivariate analysistaking into consideration the genotypic covariance betweenthose traits (rhog=0.81). The Baependi cohort was geno-typed using different GWAS platforms (custom arrays tocapture the tri-ancestry genetic structure of the Brazilianpopulation; Affymetrix Axiom Incor array and AffymetrixSNP chip 6.0; Affymetrix, Santa Clara, CA).Results: The univariate approach revealed interestinggenetic targets, but none with genome-wide significance.However, the bivariate approach identified significant hits(po5,0� 10-8) on chromosome 3 for each individual trait,albeit in distinct genomic regions. Thus, significant associa-tions for anxiety were found within the 3q13.2 region,mostly within BTLA, the B-and T-lymphocyte attenuatorgene. The same approach revealed associations betweendepression symptoms and two sets of markers. Markers werelocated in the 3p22.3 region near LOC101928135, a lncRNAgene previously associated with neuropsychiatric traitsrelevant to depression. Two markers were located in the3q26.31 region within the N-acetyl-L-aspartyl-L-glutamatepeptidase-like 2 (NAALADL2) gene, which has been asso-ciated with traits related to behavioral phenotypes such asautism spectrum disorders, sleep duration, and bipolardisorder.Discussion: Taking into consideration the genetic co-variability between anxiety and depression symptoms addedpower for the identification of genetic markers associatedwith these traits.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.342

M36. SLEEP DISORDERS AND RISK OF INCIDENT DEPRES-SION: A POPULATION CASE-CONTROL STUDY

Enda Byrnen,1, Naomi Wray1, Esben Agerbo2

1University of Queensland

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2Centre for Integrated Register-based Research, NationalCentre for Register-based Research, Aarhus University

Background: A number of studies have found that dis-turbed sleep can precede onset of a psychiatric disorder,and that there is substantial comorbidity between sleepdisorders and psychiatric disorders, particularly majordepression. However, some studies have not been able toestablish the temporal relationship between sleep disordersand psychiatric disorders, have been performed in clinicalsamples, relied on self-report information or have condi-tioned on the outcome. We sought to investigate andestimate the risk of developing new-onset depression inthose with sleep disorders in the entire population ofDenmark.Methods: Data were obtained by linking longitudinalDanish population-based registers. Information on sleepdisorders and major depression was obtained from theDanish National Hospital Register and the Danish PsychiatricCentral Research Register. The registers contain records ofall hospital visits with a diagnosis given by ICD-10 codes. Toaccount for variability in depression and sleep disorder riskover time, we used a nested case-control design. A total of65,739 individuals who had first onset of depressionbetween 1995 and 2013 were selected as cases. For eachcase, a set of 20 controls of the same sex, birth month andyear and who had not had depression by the date that thecase was diagnosed were selected at random form thepopulation (n=1,307,580 in total). We examined whetherthere was an increased rate of prior sleep disorders in MDDcases compared to controls using conditional logisticregression.Results: We found that there was an increased risk ofincident depression in cases for all sleep disorders analysed.Highest incidence rate ratios were found for circadianrhythm disorders (IRR=7.06 (2.78–17.91)) and insomnia ofinorganic origin (6.76 (4.37–10.46)). The lowest estimatedIRR was for narcolepsy (IRR=2.00 (1.26–3.17)). We alsoestimated the incidence rate ratio based on time since asleep disorder diagnosis. Those diagnosed with a sleepdisorder in the last 6 months were at highest risk ofdeveloping depression compared to those with at least1 year since diagnosis (3.10 vs 2.36).Discussion: Using data from Danish population registers,we show that all categories of sleep disorder are risk factorsfor incident major depressive disorder. Insomnia and circa-dian rhythm disorders have the highest associated risk,while narcolepsy and sleep-disordered breathing disordersexcluding obstructive sleep apnea have the lowest asso-ciated risk. We found differences in risk between men andwomen for insomnia, obstructive sleep apnea and sleepmovement disorders. Furthermore, we found that there is amoderate decrease in risk of depression as the time sincediagnosis of a sleep disorder decreases, but that most casesof depression were diagnosed more than a year afterdiagnosis of a sleep problem. Our results have implicationsfor clinical practice. Depression screening should be con-sidered for patients with sleep disorders, and where possi-ble, long-term follow up for mental health problems isadvisable. Differences in risks between genders should alsobe considered in clinical practice.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.343

M37. TAKING A POLYGENIC APPROACH TO GnG AND GnEINTERACTIONS IN THE PREDICTION OF MDD

Hei Man Wun

, Paul O'Reilly

King's College London

Background: Major Depressive Disorder (MDD) is a com-plex heterogeneous disorder, with an estimated heritabilityof �40%. Known environmental risk factors (e.g. neuroti-cism, cognition) also play an important role in the devel-opment of MDD. Despite the successful identification ofmany associated loci in the most recent MDD GWAS, thisrequired a huge sample size and so these loci explain only asmall fraction of the heritability, making clinical applicationchallenging. One way of revealing greater aetiologicalinsight, and potentially increasing disease prediction, is todetect gene-gene and gene-environment interactions. Theidentification of these interactions is challenging due to thehuge model space involved (esp. for GnG). While theseindividual variant interactions may exist, there may also beinteractions – more easily identified – between the overallpolygenic risk of a disorder and that of other disorders orenvironmental risk factors. Here we aim to 1) use PolygenicRisk Scores (PRS) to identify global genetic interactioneffects, and 2) build a predictive model of MDD case-controlstatus utilizing the rich phenotypic data available in the UKBiobank.Methods: To build and validate predictive models of MDD,we split the UK Biobank data into discovery GWAS, testingand validation datasets. The predictive model was devel-oped via model selection techniques such as stepwise AIC/BIC and lasso regression, with a large number of PRSnPRSand PRSnE predictors.Results: We identify several intriguing PRS interactioneffects and increase out-of-sample prediction of MDDcase/control status significantly via inclusion of PRSinteractions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.344

M38. GENOME-WIDE ASSOCIATION STUDY OF ANHEDO-NIA IN GENDEP USING A LINEAR MIXED MODEL IDENTI-FIES CANDIDATES WITH RELEVANT BIOLOGICALFUNCTION

Hongyan Renn,1, Chiara Fabbri2, Rudolf Uher3,

Marcella Rietschel4, Ole Mors5, Neven Henigsberg6,Joanna Hauser7, Wolfgang Maier8, Anne Farmer9,Peter McGuffin10, Cathryn Lewis9, Katherine Aitchison1

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1University of Alberta2University of Bologna3Dalhousie University4Central Institute of Mental Health5Aarhus University6Croatian Institute for Brain Research, Medical School,University of Zagreb7Laboratory of Psychiatric Genetics, Poznan University ofMedical Sciences8University of Bonn9MRC Social Genetic and Developmental Psychiatry Center,Institute of Psychiatry, King's College London10King's College London

Background: A key feature of Major Depressive Disorder(MDD) is anhedonia, which is a predictor of response toantidepressant treatment.Methods: In order to shed light on its genetic under-pinnings, we conducted a Genome-Wide Association Study(GWAS) followed by investigation of biological pathwayenrichment using the anhedonia dimension for 796 patientswith MDD in the GENDEP.Results: The GWAS identified 19 SNPs associated at gen-ome-wide significance with the top one being an intronicSNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B)located on chromosome 6 (P= 2.07� 10 �9) while gene setenrichment analysis returned one gene ontology term, axoncargo transport (GO: 0008088) with a nominal P value(1.15� 10 �5). Furthermore, on exploratory analysis, thegenetic association was positively correlated with that ofParkinson's disease (rg=0.803) and negatively correlatedwith that of nucleus accumbens gray matter volume (rg=-0.649).Discussion: We found some markers significantly asso-ciated with anhedonia, and some suggestive findings ofrelated pathways and biological functions, which could befurther investigated in other studies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.345

M39. THE ASSOCIATION OF METHYLATION OF THEPROMOTER AND ANTIDEPRESSANTS IN TRANSCRIP-TIONAL REGULATION OF THE BRAIN-DERIVED NEURO-TROPHIC FACTOR EXON IV

Hansi Pathakn,1, Helge Frieling2

1Medizinische Hochschule Hannover2University of Erlangen-Nurenberg

Background: Brain-Derived Neurotrophic Factor (BDNF) isimportant for the survival of existing neurons and promotionof the growth and differentiation of new neurons andsynapses. BDNF protein expression has been associated with

various psychiatric disorders including major depressivedisorders.

The gene contains eight exons with their individualpromoters that initiate transcription of multiple mRNAtranscripts, each of which contains an alternative 5′ exonspliced to a common 3′ coding exon IX. The use of differentpromoters allows a diverse, temporal and spatial regulationof the gene. We were particularly interested in exon IV as ithas been shown to play an important role in response tomonoaminergic anti-depressant drugs which mainly exerttheir effects via downstream signaling leading to phosphor-ylation of CREB (calcium/cAMP response element bindingprotein) and possibly a transcriptional repressor, MeCP2.The pCREB binds to the response element in the promoterregion and enhances exon IV transcription.

Our aim is to investigate the interaction between anti-depressant-mediated transcriptional regulation and BNDFexon IV methylation.Methods: We treated the SH-SY5Y neuroblastoma cell linewith Venlafaxine, Fluoxetine, and Mirtazapine and standar-dized the concentrations and time points at which thesedrugs increase the phosphorylation of CREB as well as MeCP2using western blot analysis. We cloned BDNF exon IVpromoter region upstream of the luciferase gene in a CpGfree reporter vector and reporter assays were performed inthe presence of Venlafaxine, Fluoxetine, and Mirtazapine atdesired concentrations. Immunofluorescence was used tostudy the drug-mediated changes in localization of MeCP2and CREB (phosphorylated and unphosphorylated). We usedsite-directed mutagenesis to replace the CpGs of interest inthe reporter construct by methylated CpGs.Results: An increased phosphorylation of both CREB andMeCP2 as early as 0, 5 h and up to 2hrs treatment of SHSY-5Ycells by Venlafaxine (10 μM /50 μM), Fluoxetine (5 μM/10 μM) and Mirtazapine (10 μM /50 μM) was observed. Wedid not see any increase in the exonIV transcriptionalactivity under these conditions in the unmethylated plasmidwhereas methylated plasmid showed a statistically signifi-cant upregulation with all the three drugs. Immunofluores-cence data shows that Fluoxetine changes the localizationof only unphosphorylated MeCP2 to nucleo-cytoplasmic fromnuclear. Venlafaxine and Mirtazapine showed no change inlocalization of MeCP2.Discussion: A previous study from our group has shownthat methylation of the CpG residues present on exon IVpromoter complements the increase in serum BDNF levelsby Venlafaxine and Fluoxetine, at physiological doses. Theresponse to the drugs can be predicted by the methylationof the CpGs present in the proximal promoter, -35 bp to -147bp. We hypothesize, kinases that get activated downstreamof the 5-HT receptor, phosphorylate methyl binding protein(MeCP2) and thus abrogate its binding to the methylatedCPGs. Contrary to MeCP2, phosphorylated MeCP2 can bindto unmethylated CpGs. As MeCP2 is a transcriptionalrepressor, it counteracts the upregulation of BDNF exon IVtranscript by pCREB binding and thereby determines theefficacy of the drugs.

This work commences a profound understanding of the

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epigenetic regulation of exon IV by antidepressants.Furthermore, it emerges to be in support with previousclinical findings regarding the use of CPG methylation as apredictive marker for antidepressant therapy.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.346

M40. INVESTIGATION OF THE GENETIC OVERLAPBETWEEN MAJOR DEPRESSIVE DISORDER AND BODYMASS INDEX IN HAN CHINESE WOMEN

Roseann Petersonn,1, Tim Bigdeli2, Hanna van Loo2,

Bradley Webb2, Jonathan Flint3, Kenneth Kendler1

1Virginia Commonwealth University2Virginia Institute for Psychiatric and Behavioral Genetics3University of California, Los Angeles

Background: Obesity is a major public health concern,and is often comorbid with psychiatric conditions includingMajor Depressive Disorder (MDD). Notably, several symptomsof MDD are related to energy balance, including changes inappetite, weight, and sleep. Genetic factors have consis-tently been demonstrated to influence individual differ-ences in MDD and body mass index (BMI), with twin studiesestimating heritabilities in the order of 0.37 and 0.70respectively. However, despite numerous associationsbetween MDD, BMI, and obesity there has been limitedresearch on shared genetic liability (rG) using molecularmethods.Methods: Here, we propose to advance the understandingof the MDD-obesity association by evaluating the evidencefor shared genetic liability through estimates of geneticcorrelation and also consider the predictive value of cross-trait Polygenic Risk Scores (PRS) informed by population-based meta-analyses. To move beyond phenotype-genotypeassociations, we will investigate causal mechanisms viaMendelian randomization using top findings from Genome-Wide Association Studies (GWAS). Finally, we will assessdifferences in MDD symptom networks, including BMI-PRS,among cases with and without comorbid obesity to poten-tially identify clinically relevant heterogeneity. Data arefrom China, Oxford, and VCU Experimental Research onGenetic Epidemiology (CONVERGE), a study of Han Chinesewomen with recurrent major depression aimed at identify-ing genetic risk factors for MDD in a rigorously ascertainedcohort (n=10,640) using sparse whole-genome sequencing.Results: There were no significant differences in MDDsymptom networks (strength, centrality) between MD caseswith and without comorbid obesity but elevated BMI wassignificantly associated with depression-related weight gain.In aggregate, common SNPs accounted for 15.5% of thevariance in BMI (p=8.0� 10-7), 22.6% in MDD diagnosis (p o1.0� 10–16), and 16.1% in atypical depression liability(p=0.002). Significant genetic correlations were seenbetween MDD and obesity traits ranging from rG= -0.15for percent body fat to rG=-0.38 for class III obesity. The

BMI-PRS was negatively associated with MDD case-status(effect=-0.72, p=0.014). Associations for individual var-iants previously associated with BMI among European popu-lations were not robust in CONVERGE (pFTO=0.005).Although in aggregate, BMI-PRS were significantly associatedwith BMI, accounting for 0.80% and 1.46% of the varianceamong MDD-cases and controls respectively.Discussion: Initial results were suggestive of partiallyshared genetic risk between MDD and BMI. Furthermore,results suggest genetic variation associated with BMI mayonly partially overlap between European and Han Chinesepopulations, highlighting the importance of studying geneticcontributions to complex traits in diverse populations.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.347

M41. DEPRESSION, INFLAMMATION, AND METABOLICRISK: A GENETICALLY-INFORMED EXPLORATORY STUDY

Kristen Kellyn,1, Briana Mezuk2

1University of Michigan2Virginia Commonwealth University

Background: Depression is a highly prevalent psychiatricdisorder, which has been observed to have greater-than-expected comorbidity with metabolic and inflammatorydisorders. Although standard observational study designsencounter limitations when assessing the directionality ofthe relationships underlying the comorbidities, twin studiesoffer a means to resolve competing explanations of comor-bidity. The purpose of this study is to examine the relation-ship between depression and biomarkers associated withinflammation and metabolic risk by examining patterns ofcorrelation in monozygotic twin pairs with different depres-sion histories.Methods: The sample consisted of 45 monozygotic twinpairs (mean age: 52.8, 69% female, 76% white) assessedtwice over a 6-month period. Lifetime history of MajorDepressive Disorder (MDD) was assessed using the DiagnosticInterview Schedule. Biological measures included peripheralleukocyte gene expression (data not yet available), hemo-globin A1c (HbA1c, a measure indicative of recent bloodsugar levels), and two markers of systemic inflammation,C-reactive Reactive Protein (CRP), and interleukin-6 (IL-6).Intraclass correlation coefficients (ICC) were calculatedacross members of each twin pair, and within-individualacross timepoints. Biomarker levels were also comparedbetween members of twin pairs discordant for MDD, andwith twins from pairs in which neither member had a historyof MDD.Results: Of the 40 pairs with known MDD history, 13(32.5%) had no history of MDD in either member, 14 (35%)were discordant for MDD, and 13 (32.5%) had a lifetimehistory of MDD in both twins. HbA1c showed a low ICCbetween twins (0.363), but a high ICC within individualsover time (0.873). CRP had a low ICC both between twins

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(0.189) and within individuals over time (0.174). IL-6 had amoderately high ICC both between twins (0.571) and withinindividuals over time (0.691).

In MDD-discordant pairs, the twins with MDD had highermedian HbA1c (5.55%) than their non-MDD co-twins (5.45%),while twins from MDD-free pairs were not notably different(5.50%). Change in HbA1c was highest in the twin with MDDin the discordant pairs (0.25%), followed by their non-MDDco-twins (0.20%), and lowest in MDD-free pairs (0.10%). Indiscordant twin pairs, the twin with a history of MDD hadlower median CRP (1810.95 ng/ml) than the twin withoutMDD (2683.98 ng/ml), while the lowest CRP was found inMDD-free pairs (827.213 ng/ml). For discordant pairs, thetwin with MDD had higher median IL-6 (1.53 pg/ml) thantheir non-MDD co-twins (1.08 pg/ml), and twins from MDD-free pairs had the lowest IL-6 (0.658 pg/ml).Discussion: The differing patterns in ICC suggest thatHbA1c is greatly influenced by individual-specific environ-mental factors and moderately influenced by genetic orshared environmental factors. In contrast, circulating levelsof CRP are largely influenced by short-term environmentalfactors. Finally, circulating levels of IL-6 have a notablecontribution from genetic or environmental factors sharedbetween twins. Levels of IL-6 and change in HbA1c overtime followed a pattern of highest values in twins with MDD,their non-MDD co-twin, followed by twins from MDD-freepairs. This is consistent with the hypothesis that MDD has aninfluence on these biomarkers, but much of that influence isdriven by genetic liability for MDD. These preliminaryresults demonstrate the value of longitudinal studies usingmonozygotic twins, although further analysis is needed.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.348

M42. WHOLE GENOME SEQUENCE ANALYSIS OF A COU-SIN PAIR WITH RESTRICTING ANOREXIA NERVOSA

Andrew Bergenn,1, Pei-an Betty Shih2,

Ashley Scott-Van Zeeland3, Tristan Carland4, Vikas Bansal2,Pierre Magistretti5, Christine Strobel6, Manfred Fichter6,Walter Kaye2, Nicholas Schork7

1BioRealm2University of California, San Diego3Cypher Genomics and Human Longevity4The Scripps Research Institute and J. Craig Venter Institute5Ecole Polytechnique Fédérale de Lausanne6Schoen Hospital Roseneck for Behavioral Medicine,D-83209 Prien, University of Munich (LMU)7University of California, San Diego, The Scripps ResearchInstitute and J. Craig Venter Institute

Background: Anorexia Nervosa (AN) is a serious mentalillness that often has an onset during adolescence. AN ischaracterized by emaciation, fear of gaining weight despitebeing underweight, and the highest mortality rate of allpsychiatric illnesses. AN is highly heritable and recent meta-

analyses in 3,495 anorexia nervosa cases and 10,982 con-trols has identified a region on chromosome 12 at genome-wide significance, significant common genetic heritability,and genetic correlations with both psychiatric and meta-bolic traits. AN symptoms and personality traits tend to bepresent in unaffected family members of the patients,suggesting that certain shared genetic factors within eachfamily may contribute to the unique risk underlying anaffected individual's phenotype.Methods: To gain insight into the role that unique, family-specific variants may play in the development of AN, weperformed whole genome sequencing analysis (CompleteGenomics) and extensive annotation of high quality variants(Cypher Genomics, SG-Advisor, ANNOVAR) to search forgenetic variants that may influence AN risk in six indivi-duals, consisting of two maternally-linked cousins withsevere AN and their parents. We focused on maternally-inherited shared segments; the preferred transmissionmodel for variant filtering was the dominant model. Wereviewed results from the Psychiatric Genomic ConsortiumAN GWAS and other -omic databases at identified genes.Results: Of the approximately 5.3 million variants perindividual that were analyzed, 494,712 were shared Iden-tical-By-Descent (IBD) by the cousin pair based on mater-nally derived haplotypes. Based on extensive geneticvariant annotations within maternally inherited sharedsegments, we identified variants in TTC22, MRPS9,DNAJC30, HEPACAM2, USP20, ESF1, and CDK5RAP1. Multipleprediction methods suggest that six of these variants arelikely to affect protein function. The region proximal toMRPS9 exhibits an excess of nominally significant findings inthe PGC AN GWAS, and eQTLs to MRPS9 and to an unchar-acterized antisense gene in many tissues. MRPS9 SNPs areassociated in blood with 4-androsten-3beta,17beta-diol dis-ulfate 2 and dehydroisoandrosterone sulfate (a metaboliteand a precursor of steroid sex hormones, respectively).Discussion: By capitalizing on the homogeneity of thedisease presentation and the genomic makeup among twocousins with a diagnosis of restricting-type AN, we exploitedwhole genome sequence analysis and variant annotationapproaches to identify a set of novel variants and genes thatmay influence AN. Our results suggest that there may beutility in whole genome sequencing of families withaffected individuals to detect variants that contribute to acomplex disease such as AN.

Disclosure: BioRealm, LLC - Employee, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.349

M43. A CROSS-DISORDER GENOME-WIDE ASSOCIATIONSTUDY OF ANOREXIA NERVOSA AND OBSESSIVE-COM-PULSIVE DISORDER

Zeynep Yilmazn

University of North Carolina at Chapel Hill

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Background: This work is presented on behalf of theEating Disorders and Tourette's/Obsessive-Compulsive Dis-order Working Groups of the Psychiatric Genomics Consor-tium.

Anorexia Nervosa (AN) is a serious psychiatric disorderwith high mortality and morbidity, and Obsessive-Compul-sive Disorder (OCD) is an idiopathic psychiatric conditionthat often follows a chronic course. Overlap of hallmarksymptoms (e.g., compulsivity, cognitive rigidity), notablecomorbidity, shared family history, and a high geneticcorrelation provide converging lines of evidence for sharedetiology of AN and OCD, but the biological mechanismsbehind this shared risk have yet to be uncovered. The aim ofthe present study was to examine the shared genetic riskfactors for AN and OCD.Methods: Under the umbrella of the Psychiatric GenomicsConsortium, we conducted a meta-analysis of the mostrecent and largest AN and OCD Genome-Wide AssociationStudies (GWASes) to investigate risk variants common toboth disorders. A total of 6,183 cases (3,495 AN and 2,688OCD) and 18,013 controls were included in the meta-analysis of 8,062,640 variants conducted using METALthrough the Ricopili pipeline.Results: Although no variant reached genome-wide sig-nificance, the closest nearby genes for the variants with po 5� 10-7 were MHC region on chromosome 6, FAM19A2 onchromosome 12, KIT on chromosome 4, CXCR4 on chromo-some 2, and SLC25A42 on chromosome 19. Furthermore, weused LD Score Regression to re-calculate the geneticcorrelation between AN and OCD using the most recentsummary statistics files with the largest sample sizes todate, confirming previous findings of a significant positivegenetic correlation (rg=0.48; se=0.12; p=8.2� 10-5).Discussion: In this first cross-disorder GWAS for AN andOCD, our preliminary results provide encouraging evidencefor the shared genetic architecture of these two psychiatricdisorders. Additional approaches such as gene- and gene-setbased analyses, partitioned heritability analyses, and thosemaking use of gene-expression data are underway and willsupplement current results.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.350

M44. PATIENT OUTCOMES OF PSYCHIATRIC GENETICCOUNSELING: ASSESSING THE IMPACT OF DIFFERENTFAMILY HISTORY COLLECTION MODALITIES

Jehannine Austinn

, Caitlin Slomp, Emily Morris,Angela Inglis, Anna Lehman

University of British Columbia

Background: Though often thought of as an interventionexclusively concerned with delivering information aboutgenetic testing/recurrence risk, Genetic Counseling (GC) isactually “a process of helping people to understand andadapt to the medical, psychological, and familial

implications of genetic contributions to disease.” Documen-tation of family history (Fhx) is fundamental to this processfor GC; it provides a basis for genetic risk assessment, andfor personalizing conversations about illness etiology. Theprocess of Fhx documentation can also build rapport, whichis key to optimal patient outcomes of GC. Variousapproaches for obtaining the Fhx have been employed,often motivated by a desire to increase the efficiency ofgenerating an accurate pedigree. However, no studies haveevaluated whether different modalities for collection of Fhxdata influence patient outcomes. Pre-appointment phonecalls have the theoretical advantages of helping to clarifyexpectations and initiate rapport-building prior to theappointment, and allowing the patient and counselor tomore fully attend to the content of the GC session if Fhx hasbeen documented in advance.Methods: We sought to test the hypothesis that patientoutcomes of psychiatric GC would demonstrate more dra-matic improvements when Fhx was collected via telephoneprior to their appointment (FhxPrior) as compared to whenFhx was collected during the appointment (FhxDuring). Weused data from our specialist psychiatric GC clinic, where asroutine clinical practice, patients complete the GC out-comes scale (GCOS, measuring empowerment) and IllnessManagement Self Efficacy Scale (IMSES) immediately prior toGC (T1) and at one-month follow-up (T2). Because of thehypothetical advantages of collecting Fhx before theappointment, this is standard practice for the clinic. How-ever, when a patient cannot be reached by telephonebefore the appointment, Fhx is collected during theappointment. Study inclusion criteria required: 1) that bothT1 and T2 assessments were completed between 1 Feb 2012- 31 Jan 2017, 2) that the Fhx was obtained from the patienthim/herself, and 3) that the psychiatric GC appointmentwas conducted in person (rather than by telephone orvideoconference). Change in scale scores between T1 andT2 were compared between groups using Mann-Whitney Utests.Results: Of 573 patients who had completed T1 question-naires, 240 met inclusion criteria and were included in theanalysis (FhxPrior, n=206; FhxDuring, n=34). Overall,patient GCOS and IMSES scores increased significantly fromT1-T2 (p=0.000, d=1.2 and p=0.004, d=0.24 respec-tively). The increase in IMSES scores from T1-T2 wassignificantly greater for the FhxPrior group than for theFhxDuring group (p=0.014, d=0.64). There was no differ-ence in the increase in GCOS score between groups(p=0.649).Discussion: Our data support previous findings regardingthe important positive outcomes of psychiatric GC forpatients, and suggest that obtaining Fhx via telephone priorto a psychiatric GC appointment may lead to greaterincreases in patient self-efficacy as compared to obtainingFhx during the GC appointment. Future research willinclude prospective evaluation of alternate Fhx collectionmethods to maximize patient outcomes in our clinic.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.351

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M45. NEURODEVELOPMENTAL COPY NUMBER VARIANTSAND CLINICAL RISK: A PEDIATRIC RECORD POPULATIONSTUDY

Kwangmi Ahnn,1, Frank Mentch2, Steven An3, Chally Kao2,

Hakon Hakonarson2, Judith Rapoport1

1National Institute of Mental Health2Children's Hospital of Philadelphia3Johns Hopkins University

Background: Chromosomal Copy Number Variants (CNVs)associated with schizophrenia also carry etiological risk forneurodevelopmental disorders, including autism and intel-lectual deficiency. It is not known however what is their riskfor any disorders. Here we applied well-replicated ‘neuro-developmental’ CNVs (NRXN1 del, MYT1L dup, 15q13.3 del/dup, 16p11.2 del/dup, and 22q11.2 del/dup) and interro-gated their frequency and overall clinical penetrance forbroad categories of disorder in a general pediatricpopulation.Methods: Eight selected CNVs were screened utilizingTaqMan within a population sample of 60,644 pediatricpatients. CNV carriers were examined with respect to pre-scored digitized pediatric records and compared to recordsfor a 5:1 non-carrier control group matched for eachindividual CNV. Prevalence for 12 clinical categories wereestimated.Results: Seven of these CNVs (NRXN1 (del), MYT1L (dup),22q11 (dup), 16p11 (dele/dup), and 15q11.3 (del/dup))were detected in the pediatric population at expected ratesbased on large control population studies. Having any CNVpredicted an increase for two of the 12 disease categoriesafter Bonferroni correction: Nervous system (p=1.43� 10-5) and mental/neurodevelopmental disorder (p=2.9� 10-10), and were associated with greater cost of medical care.Individual CNVs were examined in relation to their matchednon-carriers for previously described associated disorders.As anticipated, 15q13.3 deletion was associated with men-tal/neurodevelopmental disorders, and 16p11 deletion wasassociated with congenital deficits, CNS disorders andmental/neurodevelopmental disorders. 16p11 deletion car-riers showed more circulatory disorders than their matchednon-carriers. Finally, in addition to association with mentaland congenital defects, a significant association was foundbetween 22q11 duplication and pediatric gastrointestinalreflux (p=0.0037) which was more likely to be present inthe presence of developmental delay (interactionp=0.0362).Discussion: These findings extend previous clinicallybased studies providing a high prediction of risk for16p11.2 deletion, 15q13.3 deletion and 22q11.2 duplica-tions. A broader concept of overall clinical penetrance isimportant for understanding the pathophysiology of thesedisorders and may inform genetic counseling. To our knowl-edge, this is the first report of a CNV association (22q11duplication) for pediatric GERD, which may represent adelay in vagal nerve maturation, and first report of a 16p11deletion associated with circulatory disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.352

M46. DISCOVERY BIOLOGY OF NEUROPSYCHIATRIC SYN-DROMES: A CENTER FOR INTEGRATING CLINICAL MED-ICINE AND BASIC SCIENCE (DBNS): INTEGRATINGCLINICAL PSYCHIATRY AND BASIC SCIENCE

Sanjeev Jainn,1, ADBS Consortium2

1National Institute of Mental Health & Neurosciences2National Institute of Mental Health Neurosciences,National Centre for Biological Sciences, Institute for StemCell Biology and Regenerative Medicine

Background: Traditional clinical classification systemsconceptualize the psychiatric disorders as a group of relateddisorders or discrete entities syndromes that are supposedlyindependent of each other. However, there is now accumu-lating evidence that there exist overlapping genetic, envir-onmental and developmental factors, cutting across thesediagnostic boundaries. There is sufficient evidence tosuggest that these disease biological processes start longbefore manifestation being manifest as to a clinicallyrecognizable syndrome.Methods: We will establish a registry of 300 multipleaffected families in whom multiple members (more than2 affected in a nuclear family) are diagnosed with majorpsychiatric disorders (schizophrenia, bipolar disorder, obses-sive compulsive disorder, dementias and substance use dis-orders) with structured assessments and create a unifieddigital database. We will study brain structural [grey (mag-netic resonance imaging-MRI) and white matter (diffusiontensor MRI)] abnormalities, resting and task-related func-tional MRI activity, neuropsychological performance, brainelectrical activity and eye movement abnormalities in pro-bands with major psychiatric disorders and their unaffectedfirst-degree relatives (FDR); in comparison with matchedhealthy controls. The families will be subjected to a uniformset of clinical analyses; and a bio-repository will be set upusing cellular material (lymphocytes, induced pluripotentstem cells, neural stem cells). Whole exome sequencing willbe performed We will also examine the time course andprogression of brain abnormalities and study their relation-ship to course of illness and disease conversion.Results: We hypothesize that patients will have significantspecific grey matter volume deficits and white matter hypo-connectivity; aberrant neuro-hemodynamic response invol-ving frontal, striatal & limbic brain regions during fMRI;abnormal brain electrical activity and antisaccade/smoothpursuit eye movements; prominent and specific patterns ofimpairments in verbal memory, verbal fluency, sustainedattention and executive functions, in comparison withmatched healthy controls.

Unaffected relatives will have brain abnormalities thatare intermediate between affected subjects and healthycontrols. A composite endophenotype comprising of neuroi-

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maging and neurocognitive parameters should be able todifferentiate three groups Cellular assays will similarlydifferentiate cell lines derived from the three groups.Greater brain abnormalities/composite endophenotypemeasures/cellular abnormalities at baseline will predictpoorer course and outcome/ treatment response. Therelation between these, and the genetic variations, wouldbe amenable for further analysis, to understand the geno-type-phenotype conversion.Discussion: The DBNS is an enthusiastic thus an ambitiousattempt approach to create a database that combines awealth of clinical data with a comprehensive psychologicaland biological assessment, over time. clinical-basic sciencedatabase with on-going biological follow-up of recruitedindividuals; and a biorepository. The resources generatedwill hopefully serve as a platform to answer several ques-tions related to the neurobiology of psychiatric disorders; aswell as fundamental questions about neuro-developmentand degeneration.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.353

M47. OBSTETRIC COMPLICATIONS INTERACT WITHGENETICS TO INFLUENCE PSYCHOPATHOLOGY ANDPERSONALITY TRAITS

Viktoria-Eleni Gountouna, Joeri Meijsenn

, Kristin Nicodemus

University of Edinburgh

Background: Obstetric Complications (OC) have beenimplicated in the aetiology of psychiatric disorders, andare hypothesised to interact with underlying genetics toincrease risk. We undertook a genome-wide search ofinteractions with OCs for psychopathology and personalitytraits related to psychiatric disorders in the GenerationScotland cohort.Methods: OCs were obtained using medical record link-age. We used general linear models to test for interactionsbetween OCs (birth-weight, labour induction, Caesareansection, use of forceps, gestational age and neonatal careadmission) and over 500,000 SNPs on measures of psycho-pathology (General Health Questionnaire (GHQ), Schizoty-pal Personality Questionnaire (SPQ), Mood DisorderQuestionnaire (MDQ) and personality (Eysenck Extraversionand Introversion) as outcomes. Numbers for each OCanalysis were based on the availability of medical records.Results: All p-values reported are after Bonferroni correc-tion. Genome-wide significant SNP-OC interactions wereobserved for the GHQ with neonatal care admission(N=1539; rs17141144; p=6.70� 10-7; LOC107986773;intronic), use of forceps (N=1669; rs17065704;p=3.24� 10-6; PEX7; intronic) and birthweight (N=2420;rs9608151; p=0.02; intergenic). GWAS-significant interac-tions were also found for the SPQ with neonatal careadmission (N=932; rs12512245; p=0.02; intergenic) andbirthweight (N=1536; rs7803908, p=0.005; TNS3; intronic)

and for Eysenck Extraversion with birthweight (N=2629;rs7137811; p=0.007; intergenic) and gestational age(N=1541; rs17708877; p=0.01; DGKB; intronic).Discussion: To our knowledge, this is the first genome-widestudy to reveal GWAS-significant gene-by-environment interac-tions with OCs impact a wide variety of psychological traitsassociated with psychiatric disorders. As the OC data wereobtained via medical record linkage, they are not likely tosuffer from recall bias. Genes implicated include PEX7, involvedin neuronal migration, and DGKB, highly expressed in thehippocampus and linked to cognition and schizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.354

M48. DECONSTRUCTING THE NEUREXIN1 DELETIONPHENOTYPE: A NEUROPSYCHOLOGICAL, NEUROCOGNI-TIVE AND NEUROIMAGING PERSPECTIVE

Louise Gallaghern,1, Jacqueline Fitzgerald1,

Maryam Al Shehhi2, Sally Ann Lynch2, Sanbing Shen3

1Trinity College Dublin2National Centre for Medical Genetics, OLCHC3National University of Ireland Galway

Background: The Neurexin1 (NRXN1; 2p16.3) gene hasbeen identified as a rare but significant genetic risk factorfor neurodevelopmental disorders including Autism Spec-trum Disorder (ASD) schizophrenia, Intellectual Disability(ID) and bipolar disorder. NRXN1 encodes Neurexins, neuro-nal adhesion molecules on axon terminals, which bindpostsynaptic Neuroligins (encoded by NLGN). The primaryfunction of NRXN1 is to stabilise synapse formation andfacilitate neuronal transmission. Common clinical featuresare associated with NRXN1 deletions but these have notbeen deconstructed using in-depth neuropsychological,neurocognitive and neuroimaging techniques. This projectaims to deep phenotype individuals and characterise theclinicopathological features of NRXN1 deletions.Methods: 21 participants with NRXN1 deletions and 21 ageand gender matched controls were recruited. Semi-structuredneuropsychological assessments (CAPA, PAS-ADD) were per-formed and questionnaires to probe for existing and/or sub-threshold psychiatric disorders or symptoms were collated.The Wechsler Abbreviated Scale of Intelligence-second edition(WASI-II) and a comprehensive cognition battery (CANTAB;http://www.cambridgecognition.com/) was administered toall participants to assess neurocognitive functioning. HighAngular Resolution Diffusion Imaging (HARDI) data (61 direc-tions, b-value=1500 s/mm2) were acquired (n=17 per group)to evaluate neuroanatomical differences. Preprocessing wascompleted using ExploreDTI software (http://www.Explor-eDTI.com). Data quality checks were performed and subjectmotion and eddy current induced geometric distortions werecorrected for in one interpolation step to minimise blurringeffects. Fractional anisotropy (FA) values were extracted andvoxelwise statistical analysis of the FA data was carried out

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using Tract-Based Spatial Statistics (TBSS) in FSL (https://fsl.fmrib.ox.ac.uk/fsl).Results: The groups did not differ in age (t(40)=-0.015,p=0.988) but there was a significant difference in IQ (t(40)=-6.3, p=0.00) thus IQ was included as a covariate in allstatistical analyses. Neuropsychological assessments indi-cated that 6 individuals have met criteria for ASD, 3 for mildID, 2 for ADHD, 1 for a psychotic disorder and 1 for a conductdisorder. Neurocognitive assessments indicate a trendtowards executive dysfunction and aberrant social cognitionin individuals with NRXN1 deletions characterised by greaternumber of errors on spatial working memory, spatial organi-sation and emotion recognition tasks, po0.1. TBSS analysesdemonstrated reduced FA in the left body of the corpuscallosum, left superior longitudinal fasciculus and the leftinferior longitudinal fasciculus in the NRXN group relative tocontrols, p o 0.1, corrected for multiple comparisons.Discussion: Interesting clinical characteristics of NRXN1deletions are emerging. This study indicates that NRXN1deletions may contribute to neurocognitive deficits relatedto executive functioning and social cognition, two domainsthat are consistently described as aberrant in neurodeve-lopmental disorders. Furthermore, individuals with NRXN1deletions demonstrate a pattern of disrupted structuralconnectivity, which has also been described in neurodeve-lopmental disorders such as ASD and schizophrenia. Furtherclinical and neurobiological phenotyping in addition tomapping of the NRXN1 genotype may elucidate the under-lying neurobiological processes contributing to neurodeve-lopmental disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.355

M49. GENOME-WIDE ANALYSIS OF RISK-TAKING BEHA-VIOUR IN 116 255 INDIVIDUALS FROM THE UK BIOBANKCOHORT AND CROSS-DISORDER GENETICCORRELATIONS

Rona Strawbridgen,1, Joey Ward1, Breda Cullen1,

Elizabeth Tunbridge2, Sarah Hartz3, Laura Bierut4,Mark Bailey1, Nicholas Graham1, Amy Ferguson1,Donald Lyall1, Laura Pidgeon1, Michael O'Donovan5,Valentina Escott-Price6, Paul Harrison2, Daniel Smith1

1University of Glasgow2University of Oxford3Washington University in Saint Louis4Washington University School of Medicine5Cardiff University6MRC Centre for Neuropsychiatric Genetics & Genomics,Cardiff University

Background: Risk-taking is a key component of severalpsychiatric disorders and could influence lifestyle choicessuch as smoking, alcohol use and diet. Risk-taking behaviourtherefore fits within the Research Domain Criteria (RDoC)approach, whereby elucidation of the genetic determinants

of this trait has the potential to improve our understandingof behaviours that span a number of psychiatric disorders.Methods: A genome wide association study was conductedin 116 255 UK Biobank participants who responded yes/no tothe question “would you consider yourself a risk-taker?”.Genetic correlations were calculated between risk-takingand phenotypes relevant to psychiatric disorders. Expres-sion quantitative trait loci analyses in the brain wereconducted for significant loci.Results: Risk-takers (compared to controls) were morelikely to be men, smokers and have a history of mentalillness. Significant loci associated with risk-taking behaviourwere identified on chromosomes 3 (rs13084531) and 6(rs9379971). The effect of rs13084531 was comparablebetween men and women, whilst rs9379971 showed stron-ger effects in women than men. Rs13084531 on chromosome3 demonstrated significant effects on CADM2 mRNA expres-sion levels. CADM2 has previously been implicated in cogni-tion, including executive function. The chromosome 6 locusremains challenging to interpret due to the complexity ofthe HLA region, although a number of testis-specific geneswere observed in this locus. Genetic susceptibility for risk-taking behaviour was significantly correlated with schizo-phrenia (rg 0.27 p= 4.54n10–11), bipolar disorder (rg 0.26p= 1.73n10-4), attention-deficit hyperactivity disorder (rg0.31 p= 0.0132) and post-traumatic stress disorder (rg 0.51p= 0.0018), as well as with smoking (rg 0.17 p= 0.0102)andtotal obesity (rg 0.10 p= 0.0028).Discussion: Despite being based on only a single question,this study identified genetic determinants of risk-taking beha-viour and further demonstrated genetic correlation with psy-chiatric disorders where this trait is a feature. Although it is notclear which subtypes of risk-taking behaviour are beingassessed, these findings further our understanding of thebiology of risk-taking behaviour, a trait which has a majorimpact on a broad spectrum of physical and mental disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.356

M50. CHARACTERIZATION OF DNA METHYLATIONCHANGES IN THE PERIPHERAL BLOOD OF COCAINEAND CRACK DEPENDENTS

Caroline Camilo1, Mariana Maschietto2, Henrique C. Vieira1,Ana Carolina Tahira1, Gisele Rodrigues Gouveia1, AndréBrooking Negrão1, Marcelo Ribeiro3, Ronaldo Laranjeira3,Helena Brentani1, Homero Vallada

n,1

1University of São Paulo Medical School2Brazilian Bioscience National Laboratory, National Centerfor Research in Energy and Materials3Federal University of São Paulo

Background: Abuse and dependence on cocaine and itssmoked form, crack, is an important public health problem.To better understand the interaction between genes and the

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environment, we analyzed methylation changes in theperipheral blood of cocaine/crack dependents.Methods: The DNA methylation pattern in the peripheralblood of 23 cocaine and crack dependents and 24 healthycontrol subjects, all males with an age range of 23 to 29years, were characterized in the Illumina Infinium Human-Methylation450 BeadChip arrays. After identifying the dif-ferentially methylated positions (DMPs) (ChAMP andRnBeads), the closest genes were annotated and function-ally explored under a network perspective using STRING.These networks were annotated for biological processes andcellular signaling pathways.Results: ChAMP revealed 249 DMPs, being 108 hyper-methylated and 141 hypomethylated (adjPo10-5), whilstRnBeads showed 361 DMPs, being 69 hypermethylated and292 hypomethylated (adjPo10-5) with an overlap of 186DMPs (61 hypermethylated and 125 hypomethylated)related to 153 genes. We also identified four differentiallymethylated regions located in CpG islands, 48 in promo-ters, 37 in the gene body and 29 in genome-wide tilingregions. The 153 genes were enriched for immuneresponse, transcriptional regulation and signal transduc-tion pathways, regulation of gene expression, develop-ment and metabolic biological processes. The PPI networkanalyses identified three parenting modules which wereenriched for chromatin modification, negative regulationof protein polymerization, insulin receptor signaling path-way and positive regulation of protein dephosphorilation.The network analyses revealed the hub genes (the 5 or10% more connected genes): EHMT2, MAPK3, MAPK,EHMT1, MYB, RUNX2, FBXW7 and HDAC5.Discussion: Genes related to changes in the methylationin the peripheral blood probably associated with the use ofcrack were enriched for signaling pathways and biologicalprocesses related to chromatin regulation. These resultscould help to understand the mechanisms involved in theinteraction between biological and environmental factors ofabuse/dependence behavior, mainly towards cocaine/crackabuse.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.357

M51. DOES IT MATTER WHICH CELLS WE USE IN DNAMETHYLATION ANALYSES OF GLUCOCORTICOID SIGNAL-ING GENES?

Zsofia Nemodan,1, Wei-Jo Yu2, Jessica Di Sante3,

Matthew Suderman4, Emese Kruk5, Kata Fazekas5,Zsolt Unoka5, Richard Ernest Tremblay3, Moshe Szyf2,Linda Booij3

1MTA TKI2McGill University3University of Montreal4University of Bristol5Semmelweis University

Background: Numerous studies have been using periph-eral tissues (e.g., blood or saliva) for DNA methylationanalyses in psychiatric epigenetics. The glucocorticoidreceptor gene (NR3C1) was among the first ones to showDNA methylation changes due to adverse social environ-ment. Importantly, the NR3C1 gene has several alternativepromoters, out of which the 1-F showed increased DNAmethylation level at a transcription factor binding site.Afterwards, its co-chaperone molecule, FK506-binding pro-tein 5 (FKBP5) gained interest, showing allele-specificdemetylation in its glucocorticoid response element of the7th intron. This decreased methylation at FKBP5 can lead toNR3C1 resistance, because of an impaired intracellularnegative feedback loop.Methods: While it is now standard for epigenome-wideDNA methylation analyses to control for cell heterogeneityusing cell count estimates derived from the DNA methyla-tion profiles, this important technical variable of cellcomposition is rarely included in candidate gene analyses.Therefore, we aimed to (1) develop a panel of pyrosequen-cing assays for cell-specific CG-sites, and (2) evaluate theeffect of cell ratio on DNA methylation levels of candidategene regions in frequently used peripheral tissues, such asWhole Blood (WB), Peripheral Blood Mononuclear Cell(PBMC), as well as non-invasively collected buccal,mouthwash, and saliva samples in two cohorts. Sampleswere collected from 51 adults participating in a Montreal-based longitudinal cohort, out of which 16 men had beenassessed twice. In addition, 38 female patients with border-line personality disorder and 21 control women wererecruited at a psychiatric clinic in Budapest. Candidategene regions of the NR3C1-1F and FKBP5-intron7, as well astissue-specific CG-sites were assessed by pyrosequencing atboth sites.Results: The DNA methylation level of the CG-island in theNR3C1-1F promoter region showed little variance in all ofthe tissue types we investigated. However, the low CG-density region of FKBP5-intron7 was highly variable acrosssamples, especially in saliva. Notably, methylation level ofthe epithelial cell marker PTPN7 cg18384097 varied widelyamong the mouth-related samples in both cohorts (rangingfrom 9%-95%), even in buccal swab samples, where therewas � 80% buccal cell ratio on average with 10–12% SD. Theeffect of epithelial cell composition was substantial onFKBP5-intron7 methylation levels in saliva and mouthwashsamples (r=0.5–0.7), but it was less pronounced in buccalswab samples (r=0.2–0.4). Higher ratio of epithelial cellsresulted in lower methylation level at the studied FKBP5CG-sites. Importantly, the stability of the DNA methylationlevel of this gene region was significant both in saliva andbuccal swab samples (r=0.6–0.8, po0.01). In addition,methylation level of the T lymphocyte marker CD3Ecg06164961 also showed correlation with FKBP5-intron7methylation in blood samples (WB: r=0.5–0.7, PBMC:r=0.3–0.5).Discussion: Our preliminary results show that cell com-position should be taken into account at candidate geneDNA methylation analyses, especially when measuring lowCG-density regions in heterogeneous peripheral tissues,such as whole blood or saliva. Using more homogeneousbiological samples, e.g., PBMC or purified leukocytes wouldresult in less technical variability. The non-invasively

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obtained buccal swabs can also yield a relatively homo-geneous surrogate sample in psychiatric epigenetics.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.358

M52. CONVERGENT METHYLOMIC SIGNATURESBETWEEN AUTISM ASSOCIATED WITH DUPLICATIONSOF CHROMOSOME 15Q AND IDIOPATHIC AUTISM

Chloe Chung Yi Wongn,1, Rebecca G. Smith2, Eilis Hannon2,

Elham Assary1, Neelroop Parikshak3, Shyam Prabhakar4,Daniel Geschwind5, Jonathan Mill6

1Institute of Psychiatry, Psychology, & Neuroscience, King'sCollege London2University of Exeter Medical School3University of California Los Angeles4Computational and Systems Biology, Genome Institute ofSingapore5University of California Los Angeles School of Medicine6University of Exeter

Background: Autism Spectrum Disorder (ASD) includes aspectrum of genetically and clinically complex neurodevelop-mental disorders. Findings from recent discordant monozygotictwins and post-mortem brain studies suggest that alteredepigenetic processes, including DNA methylation and histoneacetylation, are involved in the etiology of ASD. This studypresents, to our knowledge, the largest post-mortem genome-wide DNA methylation analyses of autism patients, includingidiopathic ASD and chromosome 15q11.2-13.1 duplication syn-drome (dup15q) carriers, and matched controls.Methods: We performed methylomic profiling in humanpost-mortem brain tissues using samples from three brainregions (dorsolateral prefrontal cortex, primary auditorycortex and cerebellum) of idiopathic autism cases, dup15qcariers and matched controls using the Illumina InfiniumHumanMethylation450 array. Following stringent qualitycontrol and data pre-processing ASD-associated differentialmethylation analyses were performed at both probe-wiseand region-wise levels.Results: Our analyses revealed ASD-associated dysregula-tion of DNA methylation at multiple loci, with a largenumber of cross-cortex significant differentially methylatedprobes. In addition, although the differential methylationobserved in dup15q samples were much more pronouncedthan those from iASD samples, we observed a convergent ofmethylomic signatures between autism associated withduplications of chromosome 15q and idiopathic autism.Discussion: This epigenome-wide study of autism usingpost-mortem tissues represents the most comprehensivestudy to date. Findings from this study further support arole of altered epigenetics signatures in ASD and providenovel insight that idiopathic ASD and a genetically definedform of ASD (i.e. dup15q) carry similar underlying epige-netics changes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.359

M53. EPIGENETIC DIFFERENCES IN CORD BLOOD OFNEWBORNS EXPOSED TO ANTIDEPRESSANT MEDICATIONDURING PREGNANCY – A STUDY IN THE AARHUS BIRTHCOHORT

Nicklas Staunstrupn,1, Anne-Cathrine Viuff2, Gemma Sharp3,

Lars Pedersen2, Kasper Kyng2, Dheeraj Rai4,Caroline Relton4, Tine Henriksen2

1Aarhus University2Aarhus University Hospital3Bristol University4School of Social and Community Medicine, BristolUniversity

Background: Depression is common during pregnancy andincreasing numbers of women are being prescribed antide-pressant medications during pregnancy - especially SelectiveSerotonin Reuptake Inhibitors (SSRIs). There is emergingevidence suggesting that maternal use of SSRIs may beassociated with an increased risk of congenital defects andadverse neurodevelopmental outcomes. One suggestion isthat prenatal exposure to maternal depression or SSRIs mightinfluence offspring health through a mechanism involvingDNA methylation. The aim of this study was to investigate theassociation between SSRI exposure during pregnancy andmethylation changes in the cord blood of the newborn.Methods: We measured DNA methylation at over 850,000CpG sites in cord blood from 176 newborns in the AarhusBirth Cohort, selected according to maternal depression orSSRI use status. We carried out epigenome-wide associationstudies to compare DNA methylation between three groups:(1) SSRI use during pregnancy (n=88); (2) non-medicateddepression during pregnancy (n=44); (3) unexposed=nodepression or SSRI use during pregnancy (n=44). We per-formed a single-site regression analysis and a regionalanalysis adjusting the results for the following covariates:Maternal smoking, parity, maternal age at delivery, the useof other types of medication and Socio-Economic Status(SES), batch effects, and estimated cell composition.Results: We found 99 unique Differentially MethylatedRegions (DMRs) when comparing the three exposure groups.18 DMRs were specific to the SSRI exposed compared to theunexposed, and 53 DMRs were specific to the depressed, non-medicated group vs. the unexposed. 27 DMRs were specific tothe SSRI exposed compared to the non-medicated, depressedgroup. Finally, 1 DMR was found in both the SSRI exposedgroup and the depressed, non-medicated group.Discussion: Prenatal exposure to untreated depressionwas associated with more DNA methylation differences inthe newborn than prenatal exposure to SSRIs. Furtherresearch is warranted to confirm these findings and inves-tigate causality.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.360

M54. INTERACTIONS BETWEEN GENOTYPE AND ENVIR-ONMENT HAVE A STRONG EFFECT ON VARIABILITY INDNA METHYLATION IN PSYCHIATRIC PATIENTS

Yvonne Awaloffn,1, Nadine Provencal1, Tania Carrillo-Roa1,

Thora Halldorsdottir1, Dunlop Boadie2, Helen Mayberg2,Edward Craighed2, Darina Czamara1, Elisabeth Binder1

1Max Planck Institute of Psychiatry2Emory University

Background: Epigenetic modifications, in particular DNAmethylation, play an important role in many biologicalprocesses in human health and disease. Understanding thecause of inter-individual differences in DNA methylationlevels may help to identify novel molecular mechanismscontributing to a number of human diseases, includingpsychiatric diseases.Methods: The aim of this study was to determine whetherenvironmental risk factors for major depression (childabuse, socioeconomic status), genotype, or their interac-tion (GxE) best explain variablity in DNA methylation. Weanalyzed genome-wide DNA methylation (Illumina 450karrays) from whole blood and genotype data of fourindependent cohorts (total N=1,.253). The cohorts con-sisted of adult individuals with diverse ethnic backgrounds,ages, and psychiatric disease status.Results: We first identified the 15% most variably methylated(vm) CpGs in each cohort and observed that these vmCpGs hada higher correlation with brain methylation levels thanexpected by chance. Additionally, they were enriched inregulatory regions (including enhancer regions and specific,transcription factor binding sites). 40% (n=25.042) of thevmCpgGs overlapped between all 4 cohorts.

We next analyzed, which factors explained most of thevariance in methylation of these CpGs. While genotype aloneexplained most of the variance of about 20% of the vmCpGs,the majority of the vmCpGs were best explained by GxE (74%).E alone was almost never the model explaining most variance.

We then investigated, how consistent the GxE effects onDNA methylation were across the 4 cohorts. We found that 30%of the vmCpGs were best explained by GxE in all four cohortsand 74% in at least three cohorts. The CpGs with GxE effects inall 4 cohorts also showed even stronger enrichment forenhancer regions than vmCpGs overall.Discussion: Our study highlights the importance of consid-ering both genetic and environmental data in interpretingepigenetic variation and suggests that integrating genotypeswith epigenetic information could contribute to identifyingfunctional genetic variants that moderate the impact of riskenvironments on the development of psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.361

M55. PLEIOTROPIC EFFECTS OF GENETIC VARIATIONASSOCIATED WITH PSYCHIATRIC DISORDERS ON DNAMETHYLATION

Eilis Hannonn,1, Nick Bray2, Micheal Weedon1,

Tyler Gorrie-Stone3, Melissa Smart3, Meena Kumari3,Leo Schalkwyk3, Michael O'Donovan4, Jonathan Mill5

1University of Exeter Medical School2Cardiff University School of Medicine3University of Essex4Cardiff University5University of Exeter

Background: Success in the identification of geneticvariants associated with neuropsychiatric disorders is oneof the major achievements in contemporary biomedicalresearch. Most genetic variants identified in Genome-WideAssociation Studies (GWAS) of complex traits are thought toact via effects on gene regulation rather than directlyaltering the protein product. As a consequence, the actualgenes involved in disease are not necessarily the mostproximal to the associated variants. By integrating datafrom GWAS analyses with that from genetic studies ofregulatory variation, it is possible to identify variantspleiotropically-associated with both a complex trait andmeasures of gene regulation.Methods: In this study, we use Summary data–basedMendelian Randomization (SMR), a method developed toidentify variants pleiotropically associated with both com-plex traits and gene expression, to identify associationsbetween neuropsychiatric disorders and DNA methylation.Building on our previous efforts, we increased our catalogueof DNA Methylation Quantitative Trait Loci (mQTL) in wholeblood using the Illumina EPIC HumanMethylation array thatinterrogates over 800,000 genomic loci. These data alongwith mQTL data identified previously in human fetal brainwere used to prioritize genes for psychiatric disorders usingGWAS data from the Psychiatric Genomics Consortium(PGC).Results: In this study, we apply the SMR approach to test129,469 DNA methylation sites against five psychiatricphenotypes (schizophrenia, bipolar disorder, major depres-sive disorder, autism, ADHD) with robust GWAS data avail-able from the PGC using mQTLs identified in whole blood(n=1,175; mQTL P o 1� 10-10) to identify novel associa-tions with psychiatric traits. In addition, we tested 9,261DNA methylation sites using mQTL identified in fetal brain(n=166; mQTL P o 1� 10-8). In total, we identified 107associations with 37 satisfied addition criteria to be definedas pleiotropic and not an artefact of linkage disequilibrium.Discussion: We identify multiple examples of variableDNA methylation associated with GWAS variants across thefive psychiatric disorders, demonstrating the utility of theSMR approach for refining genetic association signals.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.362

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M56. WHAT SHAPES THE CHILD'S EPIGENOME: GENO-TYPE, PRENATAL ENVIRONMENT OR BOTH?

Darina Czamaran,1, Goekcen Eraslan2, Anna Suarez3,

Polina Girchenko3, Jari Lahti3, Marius Lahti3,Esa Hämäläinen3, Eero Kajantie4, Hannele Laivuori5,Rebecca M. Reynolds6, Ivan Kondofersky2, Nikola S. Müller7,Fabian J. Theis2, Katri Räikkönen3, Elisabeth B. Binder1

1Max Planck Institute of Psychiatry2Institute of Computational Biology, Helmholtz-ZentrumMünchen, German Research Center for EnvironmentalHealth3University of Helsinki4Oulu University Hospital,University of Oulu, PEDEGOResearch Unit5Medical and Clinical Genetics and Obstetrics and Gynecol-ogy, University of Helsinki, Helsinki University Hospital6British Heart Foundation Centre for CardiovascularScience, Queen's Medical Research Institute, University ofEdinburgh7Institute of Computational Biology, Helmholtz-ZentrumMünchen, German Research Center for Environmental Health

Background: Prenatal programming describes the processin which environmental events during pregnancy shape anddetermine the development of the embryo with on-goingimplications until adulthood. One main trigger of thisprocess is epigenetic changes, for example in DNA methyla-tion. We also know that the genome plays an important rolein the regulation of DNA-methylation and de-methylationand a variety of studies have identified meQTLs (methyla-tion quantitative trait loci), i.e. SNPs that are significantlyassociated with methylation status.

We evaluated whether the prenatal environment, geno-type and prenatal environment or genotype x prenatalenvironment interaction was the best predictor of methyla-tion levels in the child's epigenome.Methods: We assessed epigenome-wide DNA-methylationlevels and genome-wide SNP-genotypes from 817 Finnish cordblood samples from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO)cohort. Ten different prenatal environments with regard toprenatal stress (depression score, anxiety score, betametha-sone intake), general maternal factors (maternal age, deliv-ery mode, parity) as well as the mother's metabolism (pre-pregnancy BMI, maternal hypertension, gestational diabetes,oral glucose tolerance test) were investigated.

Focusing on Variably Methylated Regions (VMRs) and oncis-effects (maximal distance of 1MB between SNP and CpG-site), we tested if environment, SNP-genotype, genotype andenvironment or genotype x environment interaction bestfitted VMR methylation levels. We applied DeepSea, amachine-learning based method, on the top results toidentify functionally relevant SNPs.Results: 44% of all VMRs were best explained by SNPgenotype alone, 32% by SNP x environment interaction and24% by additive effects of SNP and environment. Environmentalone was only once the best predictor. 8,124 (0.1%) of allinvestigated SNPs were predicted to be of functional sig-nificance. Functionally relevant meQTL-SNPs were located in

close proximity to the specific CpG-site and enriched inpromoter regions. Functionally relevant SNPs involved ingenotype x environment models showed much broader peaksaround the CpGs and were enriched for distal intergenicregions. Both SNP groups show different patterns with regardto enrichment for specific transcription factor binding sites.Discussion: Our results suggest that either genotype,genotype and environment or genotype x environment butnot environment alone predict variable methylation innewborn cord blood. Therefore, it is important to includeenvironmental outcomes and genotypic data in epigeneticstudies. Furthermore, while meQTLs were enriched inpromoter regions, the broader peaks of SNPs involved ininteraction models suggest long-distance effects are presentin GxE interactions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.363

M57. DNA METHYLATION OF APBA3 AND MCF2 INBORDERLINE PERSONALITY DISORDER: POTENTIALBIOMARKERS FOR RESPONSE TO PSYCHOTHERAPY

Vanessa Nieratschkern

, Nora Knoblich, Friederike Gundel,Christof Brückmann, Julia Becker-Sadzio,Christian Frischholz

University of Tuebingen

Background: Borderline Personality Disorder (BPD) is asevere and complex mental disease associated with highsuicidal tendencies and hospitalization rates. Accumulatingevidence suggests that epigenetic mechanisms are impli-cated in the etiology of BPD. A recent epigenome-widestudy identified several novel genes, which are epigeneti-cally dysregulated in BPD. Those genes include APBA3, MCF2and NINJ2. Psychotherapy such as Dialectical BehaviorTherapy (DBT), an established treatment for BPD, providesan excellent setting to investigate environmental influenceson epigenetic mechanisms in order to identify biomarkersfor disease status and therapy success. However, the effectsof DBT on epigenetic regulation have only been researchedin one previous study analyzing BDNF. In the present study,we aimed to investigate the role of DNA methylation ofAPBA3, MCF2 and NINJ2 as possible biomarkers for treat-ment-outcome in BPD, whilst validating the previous find-ings of differential DNA methylation in a cohort of 44 BPDpatients and 44 well matched healthy control individuals.Methods: The sample was comprised of 44 BPD patientshospitalized for a 12-week DBT program and 44 age andgender matched healthy control individuals. Phenotypicinformation about patients and control individuals wasobtained by self-administered questionnaires. DNA methy-lation was assessed by pyrosequencing.Results: Unexpectedly, we did not detect significant DNAmethylation differences between patients and control indi-viduals. However, we found a high correlation between themethylation status of APBA3 and MCF2 and therapy

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outcome: before DBT treatment, both genes were signifi-cantly higher methylated in patients responding to therapycompared to patients that did not respond.Discussion: Our study is the first to report results pointingto possible predictive epigenetic biomarkers of DBT out-come in BPD patients. Following replication in independentcohorts our finding could facilitate the development of morepersonalized therapy concepts for BPD patients by includingepigenetic information.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.364

M58. FUNCTIONAL ANALYSIS OF THE SCHIZOPHRENIAASSOCIATED GENE AS3MT IN SH-SY5Y NEUROBLASTOMACELLS

Sam Washern

, Joe Burrage, Jonathan Mill, Aaron Jeffries,Emma Dempster

University of Exeter

Background: Schizophrenia is a neuropsychiatric disorderwith a prevalence of 1%, characterised by episodes ofpsychosis and an alteration in cognitive function. Theaetiology of Schizophrenia is still largely unknown butevidence suggests an underlying neurodevelopmentalaspect despite onset occurring in adulthood as well as aconsiderable genetic burden. Recently 108 genomic locihave robustly been associated with Schizophrenia. However,of these identified genes, very few have been characterisedfor their role in brain development.

Arsenite Methyltransferase (AS3MT) is located inthe10q24.32 GWAS locus, which is the most statisticallysignificant locus outside the Major Histocompatibility Com-plex (MHC) region associated with schizophrenia. Further-more, both mQTLs and expression quantitative trait loci(eQTL) map to this gene and a recent publication hasidentified an alternative splice variant which is increasedin schizophrenia brain. AS3MT encodes for a methyltransfer-ase involved in arsenic metabolism, however the role ofAS3MT in brain development has not been explored.Methods: CRISPR-Cas9 technology was used to create aknockout cell line of AS3MT in SH-SY5Y neuroblastoma cells.Two guide RNAs (gRNA) were designed, one to cut in exon4 and one in exon 6 of the AS3MT gene, where themethyltransferase domain is located. These guides werecloned into two expression vectors which express the gRNA,Cas9 enzyme and either EGFP or mCherry. These vectorswere transfected into P11 SH-SY5Y (neuroblastoma) cell lineand screened for double fluorescence and sorted into singlecells by Fluorescent Activated Cell Sorting after 24 hours.These cells were allowed to clonally expand for 3 weeksbefore DNA was extracted for genotyping by PCR. Proteinexpression of AS3MT was measured by western blotting,gene expression by RT-PCR and DNA methylation by theIlumina EPIC array. Immunocytochemistry techniques will beused to identify any alterations in cell morphology.

Results: Of the cells transfected with EGPF and mCherryexpressing CRISPR-Cas9 vectors 15.5% of the single sortedcells expressed both EGPF and mCherry and were sortedinto 96 well plates. Following a week of clonal expansionapproximately 38% of wells contained colonies, where 41%un-transfected control sorted cells had colonies. Followinggenotyping 27.8% (5/18) were identified as heterozygousmutants, 16.7% (3/18) were homozygous mutants and 55.6%(10/18) were wild type.Discussion: We have developed a robust protocol forcreating deletion mutants using CRISPR-Cas9 technologyand a functional domain of AS3MT has been deleted in theneuroblastoma cell line SH-SY5Y using CRISPR-Cas9 technol-ogy, further work is ongoing to characterise the molecularconsequences of this mutation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.365

M59. CHRONIC PSYCHOSOCIAL STRESS IN MICE ALTERSBRAIN MYELINATION IN A GENETIC BACKGROUNDDEPENDENT MANNER

Iiris Hovattan

, Mikaela Laine, Kalevi Trontti,Zuzanna Misiewicz, Natalia Kulesskaya, Suvi Saarnio,Eija Jokitalo, Dario Greco, Ingrid Balcells, Ewa Sokolowska

University of Helsinki

Background: Chronic psychosocial stress is a well-estab-lished risk factor for anxiety disorders and major depres-sion. Mechanisms by which chronic stress impactssusceptibility and resilience to psychiatric disorders arelargely unknown. The Chronic Social Defeat Stress (CSDS)mouse model allows us to investigate resilience and sus-ceptibility to chronic psychosocial stress, in a controlledmanner not possible in human settings. It involves daily 5–10 minute confrontations of two conspecific male mice usingthe resident-intruder paradigm for 10 days. This naturalisticstress model leads to long-term plastic changes in the brain,and consequently the defeated mice show increased depres-sion and anxiety-like behavior. Importantly, not all miceshow the typical social avoidance phenotype after CSDS.The defeated animals can be divided into stress susceptibleand resilient, allowing us to investigate mechanisms thatmake individuals resistant to behavioral effects of stress.Methods: To identify brain gene expression changes takingplace after chronic psychosocial stress, we used CSDS, andcarried out RNA-seq from Medial Prefrontal Cortex (mPFC)and Ventral Hippocampus (vHPC) of C57BL/6 (B6; a non-anxious inbred strain) and DBA/2 (D2; an anxious inbredstrain) mice. To establish whether and how myelin thicknessand structure are altered after stress, we carried outTransmission Electron Microscopy (TEM).Results: The two mouse strains showed a distinct beha-vioral response to stress, as measured by the social avoid-ance test carried out after social defeat. 69% of the B6 micebut only 11% of D2 mice were resilient to stress, the

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remainder being susceptible. We discovered that theexpression levels of several myelination-related genes dif-fered substantially due to chronic stress in both brainregions, and ‘myelination’ pathway was over-representedin gene-set enrichment analysis. Using TEM we establishedthat the B6 stress resilient mice had significantly thickermyelin of small diameter mPFC axons compared to the B6control mice. In the vHPC susceptible B6 mice had thinnermyelin compared to B6 control mice. D2 resilient mice hadthinner myelin in both brain regions compared to controls orsusceptible mice.Discussion: Our findings suggest significant white matterplasticity in response to chronic psychosocial stress in mice.Such differences have previously been observed in responseto early-life stress or social isolation in adult mice. Ourresults extend these previous findings to psychosocial stress,and demonstrate that the pattern of myelination differ-ences is dependent on the genetic background and variesacross brain regions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.366

M60. EXPRESSION SIGNATURE ASSOCIATED WITH COR-TICAL MATURATION AND ITS POTENTIAL ASSOCIATIONWITH GENETIC RISK FOR SCHIZOPHRENIA

Rodrigo Duarten,1, Timothy Powell1, Greg Anderson1,

Sang Lee1, Gerome Breen1, Douglas Nixon2, Robin Murray1,Nick Bray3, Deepak Srivastava1

1King's College London2George Washington University3Cardiff University School of Medicine

Background: The human neural progenitor cell lineCTX0E16 is a robust source of forebrain-like glutamatergiccortical neurons that display intrinsic functional properties(Anderson et al., 2015, Stem Cell Res). This cell line wasobtained from the embryonic cortex of a 12-week gestationXY fetus, and conditionally immortalised by ectopic expres-sion of the c-MycER TAM transgene. This construct allowsthe stem cells to be maintained in a proliferative stateunder the presence of hydroxytamoxifen (4-OHT), whileremoval of 4-OHT and growth factors stimulates progenitordifferentiation. The cortex is generally smaller in schizo-phrenia patients, and understanding the global gene expres-sion changes occurring during cortical development, and itsrelationship to genetic risk for schizophrenia, might revealclues as to which genetic mechanisms are responsible formediating the differences observed in patients. Our hypoth-esis is that neurodevelopmental diseases such as schizo-phrenia might share a genetic component with processesdriving early cortical maturation, which can be modelledin vitro.Methods: The CTX0E16 cell line was provided byReNeuron and total RNA was extracted from proliferatingneural progenitor cells (NPCs, n=3) and from cells that

underwent a 28-day differentiation protocol (n=3). RNAsamples were then processed on Illumina HT12 v4 chips.Raw fluorescence probe intensity values were extractedusing GenomeStudio, and were subsequently background-corrected and log-transformed in R using the lumi package.Differentially expressed probes were determined usingt-tests and the false-discovery rate of multiple testingcorrection was applied (qo0.05). Genes surviving correc-tion were submitted to Gene Ontology (GO) analysis. Gene-set enrichment analysis (MAGMA) was also used to investi-gate if the list of differentially expressed genes showedpositive associative enrichment for genes associated withschizophrenia in genome-wide association studies (GWAS).Results: We expect to identify and annotate sets of genesinvolved in cortical maturation that are additionallyinvolved in the aetiology of schizophrenia.Discussion: The discussion will focus on the role ofcortical maturation as a process that may be involved inschizophrenia aetiology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.367

M61. SITES OF ACTIVE GENE REGULATION IN THEDEVELOPING HUMAN BRAIN AND THEIR ROLE INNEUROPSYCHIATRIC DISORDERS

Manuela Kouakoun,1, Jonathan Mill2, Matthew Hill3,

Nick Bray1

1Cardiff University School of Medicine2University of Exeter3Cardiff University

Background: Neuropsychiatric conditions such as schizo-phrenia and autism are complex disorders with a neurode-velopmental origin. Most common risk loci for thesedisorders are located in non-coding regions of the genomeand are likely to index functional variants that alter generegulation rather than protein structure. Identifying regu-latory genomic regions active in the developing human brainwill therefore be important for elucidating genetic mechan-isms underpinning these conditions.Methods: We sought to identify sites of open chromatin,indicative of active regulatory regions, in frontal lobe fromtwo samples from the 2nd trimester of gestation using theAssay for Transposase-Accessible Chromatin with highthroughput sequencing (ATAC-seq). Nuclei from frozen braintissue were isolated by ultracentrifugation, followed byFACS to separate NeuN+ and Ki67+ cells. ATAC-seq librarieswere sequenced on a HiSeq. 4000 and data analyzedfollowing the ENCODE pipeline.Results: We have identified regulatory genomic regionsthat are active in the prenatal human brain. We will test forenrichment of polygenic signal for psychiatric disorders suchas schizophrenia within these regions.Discussion: These data advance our understanding ofgene regulation within cells from the developing human

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brain. Identifying risk variants for psychiatric disorderswithin regulatory regions active in the human fetal brainwill help elucidate neurodevelopmental risk mechanisms forthese conditions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.368

M62. TWO SIDES OF THE SAME COIN: SHARED POLY-GENIC RISK OF PERSONALITY TRAITS AND SUICIDEATTEMPT IMPLICATES COMMON PATHOMECHANISMS INIMPAIRED EXECUTIVE FUNCTIONING AND EXTERNALIZ-ING DISORDERS

Attila Pulayn

, János Réthelyi

Semmelweis University

Background: Suicide undoubtedly is the most devastatingcomplications of psychiatric disorders. The link betweensuicide and mental health problems is strong, particularlyfor mood disorders and personality disorders. Growingevidence suggest large extent of shared etiology andpsychopathology between psychiatric and personality dis-orders, even indicating the theory of a unified, generalpsychopathological dimension behind all mental disorder.However, little is known about the common genetic riskfactors of personality traits and suicidal behavior. The aimof our study was to assess the extent of the shared geneticetiology between suicidal behavior and the NEO Big Fivepersonality traits (NEO-FFI) by conducting a Polygenic RiskScore prediction (PRS) analysis.Methods: Target sample of the PRS analysis includedsubject with BPD from the GAIN Whole Genome AssociationStudy of Bipolar Disorder (accession: phs000017.v3.p1, totaln=999, suicidal n=358, control n=616, missing n=25)Suicidal attempt was assessed with the Diagnostic Interviewfor Genetic Studies versions 2,3 and 4. To increase thegenomic overlap between the training and target datasets,GAIN BPD samples were imputed by using SHAPEIT andIMPUTE2 with 1000 Genomes Project's Phase I v3 referencegenome. SNP-based associations were tested with PLINK,whereas PRS analyses were carried out by using PRSice. PRSscores for each NEO-FFI personality traits were computedfrom the publicly available summary result files of the firstphase of the Genetics of Personality Consortium GWASmeta-analysis (GPC1, 10 cohorts, n=17,375 subjects). AllPRS models were adjusted for sex, age and potentialpopulation stratification.Results: Nominally significant PRS prediction of suicidalattempt in the target sample were only shown for Con-scientiousness at pto0.58 (Nagelkerke R2=0.0081,p=0.0015) and Extraversion at pto0.01 (NagelkerkeR2=0.0058, p=0.043). PRS scores derived from the NEO-FFI Openness to Experience, Agreeableness or Neuroticismdid not predict suicidal attempt significantly.Discussion: Polygenic profile score analysis suggest sharedgenetic etiology between suicidal attempt and certain

personality traits. Since Conscientiousness kinks both exter-nalizing and internalizing behaviors, and low Conscientious-ness scores and high Extraversion scores correlate withimpaired executive functioning, our findings confirm theinvolvement of executive functions in the pathomechanismof suicide and support the theory of a general psychopatho-logic dimension. However, due to the relatively small size ofthe target sample, and the modest strength of PRS predic-tions, our findings should be interpreted cautiously.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.369

M63. IDENTIFICATION OF GENETIC VARIANTS FORSUICIDAL BEHAVIORS IN PATIENTS WITH BIPOLAROR MAJOR DEPRESSIVE DISORDERS

Mei-Hsin Sun,1, Yu-Li Liu2, Shih-Jen Tsai3, Ru-Band Lu4,

Yi-Hang Chiu5, Hsi-Chung Chen6, Yung Feng7,Amrita Chattopadhyay8, Tzu-Pin Lu9, Po-Hsiu Kuo9

1National Taiwan University2Center for Neuropsychiatric Research, National HealthResearch Institutes3National Yang-Ming University4Institute of Behavioral Medicine, College of Medicine,National Cheng Kung University5Wan Fang Medical Center6National Taiwan University Hospital7Far Eastern Memorial Hospital8Center of Genomic Medicine, National Taiwan University9College of Public Health, National Taiwan University

Background: Suicide is the second leading cause of deathin young adults, and is accounted for 1.4 percent of alldeaths worldwide. More than 90% of suicide attempters orvictims had been diagnosed with psychiatric disorders,particularly Major Depressive Disorder (MDD) and BipolarDisorder (BD). Suicidal behaviour has substantial heritabil-ity, however, the underlying etiology of patients diagnosedwith different mood disorders may not identical. In thecurrent study, we adopted the Genome-Wide AssociationStudy design (GWAS) to identify genetic variants associatedwith suicidal behaviors in patients with BD or MDD. Our goalis to identify possible common and unique genetic variantsthat might be associated to suicidal behavior between thetwo patient groups. We further test the predictive abilityfor suicide in the MDD group by using the calculatedPolygenic Risk Score (PRS) for suicide in BD patients andvice versa.Methods: We recruited 662 BD and 428 MDD patients inTaiwan, who were referred by psychiatrists based on DSM-IVcriteria. BD patients were interviewed to collect informa-tion of demographic, clinical characteristics, and suicidalbehaviors. In addition, the suicide item in Hamilton depres-sion rating scale was used to obtain suicide information forMDD patients. Genotyping was conducted using AffymetrixCHB1 chip for BD, and Illumina Human Omni Express Exome

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bead chip for MDD with imputation for association analyses.Genetic association and PRS analyses were employed byPlink v1.07. The significance level was set at 5E-08 foradjustment of multiple comparisons, and a p-value less than1E-06 was considered suggestive association.Results: In our samples, 45% of BD and 30% of MDD subjectswere male. The onset age for BP and MDD were 18.24 and 38.04years respectively. The prevalence of suicide attempt was 35%in BD group and 43% in MDD group. There were no loci thatreached the genome-wide significance level for suicidal beha-vior in BP patients. The most significant marker was rs34945506(p=4.13E-06) located in RCSD1 gene on chromosome 1. In MDDgroup, marker rs76015177 (p=9.94E-07) showed suggestiveassociation with suicidal behavior. This marker is located onchromosome 9 and is not mapped to any coding gene. Therewere no common SNPs associated with suicidal behavior in theMDD and BP groups.Discussion: Genetic variants that showed suggestive signalswith suicidal behavior in the present study were not reported inprevious studies. However, due to limited sample size, thepower of this study was only moderate, and large-scalereplication studies are needed for further validation. Onemapped gene, RCSD1, has been reported to regulate the abilityof F-actin-capping protein to remodel actin filament assemblyvia stress-induced phosphorylation. Actin was found to berelated to some neurodegeneration diseases, such as Alzhei-mer's disease. For MDD, two suggestive markers (rs78434258and rs79070953) on chromosome 9 are found near to the mostsignificant marker (rs76015177) were located on LOC105375976gene, which is a non-coding RNA. However, the function of thisgene is mostly unknown. Lastly, the non-overlapping geneticresults for suicidal behaviors in the MDD and BP patients mayindicate different pathogenesis and biological pathways forsuicide by different diagnosis groups.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.370

M64. POLYGENIC RISK FOR ANXIETY SHAPES PATTERNSOF COMORBIDITY IN BIPOLAR DISORDER

Fabiana Lopesn,1, Liping Hou2, Lexie Wille2, Layla Kassem1,

Francis McMahon2

1National Institute of Mental Health2National Institute of Health, National Institute of MentalHealth

Background: Anxiety disorders are one of the mostcommon comorbid conditions in people with bipolar dis-order and are associated with unfavorable outcomes,including increased recurrence, higher rates of alcohol andsubstance abuse, and more frequent suicide attempts.However, the causal direction has remained unclear: Doespoorer outcome lead to anxiety, or does comorbid anxietyresult in poorer outcomes?Methods: Here we used a Polygenic Risk Score (PGS) foranxiety to approach this question in a sample of 1754 adults

with bipolar I or schizoaffective bipolar disorder previouslycharacterized by the Diagnostic Interview for GeneticStudies (DIGS) and genotyped on Affymetrix 6.0 arrays.Anxiety PGS was calculated on the basis of results fromthe largest published GWAS meta-analysis of anxiety dis-orders (Otowa et al., 2016). Markers were LD clumped andthe p-value threshold was set at 1. First we examinedanxiety disorder comorbidity by creating a categorical‘anxiety disorders’ variable comprising any DSM anxietydisorder diagnosis.Results: Anxiety PGS was significantly associated with anxi-ety comorbidity (X2=7.756, df=1, po0.05; rsq=0.004). Next,we explored the contribution of individual anxiety disorderdiagnoses to this association. Significant contributions weredetected for obsessive-compulsive disorder (X2=6.179; df=1,OR=1.006, p=0.013), simple phobia (X2=6.178; df=1,OR=1.006; p=0.013), and social phobia (X2=4.21, df=1,OR=1.005, p=0.040), all with similar odds ratios. Neitherpanic disorder nor agoraphobia were associated with anxietyPGS, even though they were among the most common anxietydisorder comorbidities in this sample. We also explored somecommon non-anxiety comorbidities. Anxiety PGS was signifi-cantly associated with comorbid anorexia (X2=.9.72, df=1,OR=1.009, p=0.002), but not with alcohol or substance usedisorders. Finally, we explored several clinical features ofbipolar disorder. Anxiety PGS was significantly associated withmania at onset (X2=4.66, df=1, OR=0.0096, p=0.03), but notwith frequency of episodes, psychotic features, age at onset, orsuicide attempts.Discussion: Taken together, these findings indicate thatgenetic risk for anxiety contributes to patterns of comor-bidity in bipolar disorder, increasing risk for some anxietydisorders and for anorexia. Other common comorbiditiesand clinical features appear unrelated to genetic risk foranxiety, suggesting distinct etiologies.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.371

M65. EXOME SEQUENCING OF MULTIPLEX PEDIGREESWITH EARLY ONSET, RECURRENT MAJOR DEPRESSIVEDISORDER

Marc Kealhofern,1, Mehdi Pirooznia2, Martin Tehan2,

Peter Zandi2, Fernando Goes2

1Johns Hopkins Bloomberg School of Public Health2Johns Hopkins University

Background: Major Depressive Disorder (MDD) is a common,often impairing disorder that ranks as the second leading causeof disability worldwide. More effective treatments are urgentlyneeded, but few novel treatments have been developed overthe last several decades, in large part due to our limitedunderstanding of the pathophysiology of MDD. A long history offamily and twin studies has shown consistent evidence forsignificant heritability in MDD and recent large scale GWASanalyses have begun to identify strongly associated common

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variants. However, few studies have so far focused on rare morepenetrant variants, which may provide more interpretableinsights into MDD related biology.Methods: We selected 25 multiplex families from theGenetics of Early Onset Depression cohort, hypothesizingthat pedigrees with at least three family members withchildhood-onset depression, would be enriched for highlypenetrant rare variants. We have completed exome sequen-cing in 3 affected members from these 25 highly multiplexfamilies to average depth of 50X. Alignment and genotypingwas performed employing standard pipelines using BWA-mem and GATK. Given prior evidence that ultra-rare varia-tion may be most likely associated with greater penetrance,we focused our analyses on "singly-segregating" variants,defined as variants that fully segregated in a single familyand were absent in all other pedigrees. Annotation wasperformed with ANNOVAR. Selected variants were con-firmed with sanger sequencing.Results: Each of the 25 multiplex families had an averageof 4,092 segregating variants of which 412 were rare(defined as minor allele frequency o 0.1%). After restrictingthe data to "singly-segregating" variants, there were 865segregating variants, including 53 genes that showed evi-dence for segregation in 2 independent families and 6 geneswith rare segregating variants in 3 families. Focusing ondisruptive variants, we found 42 segregating rare variantsincluding several genes of interest involved in calcium ionbinding (FBN3, NOX5), mitochondrial function (MTFMT,CIDEA, NOX5) and MAPK signaling (PSMB9).Discussion: Our study represents one of the first familybased exome sequencing studies of major depressionusing an early onset, multiplex sample. We have found anumber of highly damaging segregating variants that maybe associated with MDD. Additional ongoing analyses,including pathway enrichment and replication, will alsobe presented.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.372

M66. INVESTIGATING SEX DIFFERENCES IN GENETICEFFECTS ON SUBCORTICAL BRAIN STRUCTURES ANDOVERLAP WITH PSYCHIATRIC DISORDERS

Katrina Grasbyn

, The ENIGMA2 Consortium

Queensland Institute of Medical Research

Background: Brain morphometry is both heritable andcorrelated with psychiatric disorders. Notable structuraldifferences include reduced volume in subcortical struc-tures, some are observed in several disorders while othersare specific to one or two disorders. The prevalence of mostpsychiatric disorders differs markedly by sex and sexdifferences are also observed in the volume of subcorticalstructures. Moreover, brain structure and psychiatric dis-orders are both highly heritable. Here we assess if genetic

variants influencing subcortical brain structures differbetween females and males and if the genetic overlapbetween brain structure and risk of illness differs by sex.Methods: We present preliminary results from sex-stratifiedGWAS meta-analyses on seven subcortical structures derivedfrom T1-weighted magnetic resonance imaging scans from�6000 females and �5400 males from 22 cohorts from theENIGMA consortium. This sample is a subset of the largerENIGMA consortium analyses on variation in subcortical struc-tures among �30,000 individuals. The subcortical structuresanalysed were the nucleus accumbens, amygdala, caudatenucleus, hippocampus, globus pallidus, putamen, and thalamus.The volume of these structures was calculated with validatedand freely available software, and mean volume calculatedfrom the left and right hemispheres. Genotypic data wereimputed to the 1000 genome reference panel.Results: Preliminary results in this discovery meta-analysisidentified four genome-wide significant loci, three were novel.One intergenic locus (14q22.3), which we have previouslyreported as significant in a meta-analysis that combinedfemales and males, was also associated with putamen volumein females and in males in these stratified analyses. Of thenovel loci, one was an intronic locus (11q15.2) within SPON1associated with nucleus accumbens volume in females. Thesecond was an intronic locus (2q34) within ERBB4 associatedwith amygdala volume in males. The third was an intergeniclocus (13q21.31) associated with putamen volume in males. Inthis discovery sample SNP heritability was .18 (se=.08) for thenucleus accumbens in females, was .16 (se=.08) for theputamen in females, and was .14 (se=.09) for the thalamusin males. Genetic correlations were between each of thesetraits and GWAS results from the psychiatric genetics consor-tium on schizophrenia, bipolar, major depressive disorder,anorexia, and autism were not significant. Heritability in allother structures was close to zero, thus genetic correlationswere not calculated on this discovery sample.Discussion: These preliminary results point to heterogeneitybetween females and males in genetic influence on somesubcortical structures. We plan to extend these findings withdata from the UK Biobank. We will present SNP heritability andgenetic correlation with psychiatric and cognitive traits usingthe results from the second round of meta-analysis.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.373

M67. THE 16P11.2 DISTAL COPY NUMBER VARIANTCONVEYS DOSE-RESPONSE EFFECTS ON INTRACRANIALVOLUME AND STRUCTURES OF THE BASAL GANGLIA: AMEGA-ANALYSIS FROM THE ENIGMA-CNV WORKINGGROUP

Ida Sonderbyn,1, Nhat Trung Doan2, Omar Gustafsson3,

Derrek Hibar4, Srdjan Djurovic5, Lars Tjelta Westlye2,Paul Thompson6, Ole Andreassen6, ENIGMA-CNV workinggroup

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1NORMENT, KG Jebsen Centre for Psychosis Research2NORMENT3deCODE genetics4Imaging Genetics Center, Keck School of Medicine, Uni-versity of Southern California5Oslo University Hospital6University of Oslo

Background: Carriers of large recurrent Copy NumberVariants (CNVs) have a higher risk of developing variousneurodevelopmental diseases, but their effects on the brainare largely unknown. Studies of CNV carriers may revealnew information on mechanisms of brain function anddysfunction. Even so, genotype-phenotype analysis has beenstalled as pathogenic CNVs are rare.Methods: ENIGMA-CNV is an international effort launchedto create the statistical power identify how CNVs affectbrain MRI measures, currently including �11,700 partici-pants. Here we focus on carriers of the 16p11.2 distal CNV,who are predisposed to several diseases including obesity,autism and schizophrenia. Subcortical volumes of deletion(n=6) and duplication (n=8) carriers of the 16p11.2 distalCNV were compared to a large collection of non-carriers(n=5,822).Results: We found focal negative dose-response effects ofcopy number on pallidum and putamen volumes – deepnuclei involved in learning and motor controls - and anegative dose-response effect of copy number on intracra-nial volume. The results were replicated in an independentsample.Discussion: These findings reveal a potential mechanismfor the various biological and neurodevelopmental diseasesobserved in 16p11.2 distal carriers, underlining the value oflarge-scale collaboration for studies of rare genetic variantsimplicated in brain pathology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.374

M68. THE RELATIONSHIP BETWEEN FUNCTIONAL DOPA-MINE D2 RECEPTOR HAPLOTYPES AND COGNITIVE OUT-COMES, AS MEDIATED BY REGIONAL BRAIN STRUCTURE:A COMPARISON OF CONTROL, AT-RISK, AND BIPOLARDISORDER SUBJECTS

Bronwyn J. Overs1, Rhoshel K. Lenroot1, Gloria Roberts2,Melissa J. Green2, Dusan Hadzi-Pavlovic2,Andrew Frankland2, Florence Levy2, Claudio Toma1,Peter R. Schofield1, Philip B. Mitchell2, Janice Fullerton

n,1

1Neuroscience Research Australia2School of Psychiatry, University of New South Wales

Background: Bipolar Disorder (BD) is a complex andhighly heritable mood disorder associated with a range ofcognitive deficits across all illness states. Previous researchhas demonstrated associations between the dopamine D2receptor gene (DRD2) and BD diagnosis, structural and

functional brain changes, and cognitive dysfunction. Speci-fic SNPs impacting DRD2 function have been identified:rs1800497 (Taq1A1, minor T allele) is associated withreduced striatal D2R dopamine binding; and rs1076560 andrs2283265 (minor A/T alleles) are associated with alterna-tive splicing of DRD2 exon 6, resulting in increased expres-sion of DRD2-short mRNA compared to DRD2-long isoform,and reduced inhibition of glutamate release. The presentstudy adopted a cognitive-neurogenic approach to explorethe mediating role of brain structure in the relationshipbetween DRD2 functional haplotypes and cognitiveoutcomes.Methods: Participants comprised 26 BD cases (BD-I or BD-II), 62 at-risk subjects (unaffected first-degree relatives ofBD probands), and 55 control subjects with 3 T MRI, geneticand cognitive data. DRD2 haplotypes were defined by threefunctional SNPs (rs1800497, rs1076560, rs2283265). Corticalthickness, surface area and volume were extracted forthree functionally defined regions of interest (ROIs) thatwere parcellated on the basis of resting state functionalconnectivity data – Dorsal Attention (DA), Ventral Attention(VA), and Fronto-Parietal (FP). Working memory and atten-tion were assessed using Repeatable Battery for Assessmentof Neuropsychological Status (RBANS), and intelligence (IQ)was determined using Wechsler Abbreviated Scale of Intelli-gence (WASI). A series of simple and multiple mediationmodels were implemented using SPSS PROCESS macro.These models predicted the effects of the functional DRD2haplotype on working memory, attention and intelligence,as independently and jointly mediated by cortical area,thickness and volume in the three functionally defined ROIs.Results: The frequency of CCG homozygotes versus TAAcarriers was significantly higher in at-risk subjects comparedto controls (freq=0.758 vs 0.564, p=0.013) with a trend inBD (freq=0.692, p=0.1). In the control group, CCG homo-zygotes exhibited an increase in RBANS attention scores as aresult of the mediating effects of DA area and volume (of1.6 and 1.7 standard deviations). Simple mediation effectswere also observed in the control group for IQ and RBANSimmediate memory in the absence of a significant totaleffect. In contrast, simple mediation effects were notapparent in the slightly larger at-risk group nor the BD group.While multiple mediation models reinforced many simplemediation effects observed in controls, an additional media-tion effect was observed in the BD group – TAT haplotypecarriers exhibited a 0.6 SD decrease in RBANS attentionscores as a result of the mediating effects of FP volume.Discussion: The DRD2 mediation effects observed in con-trols were absent in the at-risk and BD groups, suggestingthat the normally ameliorative effect of the CCG haplotypeon cognitive outcomes is either negated by other genetic andfamilial risk factors for BD, or is mediated by alternate brainstructures. Additionally, evidence is provided for the reversalof typically observed DRD2 effects on cognitive outcomes bythe significant mediation effect for the BD group in themultiple mediation model of attention, where carriers of theTAT haplotype demonstrated improved attention.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.375

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M69. VALIDATION OF ELECTRONIC HEALTH RECORD-BASED ASCERTAINMENT OF OBSESSIVE COMPULSIVEDISORDER CASES AND CONTROLS

Takahiro Sodan,1, James Crowley1, Emily Bruer2,

Robin Bershader2, Sarah Collier2, Emily Gantz2,Donald Hucks3, Rebecca Johnston3, Angela Maxwell-Horn3,Angelica Soto-Freita3, James Sutcliffe2, Carol Mathews4,Jeremiah Scharf5, Nancy Cox3, Lea Davis3

1University of North Carolina at Chapel Hill2Vanderbilt University3Vanderbilt University Medical Center4University of San Francisco5Massachusetts General Hospital, Harvard Medical School

Background: Obsessive-Compulsive Disorder (OCD) is acommon, disabling psychiatric disorder characterized byintrusive thoughts, images, or impulses that typically causeanxiety or distress (obsessions), and by repetitive mentalacts or behaviors that one feels compelled to do (compul-sions). Initial Genome-Wide Association Studies (GWAS) forOCD were underpowered to identify individual risk variantsbut clearly indicated that OCD is a heritable complexgenetic trait and that increased sample size will yieldsignificant loci. The use of existing Electronic MedicalRecords (EMR) in the US and other countries representsanother rapid and cost-efficient strategy to increase ascer-tainment for OCD genomic studies.Methods: BioVU is a repository of over 250,000 DNAsamples extracted from discarded blood collected duringroutine clinical testing at Vanderbilt University MedicalCenter. The DNA samples obtained are linked to a de-identified Electronic Medical Record (EMR) datamart calledthe Synthetic Derivative containing clinical informationextracted from over 2.2 million individuals in a searchableform covering the past 20 years. We thus undertook the taskof building a diagnostic algorithm for OCD which could beapplied to the EMR. To do this, we utilized ICD 9 and 10codes (300.3 and F42.n) along with Natural LanguageProcessing (NLP) to detect context-aware diagnostic key-words (e.g., Obsessive-compulsive, etc.), treatment key-words (e.g., cognitive-behavioral, etc.), and medications(e.g., fluoxetine, etc.) commonly prescribed for the treat-ment of OCD. Contextual information from 50 cases identi-fied by the algorithm was then abstracted by trained non-expert reviewers and abstracted charts were reviewed bytwo domain experts to determine the Positive PredictiveValue (PPV) of the algorithm.Results: Our algorithm identified 7,547 OCD cases in theEMR and PPV was high (4 92%) across the two reviewerswith high interrater reliability when all algorithm elementsincluding ICD codes, diagnostic keywords, and treatmentkeywords were present in case charts. We then analyzed thePPV amongst the different ways in which the cases metcriteria. Of these 7,547 potential cases, 1,528 have DNAavailable within the BioVU biobank. We are in the process ofgenotyping all of these OCD cases, along with matchedcontrols, on the Illumina MEGA array, in preparation forGWAS. Results will be meta-analyzed with those from thePGC TS/OCD Working Group.

Discussion: We have designed and validated a phenotypealgorithm for the ascertainment of OCD cases from electro-nic medical records. This algorithm can be deployed in anyEMR and we will make it freely available in a forthcomingpublication.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.376

M70. DETERMINING THE GENETIC OVERLAP BETWEENTOURETTE SYNDROME (TS), OBSESSIVE COMPULSIVEDISORDER (OCD) AND OCD/TIC-RELATED TRAITS

Joanna Widomskan,1, Janita Bralten1, Marijn Martens1,

Ward De Witte1, Ilse van de Vondervoort1, Dongmei Yu2,Carol Mathews3, Jeremiah Scharf4, Jan Buitelaar1,Jeffrey Glennon1, Barbara Franke1, Geert Poelmans1

1Radboud University Nijmegen Medical Centre2Massachussetts General Hospital3University of Florida4Massachusetts General Hospital, Harvard Medical School

Background: Tourette Syndrome (TS) and Obsessive-Com-pulsive Disorder (OCD) are heritable neuropsychiatric dis-orders with a childhood onset. TS is characterized bymultiple and involuntary motor tics and at least one vocaltic that persists for more than one year. TS has a prevalenceof 0,3-0,8%. OCD is characterized by recurring obsessionsand/or compulsions and affects up to 2% of the population.The disorders often co-occur, with their comorbidity rangingbetween 20–60%. Moreover, there are striking similarities inthe phenotypic representation of TS/tics and OCD. Previousstudies indicate that TS and OCD may share some commongenetic susceptibility factors - with an estimated geneticcorrelation of 0.41 - but also suggest that there are distinctcomponents to the genetic architectures of the two dis-orders. Two recent population-based twin sample studiesalso reported genetic correlations between tics and OCD-related traits (0.37 and 0.45). In this study we furtherinvestigated the shared genetic etiology between TS, OCD,and OCD traits as well as tic traits in the general population.Methods: We conducted a number of Polygenic Risk Score(PRS)-based analyses. For these analyses, we used thesummary statistics data from the Genome-Wide AssociationStudy (GWAS) of TS and the summary statistics from themeta-analysis of the two GWASs of OCD conducted by thePsychiatric Genomics Consortium (PGC) (unpublished, pro-vided by PGC OCD Working Group) as the 'base' sample. As'target' samples, we used summary statistics of GWASs ofOCD traits and tic traits in the general population. For theseGWASs, we used phenotypic and genotyping data from theChildren's Hospital of Philadelphia (CHOP) cohort obtainedfrom dbGaP (phs000607.v1.p1). To conduct the OCD traitGWASs, we first developed a questionnaire consisting of 22OCD trait questions and conducted a factor analysis of thequestionnaire, to reveal the subsets of OCD traits that grouptogether and may better capture the underlying genetic

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architecture. We then conducted GWASs of the total scoreon the 22 OCD trait questions and of six OCD trait factors in650 children and adolescents from the CHOP cohort. For tictraits, we conducted a GWAS on the total score on 4 tic traitquestions in 207 individuals from the CHOP cohort.Results: The factor analysis of the 22 OCD trait questionsrevealed 8 factors that constitute the best fit and explain58,6% of the variance in the total score on the 22 questions,i.e. 'impairment', 'symmetry/counting/ordering', 'contami-nation/cleaning', 'aggressive taboo thoughts (tt)', 'repeti-tion', 'guilty tt', 'distress' and 'religious tt'. The PRS-basedanalyses yielded a significant evidence for shared geneticetiology between OCD and the three OCD traits 'impairment'(1.06% variance explained (ve)), 'contamination/cleaning'(3.54% ve,) and 'guilty taboo thoughts' (5.64% ve). Further-more, we found significant shared genetic etiology betweenTS and four OCD traits: 'symmetry/counting/ordering'(3.03% ve), 'contamination/cleaning' (1.28% ve), 'aggressivetaboo thoughts' (4.96% ve) and 'distress' (1.83% ve), andbetween TS and the total score on tic traits (4.78% ve). OCDand TS did not show significant genetic overlap with thetotal score on the 22 OCD trait questions.Discussion: Our findings provide additional and novel evi-dence that certain OCD traits show genetic overlap with OCDand TS, which adds to our understanding of the genetic riskfactors that are shared by and unique to these comorbiddisorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.377

M71. HIGH-THROUGHPUT ANTIBODY-BASED PROFILINGOF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDERPATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICSPILOT STUDY

Sergi Papioln,1, David Just2, Nirmal Kannaiyan3,

Heike Anderson-Schmidt4, Monika Budde1, Katrin Gade1,Urs Heilbronner1, Moritz Rossner3, Peter Nilsson2,Thomas Schulze1

1Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich2Affinity Proteomics - SciLifeLab Stockholm, School ofBiotechnology, KTH Royal Institute of Technology3Molecular and Behavioral Neurobiology, Medical Center ofthe University of Munich4University Medical Centre Goettingen

Background: The identification of biological markers inthe peripheral blood for the prediction of the individualclinical outcome has an enormous potential in the frame ofpersonalized medicine. Previous studies have already triedto create predictive models for major psychiatric disordersbased on serum protein profiles though with inconclusiveresults. This study leverages the rich repertoire of biosam-ples available in the KFO241/PsyCourse cohort to perform a

high-throughput antibody-based serum protein profiling.The aim of this pilot study is to establish the feasibility ofsuch an analysis in the serum of these patients. This studyalso capitalizes on the availability of genomic data to carryout an integrative (genomics/proteomics) profiling.Methods: Serum samples of 113 Schizophrenia (SCZ) and125 Bipolar Disorder (BD) patients belonging to the GermanKFO241/PsyCourse cohort (www.kfo241.de; www.Psy-Course.de) were included in this study. All biomaterials inthis cohort (blood, serum, plasma, DNA, RNA), available atdifferent time points given its longitudinal design, are partof a high-end biobank. The expression of a selected panel of�100 serum proteins was determined using a set of 155antibodies in a high-throughput antibody-based assay. Thissuspension bead array technology enables a multiplexedprotein profiling and it leverages the information generatedby the Human Protein Atlas (www.proteinatlas.org). Medianfluorescent intensities were log-transformed / standardizedfor downstream analyses. DNA samples were genotyped(Infinium PsychArray) and underwent genotype imputation(1000 Genomes Phase 3 ref. panel). Polygenic Risk Scores(PRS) were calculated by summing up the weighted effect ofeach SNP contributing to the PRS to obtain an individualestimate of SCZ genetic risk burden. Age, sex and ancestryprincipal components were used as covariates.Results: Multivariate profiles based on the whole panel ofquantified proteins did not significantly discriminatebetween both diagnoses (SCZ and BD). Single-proteinANCOVA analyses revealed, after Bonferroni correction,significant differences in C4B, CFB, VWF, NRG1, BACE1 andother proteins between SCZ and BD samples. High-riskversus Low-risk patients (according to PRS thresholds 5E-8,5E-2 and 1) did not show a differential level of expression ofthese proteins. Likewise, polygenic risk did not correlatewith the serum level of any of the proteins. Suggestiveserum pQTL loci were identified.Discussion: Our results confirm the feasibility and poten-tial of this approach using serum samples of psychiatricpatients. The observed differences in protein levelsbetween diagnoses warrant replication in independentsamples controlling the effect of medication. These resultslay the groundwork for large-scale analyses for the discov-ery of predictive biomarkers of course, outcome and treat-ment response in SCZ and BD. Such an approach, joining thelongitudinal phenotyping and biosample availability at fourdifferent time points in the KFO241/PsyCourse cohort withstate-of-the-art biomarker quantification methodologies,holds promise for the generation of clinically-relevantpredictive models in complex psychiatric disorders.

Funding:

DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; Lisa-Oehler-Foundation. SP was supported by a 2016 NARSAD YoungInvestigator Grant from the Brain and Behavior ResearchFoundation. DJ and NRK were supported by the Marie-Curiefellowship from the INSENS/ FP7-PEOPLE-2013 (607616)framework.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.378

M72. GENETICS OF VACCINATION RELATED NARCOLEPSY

Hanna Ollilan,1, Annika Wennerstrom2, Markku Partinen2,

Emmanuel Mignot1, Janna Saarela3, Paivi Saavalainen4,Outi Vaarala4, Pentti Tienari5, Markus Perola6

1Stanford University School of Medicine2National Institute for Health and Welfare3Institute for Molecular Medicine Finland, University ofHelsinki4University of Helsinki5University of Helsinki, Helsinki University Central Hospital6University of Tartu, Estonian Genome Center, University ofHelsinki, Institute for Molecular Medicine, Finland (FIMM)and Diabetes and Obesity Research Program and NationalInstitute for Health and Welfare

Background: Type 1 Narcolepsy is a severe hypersomniacaused by a specific loss of neurons producing hypocretin/orexin in the hypothalamus and affecting 1/3000 indivi-duals. In 2009/2010 immunization towards pandemic H1N1Influenza-A campaign was launched and the vaccine used inNorthern European countries associated with increased riskfor narcolepsy.Methods: We built a multilocus genetic risk score withestablished narcolepsy risk variants using whole genomesequencing and exome sequencing data from 7,000 indivi-duals to examine the genetic load for narcolepsy in 75individuals with vaccination related narcolepsy, a third of allcases from Finland.Results: Previously discovered risk variants had strongpredictive power (Po2.2n10–16) in the vaccine relatednarcolepsy cases with only 4.9% of cases being assigned intothe low risk category. Furthermore, at genome-wide levelthe strongest association was seen in IL12RB1 (rs17885060,P=2.93n10-7) and ZXDC a gene required for HLA class IItranscription (rs11715293 P=7.06n10-7).Discussion: Our findings suggest that genetic risk factorshave a major role in regulating predisposition for narcolepsyand genetic risk score gives high predictive power to detectindividuals with high risk for narcolepsy.

Disclosure: Jazz Pharmaceuticals - Consultant, SelfFacebook - Consultant, Self

http://dx.doi.org/10.1016/j.euroneuro.2017.08.379

M73. CAPICE: CHILDHOOD AND ADOLESCENCE PSYCHO-PATHOLOGY: UNRAVELLING THE COMPLEX ETIOLOGY BYALARGE INTERDISCIPLINARY COLLABORATION IN EUROPE

Christel M. Middeldorpn,1, Wayne Drevets2,

Marjo-Riitta Jarvelin3, Paul Lichtenstein4,

Sebastian Lundström4, Marcus Munafo5, Robert Plomin6,Henning Tiemeier7, Stephanie M. van den Berg8,Vassilios Fanos9, Meike Bartels10,EAGLE Consortium

1Child Health Research Centre, University of Queensland2Janssen Research & Development3Imperial College London4Karolinska Institutet5University of Bristol6King's College London7Erasmus MC8University of Twente9University of Cagliari10VU Amsterdam

Background: The CAPICE project aims to 1) identifygenetic variants associated with the occurrence and courseof common childhood psychopathology including depression,anxiety and Attention Deficit Hyperactivity Disorder relatedtraits, and establish the genetic overlap within childhoodpsychiatric disorders and with adult psychiatric disorders, 2)unravel the mechanisms underlying the associationsbetween early lifestyle factors and childhood psychiatricdisorders, 3) identify new drug targets, and 4) build a riskprediction model that identifies groups of children that areat highest risk to have persistent symptoms. This posterprovides an overview of the plan to achieve these goals.Methods: CAPICE is an international training network,funded by an EU Marie Curie grant, in which 12 PhD studentswill be trained in psychiatric genomics. This network willelaborate on the EArly Genetics and Lifecourse Epidemiology(EAGLE) consortium. EAGLE is a well-established collaborationof many birth and adolescent population based (twin andfamily) cohorts, with unique longitudinal information on life-style, family environment, health, and emotional and beha-vioral problems. Phenotypic and genome-wide data areavailable for over 60,000 children, in addition to genome-widedata for over 20,000 mothers and epigenome-wide data forover 6,000 children. Analyses will include (but will not belimited to) twin analyses, genome-wide association meta-analyses, polygenic analyses, Mendelian randomization, andbiological pathway analyses.Results: We expect that the results will provide insight intothe etiology of mental health symptoms in children andadolescents and shed light on possible targets for preventionand intervention (e.g. by drug target validation or by tailoringtreatment based on the risk for persisting symptoms).Discussion: It is well known that psychiatric symptoms inchildhood be the precursor of many psychiatric disordersduring adulthood. Longitudinal population based cohortsprovide a good opportunity to show how genetic factorsinfluence development over the ages. Since these disordersare the extreme end of the continuum, collaborations withcase-control samples may strengthen the results.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.380

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M74. GENETIC CONTRIBUTIONS TO TRAIL MAKING TESTPERFORMANCE IN UK BIOBANK

Saskia Hagenaarsn,1, Simon Cox2, William Hill2, Gail Davies2,

David Liewald2, CHARGE Consortium Cognitive WorkingGroup1,2, Sarah Harris2, Andrew McIntosh2, Catharine Gale2,Ian J. Deary2

1MRC Social, Genetic & Developmental Psychiatry Centre2University of Edinburgh

Background: The Trail Making Test (TMT) is a widely usedneuropsychological test of executive function. TMT perfor-mance has been ascribed to a number of cognitive pro-cesses. Family and twin based studies have providedevidence for a genetic contribution to TMT performance.This study aims to identify genetic variants underlyingperformance of the TMT and the genetic overlap betweenTMT and other cognitive abilities.Methods: We examined the genetic architecture of TMT in23,821 individuals from UK Biobank using GWAS, GCTA-GREML, and gene-based analysis. We tested for a sharedgenetic aetiology with other cognitive abilities using geneticcorrelations and polygenic profile scores, in both UK Bio-bank, Generation Scotland, and the Lothian Birth Cohort of1936. Summary statistics based on the GWAS of TMT in theCHARGE consortium were used to created polygenic profilescores to predict TMT performance in UK Biobank.Results: The SNP-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B), and17.6% (part B – part A). Significant genetic correlations wereidentified between trail-making measures and verbal-numerical reasoning (rg 4 0.6), general cognitive function(rg 4 0.6), processing speed (rg 4 0.7), and memory (rg 40.3). Polygenic profile analysis indicated considerableshared genetic aetiology between trail making, generalcognitive function, processing speed, and memory (standar-dized β between 0.03 and 0.08).Discussion: These results, spanning methodologies andcohorts, provide strong evidence for a shared geneticarchitecture of TMT performance, general cognitive func-tion and processing speed. These findings highlight theshared genetic architecture of cognitive abilities, and sign-post new opportunities for clarifying the associationbetween cognitive ability and health, as indicated byprevious research.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.381

M75. POLYGENIC BURDEN ANALYSIS OF LONGITUDINALCLUSTERS OF PSYCHOPATHOLOGICAL FEATURES IN ACROSS-DIAGNOSTIC GROUP OF INDIVIDUALS WITHSEVERE MENTAL ILLNESS

Eva Schulten,1, Ivan Kondofersky2, Monika Budde3,

Kristina Adorjan4, Fanny Aldinger3,Heike Anderson-Schmidt5, Till F.M. Andlauer6, Katrin Gade7,

Urs Heilbronner3, Janos Kalman3, Sergi Papiol3, FabianJ. Theis2, Peter Falkai8, Nikola Müller2, Thomas G. Schulze9

1Institute for Psychiatric Phenomics and Genomics, LudwigMaximilian University2Institute of Computational Biology, Helmholtz ZentrumMunich3Institute of Psychiatric Phenomics and Genomics, MedicalCenter of the University of Munich4Institute of Psychiatric Phenomics and Genomics5University Medical Centre Goettingen6Max Planck Institute of Psychiatry7Georg-August-University8Ludwig Maximillian University9Institute of Psychiatric Phenomics and Genomics, Ludwig-MaximilianUniversity of Munich, Central Institute of MentalHealth

Background: Bipolar Disorder (BD), Schizophrenia (SZ)and Schizoaffective Disorder (SZA) are complex geneticdisorders with largely polygenic architecture and severeand overlapping psychiatric symptoms. Stratification ofcases into homogeneous subgroups across diagnoses usingboth psychometric and genetic information could identifyindividuals with higher risk for severe illness.Methods: Examined at four time points over 18-months, asubset of 198 participants (46.9712.4 yrs; 46% female) withDSM-IV diagnoses of SZ, SZA or BD from an ongoing long-itudinal cohort study (www.kfo241.de) were genotyped onIllumina's Infinium PsychArray and imputed using the1000genomes. 67 variables from the Positive and NegativeSyndrome Scale (PANSS), the Inventory of Depressive Symp-toms (IDS) and the Young Mania Rating Scale (YMRS) enteredcluster analyses. Longitudinal trajectories derived fromabstract data dimensions computed by Factor Analysis forMixed Data (FAMD) were used for clustering. SZ-polygenicrisk scores (PRS) based on the Psychiatric Genetics Con-sortium 2 SZ results were tested for cluster association at 11thresholds.Results: Two clusters were identified in the first twodimensions: (A) individuals with continuously low scores onPANSS and IDS (70.7%) and (B) individuals with consistentlyhigh scores on PANSS and IDS (29.3%). Clusters differedsignificantly with regard to Global Assessment of Function-ing (higher in (A); FDR-adjusted p-value=2.23� 10-10),while there were no significant differences regarding sex,age, diagnosis, center, age at onset, family history, durationof illness, or association with the SZ-PRS.Discussion: In this preliminary data set, longitudinalclustering identified cross-diagnostic homogeneous sub-groups. Surprisingly, more severe psychopathological fea-tures were not associated with increased genetic riskburden.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.382

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M76. A CROSS-MENTAL-DISORDERS GWAS IN THE DAN-ISH NATIONAL HEALTH REGISTER

Andrew Schorkn,1, Vivek Appadurai2, IPSYCH-BROAD Working

Group, Wes Thompson3, Alfonso Buil1, Thomas Werge2

1Institute of Biological Psychiatry2Institute of Biological Psychiatry, MHC Sct. Hans, MentalHealth Services3Research Institute for Biological Psychiatry, Mental HealthCentre Sct. Hans

Background: Quantitative psychiatric genetics has longestablished not only high heritability, but also appreciablelevels of co-heritability, or genetic correlations, amongpsychiatric disorders. More recently, it is becoming increas-ingly demonstrated that the effects of common SingleNucleotide Polymorphisms (SNPs) are likewise rarely con-fined to one psychiatric diagnosis. As such, it may bereasonable to combine psychiatric patients into a singlecross-disorder cohort with the aims of identifying SNPs thatpredispose to multiple disorders. In this study, we examinecross-disorder genetic effects in the iPsych cohort, a case-cohort collection of more than 50,000 psychiatric patientsselected by treatment records for ADHD, affective disor-ders, anorexia, autism spectrum disorders, bipolar disorder,or schizophrenia and 30,000 healthy controls.Methods: To motivate single locus cross-disorder analysiswe estimated SNP-based (co)heritability among the sixascertained psychiatric cohorts using GREML implementedin GCTA. We followed that analysis with a typical case-control GWAS, where the case group were subjects who hadreceived treatment for any psychiatric disorder and thecontrols had received treatment for no psychiatric disorder.Genome-wide significant loci were described using func-tional genomics data from the roadmap epigenetics projectand publicly available GWAS results.Results: In this study, we report moderate SNP-based (co)heritabilities for and among the six psychiatric cohorts withascertainment in the iPsych Cohort, confirming a likelypresence of cross-disorder loci. Our subsequent cross-dis-order GWAS revealed four genome-wide significant loci withplausible biological mechanisms.Discussion: In this analysis, we demonstrate moderate SNP-heritability and genetic sharing among the psychiatric treat-ment record based phenotypes in the Danish National HealthRegister, suggesting the presence of single loci with effectsacross multiple disorders. These analyses build upon and extendthe emerging relaxation of rigid psychiatric diagnostic bound-aries, suggesting at least some significant portion of risk mayemerge from shared biological disruptions.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.383

M77. COMPLEX SPATIO-TEMPORAL DISTRIBUTION ANDGENOGEOGRAPHIC AFFINITY OF MITOCHONDRIAL DNAHAPLOGROUPS IN 24,216 DANES

Jonas Grauholmn,1, Christian M. Hagen1,

Vanessa F. Gonçalves2, Christine S. Hansen1,Paula L. Hedley1, Ole Mors3, James Kennedy2, Thomas Als3,Alfonso B. Demur4, Thomas M. Werge4, Merete Nordentoft4,Anders Børglum3, Preben B. Mortensen3,David M. Hougaard1, Michael Christiansen1

1Statens Serum Institut2University of Toronto3Aarhus University4Capital Region of Denmark

Background: Mitochondrial DNA (mtDNA) haplogroups(hgs) are evolutionarily conserved sets of mtDNA SNPs.Associations of hgs with geographical origin, disease andphysiological characteristics have been reported, but havefrequently not been reproducible. We assessed, using 418mtDNA SNPs on the PsychChip (Illumina), the spatio-tem-poral distribution of mtDNA hgs in DNA isolated fromgeographically un-biased dried blood spots (DBS), collectedfrom 1981 to 2005 through the Danish National NeonatalScreening program.Methods: As part of the iPSYCH (www.iPSYCH.au.dk) recruit-ment protocol, 24,651 singletons (47.1% female), born betweenMay 1 1981 and Dec 31 2005 were selected at random from theDanish Central Person Registry. The Samples were extractedfrom the Danish National Biobank and Genotyped at the BroadInstitute as part of iPSYCH and PGC.

Haplotyping of mtDNA was performed using the definingSNPs reported in www.phylotree.org. First the affiliation tomacro-hg i.e. L0 – L6, M, N, R, and then to hgs – units moredistal in the cladogram was established. Ancestry estimationwas done using ADMIXTURE 1.3.052. Briefly, a referencepopulation consisting of Human Genome Diversity Project(HGDP) (http://www.hagsc.org/hgdp/) genotyping SNP dataset, supplemented with representative samples of danes (716individuals) and greenlanders (592 individuals) available at SSI,was used.Results: The hg distribution was typically Northern Eur-opean, and hgs were highly variable based on median-joining analysis, suggesting multiple founder events. Con-siderable heterogeneity and variation in autosomal geno-geographic affinity (ancestry) was observed. Thus, indivi-duals with hg H exhibited 95%, and U hgs 38.2% - 92.5%,Danish ancestry. Significant clines between geographicalregions and rural and metropolitan populations were found.Over 25 years, macro-hg L increased from 0.2% to 1.2%(p=1.1nE-10), and M from 1% to 2.4% (p=3.7nE-8). Hg Uincreased among the R macro-hg from 14.1% to 16.5%(p=1.9nE-3). Geno-geographic affinity, geographical skew-edness, and sub-hg distribution suggested that the L, M andU increases are due to immigration.Discussion: This study shows that the distribution ofmtDNA hgs in Denmark is highly dynamic and complex. Itcomprises 1.6% of the Danish population over a 25-yearperiod, and is by far the largest ever performed of the

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distribution of mtDNA hgs in any country. The method ofcollecting stored DBS from the PKU biobank, where thecoverage is �99%, enabled us to survey a true populationbased sample, where the time and place of birth was knownfrom national electronic registries. This is in contrast tomost other population genetic studies of adults sampled in aspecific bias-prone context, e.g. hospitalized patients orlocalized samplings.

The mtDNA haplotyping was based on array data withonly 418 mtDNA SNPs and as a consequence not all sub-hgscould be called. The stringent adherence to specific SNPsleft a number of persons, normally in the order of 1–2%, nothaplotypable. An advantage of only using a limited set ofmarkers is that confounding due to private variants isavoided.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.384

M78. GENES IMPLICATED IN NEURODEVELOPMENT AREENRICHED FOR FOXP2 BINDING SITES ASSOCIATED WITHLANGUAGE ABILITY

Tanner Koomarn

, Bruce Tomblin, Jacob Michaelson

University of Iowa

Background: Specific Language Impairment (SLI) is aneurodevelopmental condition which causes linguistic def-icits in children with otherwise normal development. SLI isdemonstrably heritable (h2 � 0.6) and relatively common(occurring in �7% of the population). Linkage, GWAS, andtwin studies of SLI have produced mixed results withinconsistent replication, necessitating the integration ofother forms of molecular data related to language abilityinto its study. The transcription factor FOXP2 is robustlyassociated with language ability, with perturbations to thecoding region of the gene resulting in severe languagedeficits. However, such coding changes in FOXP2 areexceedingly rare. Variation in FOXP2's thousands of DNAbinding sites is plentiful, on the other hand, making themattractive targets for interrogation in a common conditionlike SLI.Methods: Genetic variants overlapping FOXP2 ChIP peaksites were extracted from the whole genome sequences of acohort of 280 children (�140 SLI and �140 control), andranked based on association with overall language ability.Variation in the FOXP2 locus was also tested for associationwith language ability.Results: Genes co-expressed with FOXP2 in the developinghuman brain and implicated in neurodevelopment wereenriched for high-ranking FOXP2 binding sites. Despite theseintriguing results, this variation – and that in the FOXP2locus itself – was only able to explain a fraction ofdifferences in total language ability.Discussion: These results show the promise of integratingmolecular data into genetic analysis of SLI, while

demonstrating the inability of FOXP2 to fully explain thepreponderance of variability in human language ability.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.385

M79. GENOME-WIDE DNA METHYLATION SIGNATURESOF AGGRESSION RISK IN CHILDREN

Janitza Montalvo-Ortizn,1, James Hudziak2,

Hannah Holbrook2, Kerry O'Loughlin2, Joel Gelernter1,Joan Kaufman3

1Yale University School of Medicine2University of Vermont3Kennedy Krieger Institute, Johns Hopkins University

Background: Child abuse is a highly prevalent publichealth problem and a risk factor for numerous psychopatho-logical disorders. Early physical abuse and neglect havebeen associated with an increased risk of childhood conductdisorders. However, not all children exposed to abusedevelop aggression later in life, suggesting interplaybetween genetic and environmental factors in the predis-position to aggression.Methods: This study investigated genome-wide DNAmethylation changes associated with aggressive behaviorin children. A total of 105 9–15 years old children ofEuropean ancestry were included in the study (56% female,12 7 1.8 mean of age). The Illumina Infinium 450 KMethylation BeadChip array was used to conduct themethylation study using the genomic DNA extracted fromsaliva samples. Aggression was evaluated using the ChildBehavior Checklist (CBCL) Scores ranged from 50–87 (mean:57 7 10.5), with 39% of the sample meeting the clinical cut-off (r 63). We conducted a linear mixed effects model toexamine the main effect of trauma, main effect of DNAmethylation and an interaction term, and adjusted for age,sex, cell composition, and 10 principal components (PCs)estimated using Barfield et al. method. Significance was setto 5.0� 10-7 to correct for multiple comparisons.Results: A total of eight methylation sites were genome-wide significant (GWS) for the DNA methylation term afteradjusting for age, sex, cell type composition and 10 PCs.From these sites, cg18438793 (p=2.58� 10-7) locatedwithin the hippocalcin like 4 (HPCAL4) gene is of importancedue to its role in neuronal development and calciumsignaling and brain-specific gene expression. Further,expression of this gene is induced after fear conditioningin the lateral amygdala of mice. Additional sites (p valuerange: 10-10 – 10-7) are involved in axon guidance, myelina-tion and transcriptional regulation.Discussion: This study increases our understanding of theepigenetic changes associated with aggression in children.By identifying predictors of aggression in early life, thisstudy may provide novel tools to improve treatment andpreventive interventions for aggression risk in children.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.386

M80. METABOLIC ABNORMALITIES RELATED TO TREAT-MENT WITH SELECTIVE SEROTONIN REUPTAKE INHIBI-TORS IN PATIENTS WITH SCHIZOPHRENIA OR BIPOLARDISORDER: A GENOME WIDE ASSOCIATION STUDY

Katrine Fjukstadn,1, Lavinia Athanasiu2, Ingrid Dieset2,

Nils Steen2, Srdjan Djurovic2, Olav Spigset3, Ole Andreassen2

1Nord-Trøndelag Hospital Trust2NORMENT, KG Jebsen Centre for Psychosis Research,Institute of Clinical Medicine, University of Oslo3Norwegian University of Science and Technology, St. OlavUniversity Hospital

Background: Patients’ tolerability and experienced effi-cacy of psychopharmacological drugs such as SelectiveSerotonin Reuptake Inhibitors (SSRIs) are influenced by bothenvironmental and genetic factors. SSRIs are sometimesused as add-on therapy in schizophrenia and bipolar dis-order. Association between use of SSRIs and metabolicabnormalities has been shown, but little is known aboutthe genetic associations in this context. Our aim is to studygenetic variations associated with individual differences inSSRI-induced metabolic side effects.Methods: We conducted a genome-wide association studyto identify genetic variants affecting susceptibility to SSRI-induced metabolic abnormalities by using data from theNorwegian Thematically Organized Psychosis study. Patients(n=1120) suffering from schizophrenia (n=719) or bipolardisorder (n=401) were included. SSRI exposure wasexpressed in dosages or serum concentrations of SSRIs(n=237). Metabolic outcome variables were: Levels of totalcholesterol, low and high density lipoprotein (LDL and HDL)cholesterol, triglycerides, glucose and Body Mass Index(BMI). Single nucleotide polymorphisms (SNP) and use ofSSRIs were tested for associations to outcome variables. Toaccount for the effect of age, gender and co-medicationwith olanzapine, quetiapine or clozapine, these wereincluded as covariates in the analysis.Results: In preliminary analysis, we identified 31 regionsassociated with SSRI-induced metabolic abnormalities inoutcome variables total cholesterol level, HDL- and LDLcholesterol levels and triglycerides (significance threshold:P o 10-8). For triglycerides, our strongest association wasfor marker rs13428203 (P=3.11E-17) located upstream ofthe gene SNORD95 on chromosome 2 followed by 4 markers(Po 2.16E-14) located in intergenic regions on chromosome2, and finally (P= 1.30E-09) and rs17200837 (P= 1.33E-09)located in PRRC2A on chromosome 6. Additionally, 11 othermarkers were significantly associated with triglycerides (Po8.32E-09). One marker, rs7412, located on chromosome 19in APOE that encodes apolipoprotein E, was significantlyassociated with both total cholesterol and LDL-cholesterollevels. Moreover, we observed 15 markers that were sig-nificantly associated with HDL cholesterol levels when

accounting for SSRI use. The strongest signal was forrs4893537 in ACSL4 on chromosome x (P= 3.05E-12), whichhas a function in lipid biosynthesis and fatty aciddegradation.Discussion: The present findings indicate that SSRI-induced metabolic abnormalities are potentially affectedby common genetic variation. Several markers were asso-ciated with triglyceride levels, with strongest signal seen formarker rs13428203, and for several markers in PRRC2Agene, previously associated with age-at-onset of insulin-dependent diabetes mellitus, as well as a possible involve-ment in the inflammatory process of pancreatic beta-celldestruction during development of insulin-dependent dia-betes mellitus. Further, markers in APOE were associatedwith both total cholesterol-and LDL cholesterol levels. Inaddition, several variants in ACSL4 were associated withHDL cholesterol. Our findings warrant further investigationto elucidate the mechanisms involved, which may ulti-mately guide to the discovery of novel drug targets andpredictive markers.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.387

M81. SCHIZOPHRENIA POLYGENIC RISK SCORE PRE-DICTS ANTIPSYCHOTIC TREATMENT RESPONSE INPATIENTS WITH FIRST EPISODE PSYCHOSIS

Jianping Zhangn,1, Delbert Robinson1, Jin Yu1, Juan Gallego2,

W. Wolfgang Fleischhacker3, Rene S. Kahn4,Benedicto Crespo-Facorro5, Javier Vazquez-Bourgon5,John Kane1, Anil Malhotra1, Todd Lencz6

1Zucker Hillside Hospital2Hofstra North Shore LIJ School of Medicine3Medical University Innsbruck4University Medical Center Utrecht5CIBERSAM, IDIVAL, University Hospital Marqués de Valde-cilla, Santander6Hofstra Northwell School of Medicine

Background: The genetic basis of antipsychotic drugefficacy is likely polygenic in nature. Genetic risks ofschizophrenia may also be related to antipsychotic drugresponse. The Psychiatric Genomics Consortium (PGC) Gen-ome-Wide Association Study (GWAS) provided evidence ofassociation with schizophrenia risk for many Single Nucleo-tide Polymorphism (SNP) across the genome. We examinedwhether Polygenic Risk Scores (PRS) based on the PGC GWASare predictive of antipsychotic efficacy in four cohorts ofpatients with first episode psychosis (total n=510): 1)Zucker Hillside Hospital First Episode schizophrenia trial(ZHH-FE), 2) European First Episode Schizophrenia Trial(EUFEST), 3) Spanish First Episode Psychosis study (SFEP),and 4) the clinical trial as part of the Center for Interven-tion Development and Applied Research at ZHH (CIDAR).Methods: The discovery cohort was the ZHH-FE with 77patients (mixed ethnicity) randomized to risperidone or

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olanzapine. Three replication cohorts were: 1) EUFEST with141 patients (all Caucasian) randomized to five antipsycho-tics; 2) SFEP with 192 patients (all Caucasian) on variousantipsychotics; and 3) CIDAR with 100 patients (mixedethnicity) randomized to risperidone or aripiprazole. Geno-typing was performed using the Illumina Omni-1Quad (EUF-EST and ZHH-FE) or Illumina Infinium HumanOmniExpressExome platform (CIDAR and SFEP). SNP imputation wasconducted with IMPUTE2 against the full 1000 Genomes v3reference panel. PRS was computed based on the results ofthe PGC GWAS using PRSice software for the discoverycohort with thresholds at PTo5E-8, 0.001, 0.01, 0.05,0.10, 0.20, 0.50. Based on the findings from the discoverycohort, PRS was computed for the three replication cohortsusing a threshold of PTo0.01. Symptom measure was thetotal score of Brief Psychiatric Rating Scale (BPRS) for ZHH-FE, SFEP, and CIDAR, or Positive and Negative SymptomsScale (PANSS) for EUFEST.Results: Hierarchical linear regression was performed onthe 3-month symptom score with the PRS as the predictorwhile controlling for age, sex, and baseline symptom score.Genomic principal component scores were also covaried tocontrol for population stratification for ZHH-FE and CIDAR.In the ZHH-FE cohort, higher PRS at the thresholds ofPTo0.01, 0.05, 0.10, 0.20, and 0.50 significantly predictedhigher symptom scores at 3-month follow-up, explaining 6–8% of the variance (all p'so0.05). PTo0.01 gave thestrongest result in the discovery sample, and was used toreplicate the findings in the other three cohorts. Higher PRSsignificantly predicted worse symptoms in EUFEST and SFEPcohorts, explaining 3.5% and 3.7% of variance, (p'so0.01),but not in the CIDAR sample. Combining the four cohorts ina meta-analysis, PRS was significantly predictive of 3-monthsymptom scores (pooled partial r=0.18, p=0.002). HigherPRS was associated with higher symptom scores at 3-monthfollow-up, suggestive of less improvement in treatment.The overall results remained significant when only Europeanancestry individuals were included in the analysis.Discussion: These findings suggest that polygenic riskscores for schizophrenia may also be related to antipsycho-tic drug response. Patients with higher polygenic risk scorestended to have less improvement with antipsychotic drugtreatment. Further analysis is needed to elucidate a morerefined genomic profile for antipsychotic drug response.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.388

M82. RARE CODING VARIANTS IN TREATMENT-RESIS-TANT DEPRESSION

Christopher Songn,1, Liping Hou1, Nirmala Akula1,

Carlos Zarate2, Brian Mickey3, Francis McMahon1

1National Institute of Mental Health - Human GeneticsBranch2National Institute of Mental Health - Experimental Ther-apeutics & Pathophysiology Branch (ETPB)3University of Utah

Background: Approximately 30% of patients with MajorDepressive Disorder (MDD) meet criteria for Treatment-Resistant Depression (TRD), defined as non-response totwo or more different classes of antidepressants. Pharma-cogenomics research has shown that genetic factors canimpact medication effectiveness and tolerability by mod-ulating drug levels or target affinity. Antidepressantresponse is heritable, but genome-wide association studiesof common variants have failed to find consistent signals.Since patients with TRD occupy the extreme end of thetreatment response distribution, they may also carry allelesthat occupy an extreme of frequency and functional impact.Methods: Study participants included 146 unrelatedpatients, 130 with MDD or bipolar TRD and 16 with goodresponse to antidepressants, drawn from several sources.All participants had experienced at least two failed anti-depressant trials not explained by non-adherence or severecomorbidities. Exomes were captured with various arraysand sequenced by use of Illumina or SOLiD platforms.Variants were called and assessed for quality using the GATKbest practices pipeline.Results: After quality control, 348,077 variants wereidentified, of which 99,711 were exonic and had allelefrequencies o1% in ExAC. We sought to remove falsepositives by filtering out variants that were not found indbSNP, appeared in only one individual, or had missinggenotypes in all typical responders. Functional filtering ofvariants that were called as synonymous or non-frameshiftleft 4,456 qualifying variants in 3,370 genes. Very fewqualifying variants were found in 41 TRD patient, but LISTGENES each carried the same qualifying variant in 42individuals. A total of 820 genes carried at least 2 qualifyingvariants. This set of genes was tested for overlap with genesimplicated in MDD (Hyde et al., 2016) or antidepressanttreatment response (GENDEP, MARS, and STARn D Investiga-tors, 2013). Significant excess overlap of genes wasdetected for both MDD (OR=1.5, p=0.035) and responseto 2 wks of antidepressant treatment (OR=2.16; P=1� 10-5). The latter gene set was enriched for “actin cytoskele-ton” by ENRICHR (q=0.01).Discussion: Some of the same genes implicated in MDD orantidepressant treatment response through common var-iants may also harbor rare, functional variants in patientswith TRD. Further study of these genes could yield newinsights into the pathophysiology of treatment-resistantdepression.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.389

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M83. GENETIC DETERMINANTS OF WEIGHT CHANGEDURING ANTIDEPRESSANT TREATMENT WITH SELEC-TIVE SEROTONIN RE-UPTAKE INHIBITORS: GENOME-WIDE STUDY AND META-ANALYSIS

Alyson Zwickern,1, Chiara Fabbri2, Daniel Gaston1, Eileen

M. Denovan-Wright1, Katherine Aitchison3, McGuffin Peter2,Cathryn M. Lewis2, Roy Perlis4, Victor Castro5, Rudolf Uher1

1Dalhousie University2Kings College London3University of Alberta4Massachusetts General Hospital5Partners Healthcare

Background: Weight change is a common adverse effectof antidepressant treatment. The purpose of this study wasto identify genetic variants associated with change in bodyweight during antidepressant treatment for Major Depres-sive Disorder (MDD) with Selective Serotonin ReuptakeInhibitors (SSRIs).Methods: Genotyping and objectively measured weightchange data were available for 340 unrelated adults with MajorDepressive Disorder (MDD) treated with escitalopram over a 26-week period in the Genome-Based Therapeutic Drugs forDepression (GENDEP) project. We performed a genome-wideassociation analysis of change in Body Mass Index (BMI). Next,we meta-analyzed the GENDEP results with those obtained fromtwo cohorts of 195 and 144 individuals treated with SSRIs withobjective measurement of weight and genotyped as part of thePartners HealthCare Biobank initiative. Finally, we conductedgene-wide analyses to identify genes associated with weightchange during SSRI treatment.Results: We identified 3 independent associations (p o5� 10-8) with weight change in the GENDEP analysis,including single nucleotide polymorphisms (SNPs) inCEP41. The meta-analysis identified 2 independent associa-tions meeting genome-wide significance with consistentsignal across samples, including uncommon SNPs in aphosphodiesterase-encoding gene, PDE8A. We have furtheridentified 7 suggestively significant associations involvingcommon variants, including associations in or near genesGATA4, CDH8, and NMNAT3.Discussion: We provide preliminary evidence that uncom-mon and common genetic variation contributes to weightchange during treatment with antidepressant drugs. Con-firmation in larger samples is needed to identify clinicallyuseful variants.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.390

M84. EXOCYTOSIS-RELATED GENE-SETS AND RESPONSETO METHYLPHENIDATE TREATMENT IN ADULTS WITHADHD

Bruna da Silvan,1, Djenifer B. Kappel1, Renata B. Cupertino1,

Diego L. Rovaris1, Jaqueline B. Schuch1, Cibele Bandeira1,

Alana C. Panzenhagen1, Diana Müller1, Nina R. Mota2,Eduardo S. Vitola3, Marcelo M. Victor3, Eugenio H. Grevet3,Verônica Contini4, Claiton H.D. Bau1

1Universidade Federal do Rio Grande do Sul2Radboud University Nijmegen Medical Centre3Hospital de Clínicas de Porto Alegre4UNIVATES

Background: Substantial interindividual variability isobserved in treatment response to Methylphenidate(MPH), which is considered the first-line pharmacologicaltreatment for adults with ADHD. In addition to its mainknown mechanism of action involving the blockade of thedopamine transporter, experimental studies have also indi-cated an ability of MPH to affect vesicle synaptic transmis-sion. Consistently with this hypothesis, genes involved incalcium-triggered vesicle exocytosis have been implicatedon pharmacogenetics of MPH. In genomic approaches, path-ways involved in the neurotransmitter release are thereforepromising to be investigated in MPH response. The aim ofthis study was to assess the influence of exocytosis-relatedgene-sets on response to MPH.Methods: The sample with genome-wide data andimmediate-release MPH response comprised 189 adults withADHD. The outcome measure was the change (Δ) in severityscores of ADHD symptoms of SNAP-IV from baseline toendpoint (at least 30 days of treatment). Subsets ofinattention and hyperactivity/impulsivity symptoms wasalso evaluated separately. Samples were genotyped onPsychChip array and imputed using the Ricopili pipeline.The resulting dataset consisted of 5,842,472 SNPs afterquality control. For SNP annotation to genes, gene locationsfor build 37 (hg19) and a 2 kb upstream/1 kb downstreamwindow were used. Competitive gene-set analyses wereperformed in MAGMA v1.06 using the principal componentsregression as the gene-based model. Concomitant use ofpsychiatric medication and baseline scores of symptomswere included as covariates, as well as the 10 first principalcomponents. Eight annotated gene-sets related to functionand regulation of calcium-triggered vesicle exocytosisderived from Gene Ontology (biological process) and col-lected from Molecular Signatures Database were analyzed.Bonferroni was applied for multiple testing correction.Results: Gene-set analysis for the change in severityscores of ADHD resulted in nominal associations for calciumion regulated exocytosis (GO:0017156; p=0.0189), presy-naptic process involved in synaptic transmission(GO:0099531; p=0.0153) and neurotransmitter transport(GO:0006836; p=0.0231) gene-sets. Analyzing specific ADHDdimensions, the same gene-sets were associated to changeof inattention symptoms only, where GO:0099531 remainedsignificant after Bonferroni correction (p=0.0012). Therewas considerable overlap of genes within the tested gene-sets, therefore the gene analysis revealed a shared group ofnominally associated genes among the significant sets forboth inattention and ADHD, including STX11, STX19, PSEN1,CACNA1A and NRXN1.Discussion: Our results suggest an involvement of neuro-transmitter release genes in MPH treatment response. Thelack of association for hyperactivity/impulsivity symptoms

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might point out different treatment underlying mechanismsbetween ADHD dimensions. Despite the evaluation of com-bined effects of multiple genetic variants grouped intopredefined gene-sets is an alternative strategy to GWAS toreach increased statistical power, our small sample sizeshould be considered in the interpretation of the results.Moreover, as the selected gene-sets are not independent, anincreased precision in pathway definition would be beneficto these analyses. Notwithstanding, pathways involved inneurotransmitter release emerge as important candidatesto be explored in further pharmacogenetic studies of ADHD.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.391

M85. DNA METHYLATION AND 5-HTTLPR GENOTYPE OFTHE SEROTONIN TRANSPORTER GENE (SLC6A4) INANTIDEPRESSANT TREATMENT RESPONSE OF MAJORDEPRESSIVE DISORDER

Amanda Lisowayn,1, Clement Zai1, Arun K. Tiwari1,

Ricardo Harripaul1, Natalie Freeman1, Leon French1,Zachary Kaminsky2, James L. Kennedy1

1Centre for Addiction and Mental Health2Johns Hopkins University

Background: The current process used to prescribe anti-depressant medication is markedly inefficient, as more than50% of treated patients fail to reach remission. Antidepres-sant treatment success has been associated with geneticvariation, but studies are not well replicated and epigeneticmechanisms remain under investigated. DNA methylationmay provide more information regarding antidepressantresponse and guide physicians in choosing the most effec-tive medication for each patient. We investigated theinfluence of SLC6A4 methylation and 5-HTTLPR genotypeson antidepressant response in our sample.Methods: A subset of depression patients with completeclinical data (European Caucasian, n=166), were selectedfrom our discovery sample (IMPACT; N=8,000). Saliva sampleswere collected at enrollment and genetic testing was done ofcytochrome P450 liver enzyme, 5HTTLPR and 5HT2A variantsto guide clinical choice and dosage of psychotropic medica-tions. As such, a significant component of our sample includestreatment refractory, as well as medication intolerantpatients. DNA was bisulfite converted and methylationprofiles were interrogated using the Infinium HumanMethyla-tion450 Beadchip array. Nine CpG probes located across theSLC6A4 promoter region were selected, based on previousstudies, to quantify methylation levels. Change in BeckDepression Inventory II (BDI-II) score was used to measureantidepressant response over eight weeks. The relationshipamong genotype, methylation levels, and antidepressantresponse was analysed using linear regression modeling.Results: Increased methylation in the promoter region ofthe SLC6A4 gene was nominally associated with impairedresponse to antidepressants in our sample. The effect was

driven by methylation site cg05016953, located in exon 1 A.Increased methylation level as measured by CpGcg05016953 was associated with less improvement in BDI-IIscore over eight weeks of antidepressant treatment (F(3,163)=6.14, puncorr=0.012). 5-HTTLPR genotype wasnot associated with SLC6A4 DNA methylation or antidepres-sant treatment response.Discussion: An increase in SLC6A4 DNA methylation atcg05016953 may be associated impaired response to anti-depressant medications in our sample. The SLC6A4 tran-scriptional control region contains a CpG island, previouslyshown to functionally influence mRNA levels depending on5-HTTLPR genotypes. Typically, hypermethylation in promo-ter regions is associated with decreased gene expression.Theoretically, hypermethylation of the 5-HTT promoterwould reduce the number of serotonin transporters, andreduce serotonin re-uptake, which in simple terms shouldimprove response to SSRI treatment. Further pharmaco-epigenetic studies are required to elucidate the effect ofDNA methylation changes on antidepressant response.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.392

M86. INTEGRATIVE GENOMIC ANALYSIS OF METHYL-PHENIDATE RESPONSE IN ATTENTION-DEFICIT/HYPER-ACTIVITY DISORDER

Mireia Pagerols2, Vanesa Richarte3, Cristina Sánchez-Mora4,Paula Rovira

n,1, María Soler Artigas4, Iris Garcia-Martínez4,Bruna Santos da Silva5, Nina Roth Mota6,Luis Augusto Rohde7, Eugenio Horacio Grevet7,Claiton Henrique Dotto Bau5, Bru Cormand8, Miguel Casas3,Josep Antoni Ramos-Quiroga3, Marta Ribasés4

1Psychiatric Genetics Unit, Vall d’Hebron Research Institute(VHIR), Universitat Autònoma de Barcelona, Mental HealthHospital Universitari Vall d’Hebron2Vall d'Hebron Research Institute (VHIR), Universitat Autòn-oma de Barcelona3Hospital Universitari Vall d’Hebron4Vall d’Hebron Research Institute5Institute of Biosciences, Universidade Federal do RioGrande do Sul6Donders Institute for Brain, Cognition and Behaviour,Radboud University Nijmegen Medical Centre7ADHD Outpatient Program, Adult Division, Hospital deClínicas de Porto Alegre8Microbiologia i Estadística, Facultat de Biologia, Universi-tat de Barcelona

Background: Methylphenidate (MPH) is the most fre-quently used pharmacological treatment in children withAttention-Deficit Hyperactivity Disorder (ADHD). However, aconsiderable interindividual variability exists in clinicalresponse, which may reflect underlying genetic influences.Methods: We performed a Genome-Wide AssociationStudy (GWAS) of MPH efficacy in 173 ADHD pediatric

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patients, considering the Clinical Global Impression-Improvement scale as the primary outcome measure oftreatment success. For subsequent analyses, we prioritizedthe Single-Nucleotide Polymorphisms (SNPs) with P-valuesbelow 0.05 on the GWAS based on functional annotation andexpression quantitative trait loci (eQTL) analysis in humanbrain. Ingenuity Pathway Analysis was used to assess thebiological functions and pathways related to genes contain-ing at least one SNP nominally associated with both MPHresponse and human cortical expression levels (eSNPs), andto test for over-representation of genes previously studiedin either ADHD or treatment outcome. We subsequentlymeta-analyzed the association between clinical responseand the eSNPs identified across the discovery sample and anindependent cohort of 189 ADHD adult patients.Results: Although no variant reached genome-wide sig-nificance, the set of genes containing SNPs nominallyassociated with MPH response was significantly enrichedfor genes previously studied in ADHD or treatment outcome(Padjusted=1.56e-31). Considering these results, we prior-itized the nominally significant markers by functional anno-tation and eQTL analysis in human brain, and we identified33 SNPs tagging cis-eQTL in 32 different loci (eGenes).Pathway enrichment analyses revealed an over-representa-tion (Padjustedo0.05) of genes involved in morphology ofneurons, neuroglia, white matter and brain regions impor-tant for motor control, attention and memory among theeGenes. Categories related to neuropsychiatric disordersand behavior were also significantly enriched, includinglearning deficit and hyperactive behavior. We subsequentlymeta-analyzed the 33 eSNPs nominally associated withtreatment outcome across the discovery sample and anindependent cohort and we detected 15 suggestive signals,with rs17685420 in the PEBP4 (phosphatidylethanolaminebinding protein 4) gene surpassing Bonferroni correction(OR=3.07, P=7.90e-05).Discussion: To our knowledge, this is the first studyinvestigating the genetic basis of MPH response from anintegrative perspective that combines GWAS data, func-tional annotation, eQTL in relevant tissues to ADHD andpathway enrichment analyses. Our results highlight genesrelated to nervous system development and function,neurological diseases and psychological disorders. Thus, thiscomprehensive strategy provides a better understanding ofthe molecular mechanisms implicated in MPH treatmenteffects and suggests promising candidates that may con-tribute to clinical outcome.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.393

M87. WHOLE GENOME SEQUENCING OF MULTIPLY-AFFECTED SCHIZOPHRENIA AND BIPOLAR DISORDERFAMILIES FROM THE AZORES AND MADEIRA

Tim Bigdelin,1, Silviu Bacanu2, Benke Kelly3, Brion Maher3,

James Knowles1, Steven McCarroll4, Michele Pato1,Carlos Pato1, Ayman Fanous1

1SUNY Downstate Medical Center2Virginia Institute for Psychiatric and Behavioral Genetics3Johns Hopkins Bloomberg School of Public Health4Stanley Center for Psychiatric Research, Broad Institute ofMIT and Harvard

Background: Schizophrenia (SZ) and Bipolar Disorder (BP)are debilitating neuropsychiatric disorders, each affecting0.5–1% of the world's population, and for which a sharedpolygenic liability has been demonstrated. Here, we con-sider recent progress in an ongoing, Whole Genome Sequen-cing (WGS) study of multiply affected SZ and BP familiesfrom the Portuguese archipelagos of the Azores andMadeira.Methods: Using the Illumina HiSeq. 2000 platform, weobtained deep, WGS data (�30X) for 51 SCZ and 39 BPcases, and 72 unaffected relatives from 40 families; anadditional 16 relatives meeting criteria for some otherpsychiatric diagnosis (e.g., major depression or alcoholism)and 7 of unknown phenotype; and 30 unrelated ethnically-matched controls. We applied a prioritization strategy forfiltering putatively functional SNPs and INDELs, based onpopulation frequency and sharing between affectedrelatives.Results: We identified a disruptive INDEL in SERPINA1carried by affected members of 10 families, and a disruptiveINDEL in PCDHGA9 shared between all affected relatives in apedigree which contributed substantially to a publishedlinkage finding at 5q31-34. Individual burden scores of raredisruptive variants are markedly greater among affectedsubjects (P=0.00076) and their unaffected relatives(P=0.00034). Next, we compared lists of genes carryingfamily-specific variants shared among affected relatives tocurated, etiologically relevant gene-sets. Following correc-tion for multiple tests, we observed a significant overlap ofgenes carrying disruptive or non-synonymous variants in thePIC with genes enriched for de novo non-synonymousvariants (P=5.9E-5), associated SCZ GWAS intervals(P=3.48E-4), and human post-synaptic density genes(P=9.14E-4). Genes with disruptive or non-synonymousvariants also exhibited significant overlap with de novofindings for autism and intellectual disability, autism PPInetworks, and FMRP targets.Discussion: We demonstrate the polygenic enrichment ofrare, disruptive variants in multiply-affected families from ageographically isolated archipelago. This recapitulates thepattern of results observed for common polygenic riskscores constructed from population-based GWAS, for whichthe comparisons of affected and unaffected relatives tocontrols were also significant (P=0.01 and P=0.02, respec-tively). Ongoing analyses include prioritization of variantsleveraged by observed population structure of these geo-graphically isolated island populations, and attemptedreplication of prioritized variants an independent sampleof 220 SZ cases and 185 controls from the GenomicPsychiatry Cohort (GPC).

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.394

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M88. ASSOCIATION OF GENETIC RISK SCORES FORSCHIZOPHRENIA WITH LYMPHOBLAST AND CORTICALGENE EXPRESSION NETWORKS

Jonathan Hessn,1, Stephen V. Faraone2, Stephen J. Glatt2

1SUNY Upstate Medical University2Medical Genetics Research Center, SUNY Upstate MedicalUniversity

Background: Schizophrenia is a highly heritable disorderwith complex etiology. Genetic risk scores provide an indexof an individual's liability for schizophrenia, and may shedlight on its biological underpinnings.Methods: We investigated the association of genetic riskscores for schizophrenia using transcriptomic and genome-wide genotyping data from Lymphoblastoid Cells (LCLs) andpostmortem brain. We removed the major histocompatibil-ity region from our data and calculated genetic risk scoresusing linkage-independent risk markers for schizophrenia.Linear models were used to test the association of diagnosisor genetic risk scores with expression levels of gene net-works in LCLs and brain, in addition to exon networksderived from brain. We specified covariates in our regres-sion models to control for population stratification alongwith biological and technical variation.Results: We identified gene networks whose expressionwas significantly associated with schizophrenia genetic riskscores in LCLs and brain. Pathways involving cell growth,apoptosis, and immunity were enriched in modules ofinterest, in addition to astrocyte-specific markers.Discussion: Converging evidence shows that schizophre-nia polygenes represent multiple biological pathways andprocesses. We identified relationships between schizophre-nia polygenes and the expression of genes in pathwaysrelated to cell development and immunity, which recapitu-lates evidence from genetic, transcriptomic, epigenetic,and epidemiologic studies. Despite practical limitations, ourstudy provides key insights into the role of schizophreniapolygenes in gene expression and splicing regulation.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.395

M89. MODELING HUMAN CORTICAL BRAIN DEVELOP-MENT BY THE GENERATION OF CEREBRAL ORGANOIDSFROM PATIENT-SPECIFIC STEM CELLS FOR THE ANALY-SIS OF SCHIZOPHRENIA GENETICS

Matthias Jungn

, Jovita Schiller, Ina Giegling, Dan Rujescu

Martin Luther University Halle-Wittenberg

Background: Characteristics of schizophrenia includethe deregulation of the glutamatergic and the GABAergic

neurotransmission and the degeneration of predominantlyinhibitory interneurons within the cortex of the humanbrain. Cortical development was extensively studied inrodents, but the unique and complex architecture of thehuman cortex differs dramatically from brain of establishedanimal models. Accordingly, the analysis of schizophreniaanimal models is limited by the species differences, whichrequires the development of adequate human in vitromodels mimicking the human cortical brain development.Schizophrenia is associated with DNA variations suggestingthat genetic factors contribute to onset, progression andtreatment of the disease. We generated induced pluripotentstem cells (iPS cells), which allow the generation of disease-and patient-specific neuronal cultures for the analysis ofgenetic factors. However, the functional characterization ofgenetic factors requires the analysis of advanced tissue-based 3D disease models. Therefore, we generated cerebralorganoids for mimicking aspects of the human corticaldevelopment.Methods: Human iPS cells from healthy donors andpatient-specific iPS cells from schizophrenia patients weredifferentiated into permanent Neural Stem Cells (NSCs).Transcript and protein analysis confirmed the differentiationstatus of iPS cells and NSCs. NSCs were characterized incellular 2D differentiation models. NSCs were further dif-ferentiated as free-floating neurospheres to acquire func-tional 3D organoids. Cells were analyzed by transcript andprotein analysis. Cryosectioning of organoids was applied tovisualize the distribution of different neuronal subtypes.Results: Protein and transcript analysis of specific markersincluding OCT4 and the activity of alkaline phosphatasesverified pluripotency in patient-derived iPS cells. The analy-sis of several NSC markers such as SOX2 and PAX6 indicatedstable generation of permanent NSCs from patient-specificiPS cells. Patient-specific iPS cells were successfully differ-entiated into progenitor cells expressing a variety of neurallineage markers including neural makers such as TUBB3 andSTX as wells as glia cell markers such as GFAP and O4.Immunostaining and whole-cell patch-clamp recordings ofmature neurons showed the presence of different neuronalsubtypes including inhibitory GABAergic neurons. NSCs werealso successfully applied to the generation of 3D cerebralorganoids. The 3D organoid differentiation model showed theRNA and protein expression of neural lineage markers similarto cells obtained from the 2D monolayer cultures. Theexpression pattern of cortical markers such as TBR1 observedin cryosections of organoids revealed the induction of corticallayers mimicking the developing human cortex.Discussion: We successfully generated 3D cerebral orga-noids mimicking aspects of the early human brain develop-ment. These culture systems enable functional studies ofhealthy and diseased human cortical development for theanalysis of neurodevelopmental diseases includingschizophrenia.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.396

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183PATHWAY-FOCUSED POLYGENIC RISK SCORES INVESTIGATE THE IMPACT OF A RARE, HIGHLY PENETRANT GENETIC RISK

M90. FUNCTIONAL CHARACTERIZATION OF PSYCHIATRICDISEASE-ASSOCIATED CACNA1C VARIANTS THROUGHGENETIC, MOLECULAR AND CELLULAR APPROACHES

Hye-Yeon Park, Karrie Cahn, Ranjit Randhawa,Robert Altshuler, Katie Worringer,Masoud Sadaghiani

n,1

Novartis

Background: Despite recent advancements in humangenomics and identifying hundreds of risk loci for psychia-tric disorders, drug development in psychiatry remains achallenge. While Genome-Wide Association Studies (GWAS)provide us with a great starting point by highlighting riskregions of the genome, translating disease-associated DNAvariants to physiological function has been quite sluggish.This is mostly due to polygenic and multifactorial nature ofpsychiatric diseases which in turn have made developmentof relevant cellular and in vivo models particularly difficult.One recent GWAS identified over hundred genes that arestrongly associated with schizophrenia but contribution ofeach gene to the disease seems to be small. Each risk geneis identified with tens of SNPs, most of which are commonSNPs residing in the intronic regions of DNA.Methods: Therefore, establishing cellular models tounderstand the directionality (loss or gain) and functionaldefect caused by each risk SNP within each gene can be anenormous undertaking. On the other hand, rare exonvariants found in the disease population can serve as amore reliable starting point to understand how the functionof a risk gene is affected in the disease.Results: Here we examined effects of rare variantsreported for CACNA1C, a top schizophrenia GWAS hit, incellular models. CACNA1C is also linked to bipolar disorder,ADHD, depression and autism where schizophrenia GWASidentified over 160 risk SNPs for this gene. We used linkagedisequilibrium information to identify a small number of riskSNPs that have the highest chance of affecting the overallfunction of CACNA1C gene. We have combined these twoapproaches, built neuronal functional assays and identifiedseveral important disease related phenotypes.Discussion: These studies show a proof of concept in thecontext of the CACNA1C gene but this approach can be usedas a platform to characterize other GWAS hits several otherdisease areas.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.397

M91. POLYGENIC RISK FOR SCHIZOPHRENIA AND SEA-SON OF BIRTH WITHIN THE UK BIOBANK COHORT

Valentina Escott-Pricen,1, Daniel Smith2, Kimberley Kendall3,

Joey Ward2, George Kirov3, Michael Owen1, James Walters3,Michael O'Donovan3

1MRC Centre for Neuropsychiatric Genetics & Genomics,Cardiff University2University of Glasgow3Cardiff University

Background: People born in winter and early spring are atan elevated risk for schizophrenia [1–4]. Although the effectis small, with an increase in risk of about around 10%, thisseason of birth effect is one of the most robust findings inschizophrenia epidemiology [5]. It has also been influentialin developing hypotheses of schizophrenia pathogenesis,forming one of the central planks of the viral infectionhypothesis of the disorder [6] as well as other less inten-sively investigated putative mechanisms including vitamin Ddeficiency during fetal development [7]. However, at pre-sent, the mechanisms underpinning this season of birtheffect are unknown.Methods: We implement PRS analysis of the UK Biobank(UKBB) to determine whether season of birth is associatedwith genetic risk for schizophrenia. We generated schizo-phrenia PRS for every participant in the UKBB (June 2015release, N=136,538) and tested whether this score isassociated with month or season of birth. As a secondarytest of the plausibility of season of birth being a geneticallycorrelated confound, we also conducted a GWAS of seasonof birth as a binary phenotype, comparing winter/springbirths with summer/autumn. Our aim was to estimateheritability of season of birth as a phenotype.Results: We found no association between schizophreniaPRS and season of birth in the UK Biobank sample and nodifferences in schizophrenia risk scores with respect tomonth of birth. No SNPs were associated with season ofbirth at genome-wide significance, there was no evidencefor inflation in the test statistics indicative of polygenicinheritance and no evidence that SNP heritability contrib-uted to this trait (total liability scale h2=-0.002 SE=0.0052as estimated by LD-Score regression).Discussion: In this study, we examined seasonality inregard to genetic risk to schizophrenia within UK Biobank.We used the largest schizophrenia dataset to date foridentification of genetic risk loci and one of the largestavailable population cohorts to generate schizophrenia PRSand test for seasonal differences in genetic liability toschizophrenia. We found no trends of elevated schizophre-nia polygenic risk scores in people born in winter or spring.These results were further supported by a lack of evidencethat seasonality is a heritable trait. Since the PRS analysisand heritability estimates were based upon common SNPs,we don’t exclude a possible role for rare SNPs, however thefrequencies of rare CNVs, linked to neurodevelopmentaldisorders, also did not differ by season of birth.

Disclosure: Nothing to disclose.

References

[1] Baron & Gruen, Br J Psychiatry, 1988. 152:460-5[2] Boyd, Pulver & Stewart, Schiz Bull, 1986. 12(2):173-86[3] Bradbury & Miller, Psychol Bull, 1985. 98(3):569-94[4] Mortensen et al., N Engl J Med, 1999. 340(8):603-8

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[5] Davies et al., Schiz Bull, 2003. 29(3):587-93[6] Torrey, Torrey & Peterson, Arch Gen Psychiatry, 1977.

34 (9):1065-70[7] McGrath, Schizophr Res, 1999. 40(3): p. 173-7.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.398

M92. EXOME-SEQUENCING IN DENSLY AFFECTED PEDI-GREES IDENTIFIES NEW CANDIDATE GENES FORSCHIZOPHRENIA

Franziska Degenhardtn,1, Anna C. Koller2, Lalit Kaurani3,

Karolina Worf4, Frauke C. Degenhardt5, Konrad Klockmeier6,Till Andlauer7, Holger Thiele8, Andrew McQuillin9,Dan Rujescu10, Marcella Rietschel11, Wolfgang Maier12,Sybille Schwab13, Andreas Reif14, Markus M. Nöthen2

1Institute of Human Genetics2Institute of Human Genetics, University of Bonn3University Medical Center Goettingen4Helmholtz Zentrum München, Institute of ComputationalBiology (ICB)5Institute of Clinical Molecular Biology (IKMB), University ofKiel6Max Delbrueck Center for Molecular Medicine7Max Planck Institute of Psychiatry85Cologne Center for Genomics, University of Cologne9University College London10University of Halle11Central Institute of Mental Health, Medical FacultyMannheim, University of Heidelberg12University of Bonn13University of Wollongong14University of Frankfurt

Background: Schizophrenia (SCZ) is a multifactorial dis-order with heritability estimates of � 65%. Even thoughmajor breakthroughs have been made in the identificationof genetic risk factors, large proportions of the heritabilityremain unaccounted for.

Analysing multiply affected families using Whole ExomeSequencing (WES) is a very promising approach to identifynew SCZ risk factors as in these families genetic variantswith particularly strong effect might co-segregate with thedisorder. The present study is the worldwide largest SCZfamily study using WES.Methods: WES was performed in 2–5 affected individualsfrom4 50 families, each. The analyses focused on rare variantsthat were in silico predicted to be pathogenic and that wereshared between all affected individuals in one family. In orderto prioritize the identified candidate genes, a multi-tier datainterpretation approach including protein-protein-interactionand gene expression analyses was applied.Results: We have built a SCZ network implicating newgenes in the pathogenesis of the disorder and also providingadditional genetic evidence for previously reported candi-date genes; i.e. co-segregating mutations in DGCR2 (risklocus 22q11.2).Discussion: Our work - the so far largest family-based SCZWES study - provides new insight into the genetic architec-ture of SCZ. Follow-up studies (both genetic and functional

studies) are now warranted to provide further support forthe newly implicated candidate genes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.399

M93. A COMPREHENSIVE ANALYSIS OF NUCLEAR-ENCODED MITOCHONDRIAL GENES IN SCHIZOPHRENIA

Vanessa Gonçalvesn,1, Carolina Cappi2, Christian M. Hagen3,

Andriy Derkach4, Clement Zai1, Adolfo Sequeira5,Jonas Bybjerg-Grauholm3, Paula L. Hedley3, Jennie Pouget1,Ari Cuperfain1, Patrick Sullivan6, Michael Christiansen3,James L. Kennedy1, Lei Sun7

1Centre for Addiction and Mental Health2University of São Paulo3Statens Serum Institut4National Cancer Institute5University of California, Irvine6University of North Carolina at Chapel Hill7University of Toronto

Background: Schizophrenia (SCZ) is a severe psychiatricdisorder wherein the genetic risk factors are far from beingfully understood. Multiple lines of evidence have suggestedmitochondrial dysfunction in SCZ, but association of mitochon-drial variants with SCZ has not been extensively investigated.Methods: We conducted gene-based and gene-set ana-lyses to test the hypothesis that variants in nuclear-encodedmitochondrial genes influence susceptibility to SCZ, usingresults from the most recent release of the SchizophreniaPsychiatric Genomics Consortium GWAS (35,476 cases and46,839 controls). We applied the MAGMA statistical tool tothree gene sets: oxidative phosphorylation genes, othernuclear-encoded mitochondrial genes, and genes involved innucleus-mitochondria communication signaling.Results: For gene-based analysis, a total of 1,187 mito-chondrial genes were analyzed and 19 were significant aftercorrection for multiple testing. We applied the method foran independent sample (iPSYCH study, 2,290 SCZ cases and21,621 controls) and 12 genes had replication p-values o0.05. We also provided corroborating evidence from thestratified false discovery rate analysis. However, for gene-set analysis, none of the three gene sets showed statisticallysignificant enrichment of variants associated with SCZ. Weextended our analysis to include an in silico protein-proteininteraction (PPI) network analysis, and we tested theinteraction of the genes that code for these interactingproteins. We showed that 15 nuclear-encoded mitochondrialgenes interacted directly with risk genes for SCZ in a PPInetwork (permuted p=0.03). Also, we found that 22mitochondrial genes form a connected network (permutedp=0.008), and are associated with two canonical biologicalpathways involving Notch signaling pathway.Discussion: Overall, our study showed evidence thatmitochondria play a role in SCZ. Results from our study,combined with future availability of mitochondrial DNA

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data, will assist researchers to evaluate the role of mito-chondrial genomics, potentially across all complex geneticdisorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.400

M94. THE GENOMICS OF HIGHLY TREATMENT RESIS-TANT SCHIZOPHRENIA

Martilias Farrelln,1, Maya Lichtenstein2, James Crowley1,

Dawn Filmyer3, Gabriel Lázaro-Muñoz4, Rita Shaughnessy3,Ian R. Mackenzie5, Veronica Hirsch-Reinshagen5,Robert Stowe5, James Evans1, Jonathan Berg1,Jin Szatkiewicz1, Richard Josiassen3, Patrick F. Sullivan6

1University of North Carolina at Chapel Hill2Giesinger Health System3Translational Neuroscience4Baylor College of Medicine5University of British Columbia6University of North Carolina at Chapel Hill, KarolinskaInstitutet

Background: Understanding the molecular basis of Schi-zophrenia (SCZ) is one of the most significant problems inpsychiatry. The minimal identification of single genesgreatly limits the actionability of genomic findings - weneed single gene targets for clinical utility, etiologicalinvestigation, and therapeutic development. Modern SCZassociation studies analyze �105 subjects to achieve sta-tistical power. To achieve these sample sizes, a range of SCZsubjects – from mild to severe – are included. A time-honored and complementary strategy in genetics is to studyan extreme phenotype– here, highly-treatment resistantSCZ (HTRS). It is known that rare Mendelian disorders(e.g., Wilson's Disease) can be misdiagnosed as SCZ becausethey initially present with psychosis in some individuals. Insome of these misdiagnosed cases, antipsychotics are noteffective. Therefore, genetically screening individuals withHTRS may uncover Mendelian disorders that present aspsychosis and are misdiagnosed as SCZ. If ideal HTRSsubjects can be identified, we can screen their genomesfor rare Mendelian disorders that mimic SCZ.Methods: The Pennsylvania state psychiatric hospitalscontain an ideal HTRS sample, and we are recruitingparticipants for genomic assays (n=1000). Our formalinclusion criteria are: provision of written informed con-sent; age Z18 years; DSM-IV diagnosis of SCZ, schizoaffec-tive disorder, or psychosis NOS; Z5 years of continuousinpatient hospitalization; Z5 years of persistent psychoticsymptoms with GAF scores r40 over the course of docu-mented hospitalization; a history of poor treatmentresponse to adequate trials of Z3 different classes ofantipsychotic drugs at recommended maximum dose intrials lasting Z6 weeks. Medications must include a first-generation antipsychotic and two second-generation anti-psychotics (e.g., HTRS with adequate trials of haloperidol,

clozapine, and quetiapine). Our exclusion criteria are asfollows: DSM-IV psychotic disorder consequent to licit orillicit drug dependence; sustained treatment response (GAFscore 440 for any 3-month period); or sustained refusal totake prescribed medications (45% of the 5-year screeningwindow). For our pilot study, we selected 3 extreme casesfor whole genome sequencing and array genotyping.Results: In our small pilot study, we identified 22q11DSand pathologically confirmed Huntington Disease in anindividual with HTRS, the first reported instance of thiscombination. This rare combination of genetic variantscreated a clinical portrait initially indistinguishable fromSCZ – the individual was originally treatment responsive.Discussion: We are collecting a sample of HTRS that willbe screened for Mendelian disorders that mimic schizophre-nia. Our preliminary findings suggest that our sample maycontain a novel source of genotype-phenotype relationshipsthat can be used to identify actionable variation foretiological research, clinical utility, and therapeuticdevelopment.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.401

M95. SCHIZOPHRENIA RELATED MIRNAS SELECTION IN ABRAZILIAN SAMPLE

Gabriela Xaviern,1, Fernanda Talarico1, Marcos Santoro1,

Vanessa Ota1, Patricia Moretti2, Giovany Costa1,Ary Gadelha1, Renata Pellegrino3, Rodrigo Bressan1,Hakon Hakonarson4, Sintia Belangero1

1Federal University of São Paulo2University of Brasilia3Center for Applied Genomics, Children's Hospital ofPhiladelphia4Children's Hospital of Philadelphia

Background: Schizophrenia is a multifactorial complexdisease that strikes approximately 1% of world population. Acomplex interaction between genetic and environmentalfactors seems to play a role in schizophrenia, and microRNAsmight be involved. Single Nucleotide Polymorphism (SNP) ingenes related to miRNAs biogenesis (such as DGCR8 locatedin the 22q11.2 region), in miRNA-encoding genomic loci (asin MIR137, classically associated to schizophrenia) or in seedmatch sequences of miRNAs target genes have been asso-ciated with a higher risk of developing psychiatric disorders.Although many studies on miRNAs have been conducted,few new miRNA targets are identified. In search of a betterselection of target miRNAs, we propose to select miRNAswith a higher chance to be involved in schizophrenia takingas starting point SNPs associated to schizophrenia in aBrazilian sample of patients. Therefore, we aim to examinewhether schizophrenia risk genes are more prone to beregulated by miRNA, identifying which miRNAs act in theregulation of the main risk genes involved in the disease.

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Methods: The design of our study in a Brazilian mixed racesample was based on Engel Hauberg et al. study (2016).Differently, we are going to analyze an admixture casuistic,counting on 258 schizophrenia patients and 239 healthycontrol SNParray data. The samples were genotyped usingSNParray HumanOmniExpress BeadChip (Illumina). The top1% and 5% polymorphisms associated to schizophrenia andonly those that codify proteins will be investigated regard-ing the regulation by miRNAs.Results: The data are still under analysis. After applyingquality control, 24365 variants and 6 individuals wereexcluded, remaining for analysis 668703 variants and 491individuals (256 cases and 235 controls). In our preliminaryresults, the most significant analyzed SNPs were intergenicvariants and in intronic regions and the most associated SNPpresented a significance of 2.125� 10-5. From the finalassociation analysis results, we will select the SNPs atprotein codifying genes and then proceed the remaininganalysis. At the congress date we will present the maingenes and related miRNAs probably involved inschizophrenia.Discussion: This study will be the starting point to adeeper miRNA analysis. Although this is an in silico analysis,the results obtained from this study will be compared withmiRNA-seq results as a study validation. As our next step,we intend to evaluate by miRNA-seq the miRNAs resultingfrom this analysis in serum exosome, once we already havethis collected material of patients and health controls. Oncethe results have been confirmed, this may turn a usefulmethod of selecting target miRNAs for new studies. It isworth remembering Engels-Hauberg et al. have recruited aCaucasian cohort and, replicating it in a mixed sample, suchas the Brazilian one, will show the consistency of thismethod that, in a near future, may be used in studies ofother diseases, whether psychiatric or not.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.402

M96. GENOME-WIDE DNA METHYLATION ANALYSIS IN ALONGITUDINAL COHORT OF ANTIPSYCHOTIC-NAIVEFIRST EPISODE OF PSYCHOSIS PATIENTS

Vanessa Ota1, Marcos Santoron,1, Fernanda Talarico1,

Simone de Jong2, Cristiano Noto1, Gabriela Xavier1,Carolina Carvalho1, Eduardo Gouvea1, Leticia Spindola1,Ary Gadelha1, Quirino Cordeiro1, Rodrigo Bressan1,Gerome Breen2, Sintia Belangero1

1Interdisciplinary Laboratory of Clinical Neurosciences,Universidad Federal de São Paulo2King's College London

Background: The study of the early stages of schizophre-nia, the First-Episode Psychosis (FEP), is critical given thatbrain abnormalities and cognitive deficits are already pre-sent. Although less investigated than chronic schizophrenia,FEP individuals have a shorter period of medication and

duration of symptoms. In this study, we aimed to identifygenetic markers, using whole DNA methylation, for psycho-tic disorder and antipsychotic treatment in blood of a FEPcohort before and after two months of risperidone.Methods: Sixty controls and sixty antipsychotic naïve FEPpatients followed-up for two months after risperidone (FEP-2M) were recruited. All patients were 16–40 years old andhave met the criteria of psychotic diagnoses according toDSM-IV. We generated the DNA methylation data using theHuman Illumina 450 K BeadChip microarray. We used limmaR package, using two separate analyses: FEP x HC andFEPxFEP-2M (paired); and addind sex, age, smoking dataand cell type proportion as covariates. We considered assignificant Differentially Methylated Positions (DMPs) with pvalue lower than 0.05 after a Bonferroni correction formultiple comparisons and differentially methylated regions(DMRs) with at least two significant DMPs (FDR) within a500 bp region.Results: We found 5 DMRs and 16 DMPs comparing controlsand FEP, and 14 DMRs and 77 DMPs between FEP before andafter treatment.Discussion: To our knowledge, this is the first study to findDMRs in a longitudinal cohort of antipsychotic naïve FEPpatients. Collectively, DMRs in the longitudinal comparisonseem to be related to the adverse effects and the responseto risperidone. Notably, the most associated genomic regionin schizophrenia (previously reported by the PGC), the MHCregion, is differentially methylated in patients after thetreatment, demonstrating an epigenetic modificationcaused by risperidone in an important schizophrenia geno-mic region. Identifying the genetic and molecular changesof drug response is one of the first steps through persona-lized medicine, further studies should replicate theseresults and aim antipsychotic naive individuals treated withother antipsychotics.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.403

M97. TRANSCRIPTIONAL SIGNATURES OF CHILDHOODONSET SCHIZOPHRENIA IN HIPSC-DERIVED NPCS ANDNEURONS ARE CONCORDANT WITH SIGNATURES FROMPOST MORTEM ADULT BRAINS

Gabriel Hoffmann,1, Brigham Hartley2, Erin Flaherty2,

Ian Ladran2, Peter Gochman3, Doug Ruderfer4,Judith Rapoport5, Pamela Sklar4, Kristen Brennand4

1Icahn School of Medicine at Mount Sinai2Friedman Brain Institute, Icahn School of Medicine atMount Sinai3Childhood Psychiatry Branch, National Institute of MentalHealth, National Institutes of Health4Institute of Genomics and Multiscale Biology, Icahn Schoolof Medicine at Mount Sinai5National Institute of Mental Health, National Institutes ofHealth

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Background: Large-scale Genome Wide Association Stu-dies (GWAS) revealed that Schizophrenia (SZ) risk reflectsboth rare and common variants. Whereas highly penetrantrare variants have proven well-suited to human inducedpluripotent stem cell (hiPSC)-based models, the power ofhiPSC-based studies to resolve the much smaller effects ofcommon variants within the size of cohorts that can berealistically assembled remains uncertain. Childhood-Onset-SZ (COS) patients have both a higher rate of rare SZ-associated Copy Number Variations (CNVs), and also stron-ger common SZ polygenic risk scores.Methods: We developed a case/control hiPSC cohort (12individuals with COS and 10 controls) with which to conducta comprehensive evaluation of global gene expression inhiPSC-derived neural progenitor cells (NPCs) and neurons.Results: Although we identified many sources of variationacross our 94 RNAseq samples, this was partially addressedby establishing a rigorous series of bioinformatic practicesto reduce and assess the variance inherent in this approach.We report that the donor-specific signal is enriched for post-mortem brain Expression Quantitative Trait Loci (eQTLs),but also that there is a significant correlation between thecase/control differential expression observed in our hiPSC-derived COS neurons and the CommonMind Consortium post-mortem study. While the issue of small sample size is sharedbetween post-mortem and hiPSC-based studies, and may beexacerbated in hiPSC-based experiments through the varia-bility that arises as a result of the reprogramming andneural differentiation processes, we find that the commonvariation effects predicted in GWAS and detected in muchlarger post-mortem analyses are reflected in hiPSC-neurons.Discussion: We predict a growing convergence of commonvariation findings between hiPSC and post-mortem studiesas both approaches expand to larger cohort sizes.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.404

M98. EVENT-RELATED P300 AMPLITUDE AS AN ENDO-PHENOTYPE OF SCHIZOPHRENIA: ASSOCIATION WITHGENOME WIDE SIGNIFICANT INDEX SINGLE NUCLEOTIDEPOLYMORPHISMS

Frank Pillmannn,1, Bettina Konte1, Annette M. Hartmann1,

Gregor Leicht2, Susanne Karch3, Georg Juckel4,Ulrich Hegerl5, Oliver Pogarell3, Ina Giegling1,Christoph Mulert2, Dan Rujescu1

1Martin Luther University Halle-Wittenberg2University Medical Center Hamburg-Eppendorf3Ludwig Maximilian University of Munich4Ruhr University Bochum, LWL University Hospital5University of Leipzig

Background: Reduced amplitude of the event relatedP300 potential is a prominent finding in schizophreniapatients and a promising endophenotype for genetic

research. As yet, little is known on common genetic riskfactors for P300 amplitude reduction and the clinicalmanifestation of schizophrenia. Recently, the PsychiatricGenomics Consortium (PGC2) identified 128 independentassociations spanning 108 conservatively defined loci thatmeet genome-wide significance. We used data from 269normal subjects with both electrophysiological and geno-type data to explore the possible relevance of theseschizophrenia index SNPs on the P300 amplitude.Methods: The sample comprised 269 unrelated healthyvolunteers of German descent from the general populationof Munich, Germany. Subjects with neuropsychiatric disor-ders were excluded. Evoked potentials were recorded usingan auditory oddball paradigm with 80% non-target stimuli(540 tones, 500 Hz) and 20% target stimuli (135 tones,1000 Hz) presented binaurally through headphones in apseudo randomized order. The P300 amplitude was detectedsemiautomatically as the most positive value in the time-frame 250–500ms post-stimulus with a visual control after-wards at the electrode position Fz. The sample wasgenotyped on different platforms following establishedquality control and imputation protocols. After excludingtwo SNPs with insufficient quality of imputation, 126genome-wide significant schizophrenia index SNPs fromPGC2 could be evaluated for association with P300 ampli-tude by linear regression.Results: There were 12 associations significant on thep=0.05 level (chr5_140143664_I, rs6002655, rs12887734,rs11191419, rs75059851, rs7907645, rs7432375, rs12421382,rs36068923, rs6065094, chr10_104957618_I, rs6670165).None of the associations survived Bonferroni correction for126 comparisons. When employing the exact binomial testthe number of significant associations observed exceededchance expectation (p=0,024). Only one half of the asso-ciations showed effects in the expected direction (lowerP300 amplitude associated with schizophrenia risk allele oramplitude associated with protective allele).Discussion: Although we found an overrepresentation ofsignificant associations of schizophrenia index SNPs withevent related P300 amplitudes we were unable to establishthe connection for any specific locus with sufficient statis-tical power. The pattern of observed effects was notsupportive of a specific role of PGC2 schizophrenia riskalleles in P300 amplitude in normal subjects.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.405

M99. CELL-SPECIFIC HISTONE MODIFICATION MAPSLINK SCHIZOPHRENIA RISK TO THE NEURONALEPIGENOME

Kiran Girdharn,1, Gabriel Hoffman1, Yan Jiang1,

Marija Kundakovic1, Mads Engel Hauberg2, Ying-chih Wang1,Hardik Shah1, Zhiping Weng3, Solveig K. Sieberts4, Mette A.Peters4, Brent T. Harris6, Barbara Lipska6, Pamela Sklar1,Panos Roussos1, Schahram Akbarian1

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1Icahn School of Medicine at Mount Sinai2Aarhus University3University of Massachusetts Medical School4Systems Biology5Sage Bionetworks6National Institute of Mental Health

Background: Recent progress in understanding thegenetic basis of many psychiatric diseases has identifiedrare and common variants responsible for genetic risk.Integrating epigenomics data from disease-relevant celltypes and tissues promises to enhance interpretation ofthese risk variants and the mechanisms by which they conferdisease liability. A better understanding of the role of non-coding regulatory DNA and variation in histone modificationin mediating the effects of genetic risk variants promises togive insights into the molecular mechanisms underlyingpsychiatric disease. With this goal in mind, the PsychEN-CODE Consortium generated a large-scale epigenomicsresource for the human brain to serve as a foundation forintegrative genomics in psychiatric research.Methods: We performed ChIP-Seq on 17 subjects, 2 brainregions, 2 cell types and 2 histone marks that yielded 136total ChIP-Seq samples. Of these 129 (n=63 H3K4me3; n=66H3K27ac) passed quality control. For each combination ofbrain region, cell type and histone mark, reads fromcorresponding samples were combined into a consolidatedsubset of the data. This produced 8 consolidated subsets,corresponding to: ACC-neuronal-H3K4me3, PFC-neuronal-H3K4me3, etc. The entire data set was then processedand analyzed through the annotation, peak calling, covari-ate and pathway analyses pipeline.Results: We have generated the largest cell type-specificdataset of histone-modification in the human brain to dateacross two brain cortical regions, composed of referencemaps from 129 samples collected from 17 healthy subjects.These reference maps consist of ChIP-Seq for two histonemarks associated with promoters and active enhancers, H3-trimethyl-lysine 4 (H3K4me3) and H3-acetyl-lysine 27(H3K27ac) from either neurons, or surrounding non-neuronalcells. Analysis of this data has revealed unexplored insightsinto cell-, brain region- and to a lesser extent, subject- andsex-specific histone methylation and acetylation landscapesshaping the epigenome of the adult human cerebral cortex.We identify multiple loci with robust region-specific differ-ences separating prefrontal from cingulate neurons, andnumerous genome loci with extraordinary high inter-indivi-dual variability in H3K27ac and H3K4me3. Finally, we founda significant enrichment of risk variants for schizophrenia,educational attainment and depressive symptoms only inneuronal markers, further indicating the importance ofconducting cell type-specific epigenome studies.Discussion: Risk variants for schizophrenia, depressivesymptoms, neuroticism and educational years are signifi-cantly enriched in genomic loci marked specifically inneuronal cells. The difference between neuronal and non-neuronal cells is the major axis of variation in histonemodification, yet many genomic loci show substantial epige-netic variability across subjects and brain regions. Thesefindings highlight the utility of this NIMH PsychENCODE-sponsored resource to elucidate epigenomic architectures

of regulatory and disease-associated non-coding DNA in thehuman brain.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.406

M100. A MULTI-LEVEL FUNCTIONAL STUDY OF ASNAP25 AT-RISK VARIANT FOR BIPOLAR DISORDERAND SCHIZOPHRENIA

Stephane Jamainn,1, Josselin Houenou1,

Jennifer Boisgontier1, Annabelle Henrion1,Marc-Antoine d'Albis1, Anne Dumaine1, Julia Linke2,Michèle Wessa2, Pierre-Michel Llorca3, Franck Schürhoff3,Andrei Szoke3, Caroline Barau4, Bruno Etain5, Cyril Poupon6,Marion Leboyer4

1Inserm U955, Psychiatrie Translationnelle2Institute for Psychology Johannes Gutenberg-University ofMainz3CHU Clermont Ferrand, Fondation FondaMental4AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme deRessources Biologiques5AP-HP, Service de Psychiatrie, Hôpital Lariboisiere FernandWidal, INSERM U 705 CNRS UMR 8206, Paris DiderotUniversity6UNIRS Lab, NeuroSpin Neuroimaging Platform, CEA Saclay

Background: The synaptosomal associated proteinSNAP25 is crucial for synaptic vesicle docking and fusionand has been associated with multiple psychiatric condi-tions. We recently identified a promoter variant in SNAP25,rs6039769, associated with bipolar disorder and geneexpression in prefrontal cortex.Methods: Here, we performed a genetic association studyusing this variation on two independent cohorts of 288 and173 subjects with schizophrenia and 315 unaffected controlindividuals. We replicated our results using data from theschizophrenia group of the Psychiatric Genomics Consortium(PGC). Functional consequences combined both in vitro andpost-mortem gene expression analysis on 30 patients withschizophrenia and 33 unaffected controls. Structural andfunctional magnetic resonance imaging in regards to SNAP25genotypes was performed on 71 subjects and replicated on121 individuals.Results: We showed that rs6039769 was associated withschizophrenia in the two cohorts of patients as well as in theCaucasian population of the PGC cohort and demonstratedin vitro this variant was sufficient to increase the SNAP25transcription level. In a postmortem expression analysis, weshowed that the SNAP25b:SNAP25a ratio was increased inpatients carrying the at-risk allele. Imaging genetics studiesrevealed that risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity anda larger amygdala.Discussion: This multi-level functional study brings strongevidence for the functional consequences of this SNAP25

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variation on the prefrontal-limbic network and the increasedrisk of developing associated psychiatric disorders.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.407

M101. THE DISC1 GENE AND MAJOR MENTAL ILLNESS INFINLAND

Vishal Sinhan,1, William Hennah2, Liisa Ukkola-Vuoti2,

Alfredo Ortega-Alonso3, Timo Partonen4, Minna Torniainen4,Iiris Hovatta1, Tyrone Cannon5, Tiina Paunio4, Jari Haukka6,Jaana Suvisaari4, Sebastian Therman4, Jouko Lönnqvist4,Jaakko Kaprio1

1University of Helsinki2Institute for Molecular Medicine3Institute for Molecular Medicine, University of Helsinki4National Institute for Health and Welfare5Yale University6Hjelt Institute, University of Helsinki

Background: Linkage and association studies of majormental illness in Finland have continually identified the1q42 region, and the Disrupted in Schizophrenia 1 (DISC1)gene in particular, as being a key locus of interest.Haplotypes and variants in the DISC1 gene have beenassociated with Schizophrenia (SCZ), bipolar disorder, andautism spectrum disorders, as well as to variations inrelated endophenotypes such as visual working memory,anhedonia, and gray matter volume in the dorsal lateralprefrontal cortex. Despite this consistent line of evidencefor these loci in the Finnish population, any true causalvariants within the DISC1 gene are yet to be identified.Methods: To identify any potential mutations, a subset offamilies ascertained for SCZ (n=20 families, 96 individuals)were sequenced using Nimblegen SeqCap EZ for the DISC1gene locus, including TSNAX. All identified variants were thenprioritized using association analysis (po0.05) combined withbioinformatic prediction of function, with major focus onexonic and regulatory variants. Selected variants (n=28)were then genotyped in a larger sub-cohort of the familialSCZ cohort (n=1,133 individuals in 301 families), alongsidepopulation based controls (n=323), to verify these observa-tions we obtained in the small discovery sample. Verificationof both the variants existence and association (po0.05) toSCZ, or alternative phenotypes available in these families,led to the selection of 7 variants to be genotyped acrossFinnish cohorts for different major mental illnesses. Includingthe rest of the SCZ cohort (n= 2,837), a family cohort forbipolar disorder (n=650), twin pairs concordant and discor-dant for SCZ (n=303), a population cohort for anxietydisorders (n=823), a cohort for psychosis (n=125) andpopulation based controls (n=1,117).Results: With the aid of this three-step sequencing andgenotyping approach, we identified 1,828 variants in theDISC1 gene, of which 28 variants were identified as

associated (po0.05) and located in potentially functionalregions. Of these, 7 variants could be verified in a largercohort, and thus studied across multiple cohorts. Prelimin-ary results highlight a specific 5’ exonic variant associatingto both schizophrenia and anxiety disorders(pscz=3.24� 10–11; panxiety=0.011), and a 3’ intronicvariant associated with schizophrenia and bipolar disorder(pscz=0.0024; pbipolar=0.031).Discussion: We aim to identify the potential mutationswithin the DISC1 gene which have been alluded to throughour previous studies of Finnish cohorts for major mentalillness. Our initial findings confirm the observation ofassociation for several variants in the DISC1 gene for variedphenotypes, while focusing on the specific variants thathave potential functional consequences. The variants wereport may represent the principal major mental illnessmutations within the DISC1 gene in the Finnish population.Once the relevance of these mutations to multiple diag-nostic criteria is determined, we will study these mutationswith respect to alternative phenotypes to the diagnosesavailable in these cohorts, including neuropsychologicalendophenotypes, neuroimaging, gene expression levels fromlymphocytes, and medication usage.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.408

M102. VARIATION IN VOLTAGE-GATED CALCIUM CHAN-NEL GENES IS ASSOCIATED WITH ANTIPSYCHOTICTREATMENT RESPONSE IN A SOUTH AFRICAN FIRSTEPISODE SCHIZOPHRENIA COHORT

Kevin O'Connelln

, Nathaniel McGregor, Louisa Warnich

Stellenbosch University

Background: Voltage-gated calcium channels have beenimplicated in schizophrenia aetiology, however little is knownabout their involvement in antipsychotic treatment response.This study investigated variants within the calcium channelsubunit genes for association with antipsychotic treatmentresponse in a first episode schizophrenia cohort.Methods: The patient cohort included 103 unrelatedSouth African FES patients (80% South African Coloured,12% Xhosa and 8% European descent). Treatment responsewas assessed using the positive and negative syndrome scale(PANSS) over a period of 12 months, with measurementstaken biweekly for the first six weeks, and every threemonths thereafter. Variants within the calcium channelsubunit genes (α1, α2δ, β and γ subunits) were mined fromavailable GWAS data produced using the Infinium OmniEx-pressExome-8 Kit (Illumina, California, USA). In total 1830variants were identified within 10 CACNA1 genes, fourCACNB genes, four CACNA2D genes and eight CACNG genes.Linear mixed-effects models were used to investigate theeffect of genetic variants on change in PANSS scores foreach domain (positive, negative, general and total) over the

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twelve-month period, adjusting for age, gender, proportionancestry, and baseline PANSS scores. Multiple modes ofinheritance were considered and the best-fit model wasselected for further analysis.Results: Twelve regulatory variants were shown to besignificantly associated with treatment outcome. Mostnotably the CACNA1B rs2229949 CC genotype was associatedwith improved negative symptomology, where the C-allelewas predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of actionthrough which this variant may have an effect.Discussion: These results implicate the calcium channelsubunits in antipsychotic treatment response and suggestthat increased activation of these channels may be exploredto enhance or predict antipsychotic treatment outcome.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.409

M103. WHOLE GENOME SEQUENCING APPROACH TOIDENTIFY SUSCEPTIBILITY RARE VARIANTS IN A MULTI-PLEX NUCLEAR FAMILY OF SCHIZOPHRENIA AND FOL-LOW-UP RESEQUENCING

Shun-Chun Yun,1, Hsuan-Yu Chen2, Sung-Liang Yu3,

Chih-Min Liu4, Hai-Gwo Hwu5, Wei J. Chen6

1Institute of Epidemiology and Preventive Medicine,National Taiwan University2Institute of Statistical Science, Academia Sinica3College of Medicine, National Taiwan University; Center ofGenomic Medicine, National Taiwan University4National Taiwan University Hospital5National Taiwan University6College of Public Health, National Taiwan University

Background: Previous family, twins, and adoption studieshave indicated substantial genetic contribution to schizo-phrenia. With the advent of Next-Generation Sequencing(NGS), a massively parallel throughput method that cansequence the whole human genome, it becomes feasible tosearch the whole genome for rare genetic variants specificto schizophrenia patients. A previous study among a largenumber of families of sib-pair co-affected with schizophre-nia in Taiwan has revealed several linkage signals byincorporating several endophenotypes. This implies exis-tence of genetic heterogeneity in schizophrenia. Wehypothesized that there may be some rare but highlypenetrant variants which segregate with schizophreniawithin multiplex families. We hence postulated that multi-plex nuclear families of schizophrenia may help identifycertain inherited rare variants that can be used for replica-tion in other multiplex families of schizophrenia.

Methods: We selected one high density schizophrenia familyfrom Taiwan Schizophrenia Linkage Study (TSLS), whichrecruited schizophrenia patients and their first-degree relativesthroughout Taiwan from 1998 to 2002. Whole genome sequen-cing was performed to sequence the whole genomes of a5-member nuclear family, in which the mother and 2 childrenaffected with schizophrenia, and the father and another childunaffected. Both dominant and recessive inheritance modelswere used to explore schizophrenia related genomic variations.The candidate variants selected from both dominant andrecessive inheritance models warrant further replication inother multiplex families from TSLS.Results: The results showed that total 1,147 variants wereselected under recessive inheritance model. Whereas therewere 39,330 variants selected under the dominant inheri-tance model. After comparing with the alleles listed in the1000 Genomes Project, 1,626 variants that exhibited inheri-tance in the family but not seen in other known data baseswere identified for those in accordance with dominantinheritance model. Besides, 3 non-synonymous exonic SNVswere resequenced in 5 individuals of the schizophreniamultiplex family by Sanger sequencing. One of these3 non-synonymous exonic SNVs were replicated in other7 multiplex families from TSLS with higher allele frequencywithin TSLS than Taiwan biobank. The other 2 non-synon-ymous exonic SNVs were private to this schizophreniamultiplex family.Discussion: Our findings demonstrated the utility of NGSin identifying inherited rare genetic variants that arepotentially associated with multiplex schizophrenia. Ouruse of a multiplex family can help exclude those variantsdue to typing error, or de novo mutations, and hence selectthose with high-penetrating susceptibility genetic variantsfor schizophrenia. In particular, one of the 3 non-synon-ymous exonic SNVs was identified in other 7 multiplexfamilies from TSLS. The other 2 private non-synonymousexonic SNVs and remaining intronic SNVs require furtherevaluation in context of supporting data. This may lead todiscovery if rare but inheritable susceptibility variants forschizophrenia and their underlying pathophysiology.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.410

M104. EXAMINING ATTENTION DEFICIT HYPERACTIVITYDISORDER (ADHD) INATTENTION SYMPTOMS AS ANTE-CEDENTS OF PSYCHOSIS RISK IN 22Q11.2 DELETIONSYNDROME (22Q11.2DS)

Maria Niarchoun,1, Jacob Vorstman2, Maude Schneider3,

Stephan Eliez3, Marco Armando4, Donna McDonald-McGinn5,Carrie Bearden6, Vandana Shashi7, Stephen Hooper7,Marianne Van Den Bree1, Michael Owen8, Raquel E. Gur9,Naomi Wray10, Anita Thapar1

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1Cardiff University2Rudolf Magnus Institute3University of Geneva4University of Rome La Sapienza5Childrens Hospital of Philadelphia6University of California Los Angeles7Duke University8MRC Centre for Neuropsychaitric Genetics and Genomics,Cardiff University9University of Pennsylvania10The University of Queensland

Background: 22q11.2 Deletion Syndrome (22q11.2DS) isassociated with high risk for developing schizophrenia inadulthood while Attention Deficit Hyperactivity Disorder(ADHD) constitutes the most frequent diagnosis in child-hood. Individuals with 22q11.2DS show marked inattentionsymptoms. Interestingly, schizophrenia is also characterizedby attentional deficits. This raises the question of whetherchildhood inattention is an antecedent of psychosis in22q11.2DS. This is the first longitudinal study to examinewhether childhood inattention is associated with the lateremergence of Psychotic Experiences (PEs) and psychosisspectrum disorders in 22q11.2DS.Methods: 294 individuals (mean age (SD):15.9(5.8)) com-pleted assessments on psychotic symptoms and ADHD at twotime points and did not report PEs at time 1(T1).Results: Inattention symptoms and ADHD diagnosis at T1were associated with PEs at T2 when adjusting for age, sex,IQ and assessment differences (Odds Ratio: 1.18, p=0.02).ADHD diagnosis at T1 was also associated with psychosisspectrum disorder at T2 (Odds Ratio: 4.8, po0.001).Discussion: This is the first study to examine the long-itudinal associations between ADHD and psychosis in22q11.2DS. Our findings support an important role of ADHDinattention symptoms in the development of psychosis in22q11.2DS.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.411

M105. POTENTIAL ASSOCIATION OF MIR-137 WITH AGEOF ONSET OF SCHIZOPHRENIA

Gabriela Chavarria-Soleyn,1, Javier Contreras2,

Patricia Bolaños-Palmieri3, Daniela Ugalde-Araya3,Alejandro Avila-Aguirre3, Christopher Mairena-Acuña2,Henriette Raventos3

1Escuela de Biologia, Universidad de Costa Rica2Centro de Investigación en Biología Celular y Molecular3Centro de Investigación en Biología Celular y Molecular andEscuela de Biología, UCR

Background: MicroRNAs (miRNAs) play a vital role in neuro-development and neuronal processes by regulating the activityof multiple genes. Noncoding variants in the miR-137 gene locushave been reported to increase the risk of schizophrenia. This

microRNA has been shown to be involved in different brainprocesses necessary for neurogenesis, which is an importantfactor in schizophrenia. Additionally, several of the confirmedor predicted target genes for miR-137 have been associatedwith schizophrenia risk.Methods: In the present study, we sequenced the miR-137gene (including the upstream and downstream region) in 52Costa Rican trios, consisting of individuals diagnosed withschizophrenia and their parents. A TDT test was performedfor the two detected variants: the schizophrenia-associatedSNP rs1625579 and a previously reported VNTR locatedupstream of miR-137.Results: No association was found between any rs1625579allele and schizophrenia (X2=1, p=0.32). The minor allelefrequency (MAF; corresponding to the C allele) in the CostaRican sample is 0.08. For the VNTR upstream of miR-137only the 3 and 4-repeat alleles were found. The frequencyof the 4-repeat allele in our sample (MAF) was 0.19. Noassociation (using the TDT test) was detected between anyof the alleles and schizophrenia (X2=0.05, p=0.83). How-ever, we found a lower age of onset in the affectedindividuals with at least one 4-repeat allele, when com-pared with individuals homozygous for the 3-repeat allele(t=2,3, g.l.=44, p=0,026).Discussion: Age of onset of schizophrenia has clinicalconsequences for affected individuals; an early onset ofthe disorder has been reported to be associated with worsecognitive performance as well as worse functional out-comes. The presence of a higher number of repeats forthe VNTR upstream of miR-137 could potentially affectexpression of the gene, and in this way have an effect onthe age of onset of schizophrenia symptoms. Genotyping ofthe VNTR in other 100 individuals with schizophrenia isongoing, in order to confirm the putative role of variants inthis locus on age of onset of the disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.412

M106. GENE CO-EXPRESSION REVEALS PATHWAYS OFCONVERGENCE OF SCHIZOPHRENIA RISK GENES

Giulio Pergola1, Pasquale Di Carlo1, Andrew Jaffe2,Marco Papalino

n,1, Giuseppe Blasi3, Daniel Weinberger2,Alessandro Bertolino1

1University of Bari Aldo Moro2Lieber Institute for Brain Development3Bari University Hospital

Background: Schizophrenia (SCZ) is associated withgenetic factors, and specific risk loci have recently beenidentified. Still, the biology and functional or clinicaltranslation of SCZ risk genes remain largely unknown. Atleast some of the Psychiatric Genomic Consortium (PGC)genetic variants control gene expression [1]. Since theexpression of individual genes is co-regulated and resultsin the co-expression of gene sets, we hypothesized that SCZ

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risk genes may converge into co-expression pathways which,in turn, may be associated with clinical phenotypes inpatients with SCZ. Previous work in microarray post-mortembrain gene expression data shows that co-expression net-works have biological plausibility for SCZ [2].Methods: Here, we used RNA sequencing data from theLieber Institute for Brain Development (LIBD, N=343) [1] andthe Common Mind Consortium (CMC, N=345) [3] to identifygene co-expression networks through Weighted Gene Co-expression Analysis. To detect gene modules in which PGCSCZ risk protein coding genes (n=300) were overrepresented,we computed hypergeometric tests and corrected the resultsfor multiple comparisons (Bonferroni, number of modules=43).Then, we generated a Polygenic Co-expression Index (PCI)predicting gene co-expression based on a meta-analysis of LIBDand CMC. We replicated the PCI-co-expression association inBrainEAC, an independent post mortem microarray dataset(N=38). Finally, we studied a clinical cohort of drug-freepatients with SCZ treated with olanzapine in monotherapy(N=49). We correlated patients’ PCI both with symptomsseverity at the baseline assessment and treatment response(endpoint – baseline) in terms of positive, negative, and generalPANSS domains. We Bonferroni-corrected results for the numberof PANSS subscales (n=3).Results: In LIBD, we discovered a single gene set enrichedfor SCZ risk loci (157 protein coding genes; PGC hits=12;corrected p=.0007), which was successfully replicated inCMC (empirical po.0001). The PCI computed using the firstsix variants predicting the co-expression of this gene set inLIBD and CMC was also replicated in BrainEAC (p=0.041). ThePCI was significantly correlated both with positive symptomsseverity at the baseline (Spearman's rho=-.44; correctedp=.0068) and with treatment response in terms of positivesymptoms (Spearman's rho=-.44; corrected p=.0068).Discussion: These results corroborate the hypothesis thatco-expression pathways are relevant to the neurobiology ofSCZ and that a significant proportion of the risk genes is co-expressed in the dorsolateral prefrontal cortex. Further-more, these findings provide preliminary evidence for theclinical relevance of this co-expression pathway and of thegenetic variants associated with it.

Disclosure: Nothing to disclose.

References

[1] Jaffe AE, et al. 2017. bioRxiv doi: http://dx.doi.org/10.1101/124321.

[2] Pergola G, et al. Translational Psychiatry 2017;7(1):e1006.

[3] Fromer, M., et al., Nat Neurosci, 2016. 19(11): p. 1442–1453.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.413

M107. IDENTIFICATION OF CLINICAL FEATURES THATPREDICT FUTURE WEIGHT TRAJECTORY IN A NOVELCOHORT OF CLOZAPINE-TREATED PATIENTS

Rebecca Harrisonn,1, Gerome Breen1, Lewis Couchman2,

Adam Socrates1, Omowonuola Akingbuwa1, Alice Coulson1,David Dempster1, Rufina Leung1, Xiaohui Xu1,Danielle Fisher2, Krithika Subramaniam2, Robert Flanagan2

1King's College London2King's College Hospital NHS Foundation Trust

Background: There is a lack of genetic and epidemiolo-gical studies specific to weight gain among individualsreceiving clozapine treatment for established psychosis.Knowing if patients have factors that predispose them toweight gain trajectory or a weight constant trajectorywould enable more effective targeting of weight lossprograms to avoid problematic weight gain. This study aimsto assess the trajectory of weight gain using data routinelycollected by Clozapine Therapeutic Monitoring Services in anovel longitudinal cohort of clozapine patients from theUnited Kingdom and Ireland. We use genetic, clinical anddemographic data to determine the influence of thesevariables on trajectory membership.Methods: A total of 3500 individuals had clinical and candi-date/proven gene data available. Weight trajectory was calcu-lated from individuals who had at least two weight records overa period of 24 months from the first available record.Trajectories were developed utilising K-Means for Longitudinaldata (KML), an algorithm that assigns individuals to a user-defined number of trajectories based on their similarity.Results: There are three distinct trajectories patientstake within the first 2 years of clozapine treatment, whichare influenced by age, starting weight and clozapine plasmalevel. Weight gain is more likely to be seen in individualswith younger age, lower plasma levels and lower startingweight.Discussion: Individuals under the age of 25 with lowerstarting weight were more likely to be in the weight gaintrajectory, whereas older people with higher startingweights were more likely to be in the weight loss trajectory.This could be due to individuals in the weight loss trajectoryactively reducing weight after prior weight gain from otherantipsychotics. Clozapine plasma levels were also lower inthe weight gain trajectory, possibly reflecting incorrectdosage or non-compliance. Clozapine levels were morelikely to be in the normal range for individuals in theweight-constant or weight -loss trajectory, reflecting astable maintenance dosage and increased compliance.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.414

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M108. A NOVEL RARE VARIANT R292H IN RTN4RAFFECTS GROWTH CONE FORMATION AND POSSIBLYCONTRIBUTES TO SCHIZOPHRENIA SUSCEPTIBILITY

Hiroki Kimuran,1, Kanako Ishizuka2, Chenyao Wang1,

Itaru Kushima3, Mako Morikawa1, Yota Uno4, Takashi Okada3,Toshiya Inanda1, Branko Aleksic1, Daisuke Mori1,Norio Ozaki3

1Nagoya University2Nagoya University Hospital3Nagoya University, Graduate School of Medicine4Laboratory for Psychiatric and Molecular Neuroscience,McLean Hospital

Background: RTN4R (Reticulon 4 receptor) plays anessential role in regulating axonal regeneration and plasti-city in the central nervous system through the activation ofrho kinase, and is located within chromosome 22q11.2, aregion that is known to be a hot-spot for Schizophrenia(SCZ) and Autism Spectrum Disorder (ASD). Recently, rarevariants such as Copy Number Variants (CNV) and SingleNucleotide Variants (SNV) have been a focus of researchbecause of their large effect size associated with increasedsusceptibility to SCZ and ASD and the possibility of elucidat-ing the pathophysiology of mental disorder through func-tional analysis of the discovered rare variants.Methods: In order to discover rare variants with largeeffect size and to explore their role in the etiopathophy-siology of SCZ and ASD, we performed mutation screening ofRTN4R coding exons using a sample comprised of 370 SCZand 192 ASD patients, and association analysis using a largenumber of unrelated individuals (1716 SCZ, 382 ASD and4009 controls).Results: Through this mutation screening, we discoveredfour rare (minor allele frequency o 1%) missense mutations(R68H, D259N, R292H, and V363M) of RTN4R. Among thesediscovered rare mutations, R292H was found to be signifi-cantly associated with SCZ (p=0.048). Furthermore, in vitrofunctional assays showed that the R292H mutation affectedthe formation of growth cones.Discussion: This study strengthens the evidence for asso-ciation between rare variants within RTN4R and SCZ, andmay shed light on the molecular mechanisms underlying theneurodevelopmental disorder.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.415

M109. DNA METHYLATION MARKERS ASSOCIATED WITHINJECTION DRUG USE STATUS AND HIV INFECTIONAMONG CHRONIC INJECTION DRUG USERS IN THE ALIVESTUDY

Chang Shun,1, Kelly Bakulski2, Kelly Benke1, Andrew Jaffe3,

Shaocheng Wang1, Sarven Sabunciyan1, Shruti Mehta1,Gregory Kirk1, Brion Maher1

1Johns Hopkins Bloomberg School of Public Health2University of Michigan3Lieber Institute for Brain Development

Background: Injection Drug Use (IDU) is associated withbiological modification of the genome, i.e., epigeneticsmarks such as DNA methylation and histone modification.However, the biological mechanisms of how substance useand cessation affects epigenetic outcomes remain largelyunknown.Methods: In the AIDS Linked to the Intravenous Experi-ence (ALIVE) study, blood was obtained from 288 currentIDUs, resampled after cessation and then again after relapse(total samples=774). Blood DNA methylation marks weremeasured using the Illumina Infinium MethylationEPIC Bead-Chip. Standard procedures in the minfi R package were usedto preprocess raw Illumina image files into noob processedmethylation beta values. Differences in DNA methylation atindividual probes by current injection status were testedusing generalized linear regression including age, gender,race and cell heterogeneity as covariates. DNA methylationage was estimated for study subjects using the epigeneticclock method developed by Horvath et al.Results: DNA methylation at individual loci (cg10801015,p=2.47n10(-11); cg11415166, p=5.15n10(-10); cg03426703,p=2.62n10(-9); cg14977491, p=9.94n10(-8) is significantlyassociated with current injection drug use status aftercorrection for multiple testing. Those CpG sites were nearthe PDP1, NARFL, DVL2 and PFN2 genes correspondingly.Single-site epigenetic analysis of HIV status was also per-formed. HIV positive individual's average biological age isabout 3 years older than their chronological age, but thebiological age among HIV negative individuals, injection drugusers and non-users is no different from their chronologicalage.Discussion: In a preliminary study, we performed a gen-ome-wide scan of methylation changes in a longitudinalstudy of injection drug use and identified genomic locationsexhibiting significant changes in peripheral DNA methylationassociated with injection drug use status. Individuals withHIV infection's biological age is older than their chronologi-cal age, which is consistent with the literature.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.416

M110. ELECTROPHYSIOLOGIC DIFFERENCES TO ALCO-HOL CHALLENGE IN INDIVIDUALS POLYMORPHIC ATADH1B LOCI

Walid Azizn,1, Denise Scott2, Maria Mananita Hipolito2,

Evaristus Nwulia2

1Howard University Hospital2Howard University

Background: The ADH Class 1 is the major group formetabolizing alcohol in humans. Subunits which constitute

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class 1 ADH are encoded by the three genes ADH1A, ADH1B,and ADH1C, giving rise to A, B, and C subunits. Geneticpolymorphisms, occur at ADH1B to give rise to ADH1B1,ADH1B2, and ADH1B3 subunits. Concerning the ADH1B gene,individuals with the ADH1B3 genotype appear to be moreresistant to the stimulating effects of alcohol, possibly dueto a faster-metabolizing capacity of this variant comparedto the wild-type (ADH1B1). The purpose of this study was toexamine the effect of ADH1B polymorphisms on electro-encephalography, using the alcohol clamp technique. Wehypothesize that individuals heterozygous for the ADH1B3allele will have lower alpha power in frontoparietal elec-trodes, suggesting less relaxation effect during alcoholingestion compared to those homozygous for ADH1B1.Methods: A pilot sample of individuals (N=28) genotypedat the ADH1B locus received continuous EEG recordingduring infusion, using the alcohol clamp technique. Thecollected EEG data was analyzed using EEGLAB, an opensource electrophysiological data analysis software applica-tion. The data was preprocessed using FASTER, an EEGLABplugin for Automated EEG artifact Rejection. The FASTERprocess applies independent component analysis and statis-tical thresholds for artifact rejection. The accepted EEGepochs were then submitted to the pwelch FFT implemen-tation using the inbuilt functions of EEGLAB, which com-puted the power of the EEG in 0.24 Hz steps over a totalrange of 1.5 – 40 Hz. The power spectra were averaged overepochs and averaged amplitude peaks extracted. Theestimates of power within the delta (1.5–3.2 Hz), theta(3.8– 7.02 Hz), alpha (7.8–12.5 Hz), and slow (13.2–18.75 Hz)and fast (19.5–39.8 Hz) beta frequency bands were com-puted as the area under the PSD curve.Results: Subjects with ADH1B1/1 have increased alphapower in CZ, FZ and PZ leads during baseline (i.e. pre-alcohol exposure) eye-closed resting EEG, with the greatestdifference (between ADH1B1/1 and ADH1B1/3 observed inthe PZ leads (Po0.008).Discussion: Based on rich evidence from neurophysiologi-cal studies, increased alpha power is indicative of hypoar-ousal; therefore, our data subjects more evidence forcortical hypoarousal in anticipation of alcohol challengeamong individuals with ADH1B1/1 polymorphism.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.417

M111. EXOME SEQUENCING IN SEVERE ALCOHOL USEDISORDER CASES

Jeffry Alexander1, Silviu Bacanu1, Ken Kendler2,Bradley Webb1, Brien Riley

n,2

1Virginia Institute for Psychiatric and Behavioral Genetics2Virginia Commonwealth University

Background: Alcohol Use Disorders (AUD) have been esti-mated to have a heritability of approximately 50%. Whilemost of this heritability is accounted for by common varia-tion, exome studies also implicate rare variants in complextrait liability. Rare functional variants that interfere withethanol metabolism have been shown to reduce AUD risk. Wesought to exome sequence a cohort of severely affected AUDcases to identify rare variation that increases AUD risk.Methods: We completed sequencing of the 71 Mb exome +UTR target to a mean of 60.5x (SD=14.5) depth in 133 AUDcases, with 62 further cases currently in processing. In thecurrent data, 97% of target was coved at 10x. Post-sequencingcalling and recalibration were performed per the GenomeAnalysis Toolkit (GATK) best practices. Markers were limitedto those with a minimum genotype quality score of 20 and aminimum depth of 10, in addition to having passed GATK variantquality score recalibration (VQSR).Results: In the data from the first 133 cases, we detected688949 variants. After filtering for variants having a minorallele frequency (MAF) 4 0.05 in European data from ExAC,UK10K, or 1000 Genomes, 299191 remained, 72277 (24.2%)of which were novel. We identified 1372 loss-of-function(LOF), 29247 missense, and 19365 synonymous changes.

We focused preliminary analyses on alcohol metabolizinggenes. We detected 6 variants present at higher MAF thanfound in UK10K control data: ADH5 (rs28730652, 2=8.62,p=0.003; rs201786928 2=8.31, p=0.004), ADH6(rs189318592, 2=36.63, p=1.43E-9; rs146084391, 2=25.57, p=4.27E-7), and ADH1B (rs375691484, 2=18.31,p=1.87E-5; rs41275699 2=10.42, p=0.001). Some of thesechanges may have relevant functional consequence.Further, these markers are currently being genotyped inour full case-control sample.Discussion: Since known LOF mutations in ADH1B andALDH2 reduce risk for AUD, we are currently performinganalyses of these 2 genes as well as the complete set ofalcohol and aldehyde metabolizing genes (ADH1-6, ALDH1-18, CAT and CYP2E1, N=27 loci) to test the hypothesis thatnumbers of high-impact variants in these genes are signifi-cantly different than matched gene sets in the AUD cases.We matched for 1) coding basepair length, 2) genomicinterval length, 3) N of exons, N of 4) LOF, 5) missense,and 6) synonymous mutations, and the 7) probability of LOFintolerance (pLI) from ExAC data to create comparison genesets for each gene of interest (GOI) to determine if the GOIwere different from their matched clusters for LOF, mis-sense, and synonymous mutations.

Here we have identified 6 possibly functional rarevariants in key alcohol dehydrogenase genes. In addition,we are applying a novel method to investigate whetherpatterns of variation in these target genes are differentthan would be expected based on matched case genesdetermined by current reference data.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.418

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M112. A STUDY ON THE ASSOCIATION OF POLYMORPH-ISMS AND METHYLATION STATUS OF DOPAMINE PATH-WAY GENES IN ALCOHOL DEPENDENCE

Ranjan Guptan

, Renu Singh, Atul Ambekar, Tripti Grover,Arundhati Sharma

AIIMS

Background: Alcohol Dependence (AD), a chronic relap-sing disorder, is a serious social and public health concernglobally. Risk of AD is reportedly increased due to poly-morphisms and methylation changes affecting transcriptionof the genes involved in various dopamine neurotransmittergene pathways. The aim of this study was to identifypolymorphisms and methylation changes in the SNCA andDAT genes of dopamine pathway in subjects with AD.Methods: A total of 145 AD subjects from the outpatientdepartment of Psychiatry and 110 healthy volunteers wererecruited for the study. All subjects were interviewed with asemi-structured and WHO assist questionnaire. Blood sam-ples drawn were subjected to DNA extraction, followed bysodium bisulphite modification and methylation specific PCRof the SNCA and DAT genes. DNA was also used to screen sixpolymorphisms of the dopamine pathway namely DRD4120 bp duplication, DRD3 Ser9Gly, DRD2 Taq1α, COMTrs4680, COMT-287A4G and DRD4 -521C/T by PCR/RFLP.Genotype frequencies were calculated and their signifi-cance assessed using chi-square test and correlated withduration of alcohol use, age at onset of alcohol use,quantity of alcohol consumed (gms/day) and liver function.Statistical analysis was done through SPSS software V21.0.Results: Of all the polymorphisms studied COMT Val158-Met (rs4680) showed significant association with AD (p-0.03)compared to the others. SNCA gene methylation levels weresignificantly different between AD subjects and controls (po 0.0001), while the difference between methylation levelsof the DAT gene were similar between subjects and controls(p= 0.839). Analysis of methylation levels of the DAT genewith duration of alcohol use showed an increase in methyla-tion from one allele to both alleles being methylated withincrease in duration of use ranging from 7.8071.31 to15.1270.864 years respectively (p= 0.003). Similarincrease in methylation levels were also observed withage of the subject which ranged from 30.072.25 to37.2371.01 years (p=0.043).Discussion: In the present study, significant differencebetween COMT rs4680 was observed between cases andcontrols. More heterozygosity was observed in cases whichimply presence of low activity allele of COMT gene whichaffects the activity of enzyme and makes the individualmore vulnerable to alcohol dependence. However,increased methylation at promoter region of DAT gene withboth age and duration of alcohol use may lead to less re-uptake of dopamine from the synapse. Whereas, decreasedmethylation at promoter region of SNCA gene may help inthe formation of synapse and hence increased dopamineneurotransmission. Therefore, this preliminary report sug-gests association of COMT rs4680 and methylation changesof SNCA and DAT genes with alcohol dependence.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.419

M113. INFLUENCE OF NICOTINIC RECEPTOR GENE –

CHRNA5 – ON CRACK COCAINE DEPENDENCE ANDSEVERITY

Jaqueline B. Schuchn,1, Angelita P. Aroche1,

Diego L. Rovaris1, Anderson Stolf2, Breno Sanvicente Vieira3,Eduardo S. Vitola1, Eugênio H. Grevet1, Flavio Pechanski2,Felix Henrique Paim Kessler2, Lisia von Diemen2,Rodrigo Grassi-Oliveira3, Claiton Bau1

1Universidade Federal do Rio Grande do Sul2Center for Drug and Alcohol Research/HCPA3Pontifical Catholic University of Rio Grande do Sul

Background: Crack cocaine is a highly addictive sub-stance and this dependence has a significant prevalenceworldwide, especially in Brazil. Several factors are involvedon crack cocaine dependence, and heritability estimateshave highlighted the influence of genetic variants in thedependence susceptibility. Previous studies have shown thatgenetic variants in nicotine receptor genes are not onlyassociated with nicotine abuse, but also with cocainedependence. Our aim was to investigate the effects ofpolymorphisms in the nicotinic receptor alpha 5 gene -CHRNA5 - on crack cocaine dependence.Methods: Three hundred crack cocaine users and sixhundred and thirty-three healthy controls were enrolled inthis study. The sample was composed of white Brazilianswith European descent. Diagnoses and clinical assessmentswere performed according to DSM-IV criteria. The AddictionSeverity Index - 6 (ASI-6) was used to assess the severity ofdependence. Three polymorphisms were analyzed in theCHRNA5 gene (rs588765, rs16969968, and rs514743). Logis-tic regression models and general linear models were usedto evaluated the effect of SNPs on crack cocaine addictionand severity of dependence, respectively.Results: Significant effects were found for two poly-morphisms. Genotypes TT-rs588765 and AA-rs16969968 wereassociated with reduced risk to crack cocaine dependence(OR=0.581, P=0.037; OR=0.532, P=0.009, respectively).However, only a trend towards association for rs514743 wasdetected (TT, OR=0.571, P=0.065). Analyses regardingseverity of dependence did not reveal any significantassociation between SNPs and scores generated by ASI-6.Discussion: We replicated previous findings regarding theinfluence of CHRNA5 gene on cocaine addiction. Notwith-standing, studies have demonstrated that rs16969968 appar-ently presents opposite effects in nicotine and crack/cocaine addictions. Our perspectives include increasingsample size and further explore other aspects possiblyinvolved with addiction, such as age of first use andpsychiatric comorbidities. Potential implications of thesegenetic factors should be more explored in future studies.

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Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.420

M114. EXPLORING ALLELE SPECIFIC METHYLATION(ASM) IN DRUG DEPENDENCE SUSCEPTIBILITY

Laura Pineda-Cirera1, Judit Cabana-Domínguez1,Carlos Roncero2, Laia Rodriguez-Cintas3, Lara Grau-López2,R. Felipe Palma-Álvarez3, Constanza Daigre4,Josep Antoni Ramos-Quiroga5, Marta Ribases6,Miguel Casas7, Bru Cormand1, Noèlia Fernàndez-Castillo

n,1

1University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER), Insti-tuto de Salud Carlos III. Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat2Addiction and Dual Diagnosis Unit, Psychiatric Services,Hospital Universitari Vall d’Hebron-ASPB, Biomedical Net-work Research Center on Mental Health (CIBERSAM), Insti-tuto de Salud Carlos III, Hospital Universitari Vall d’Hebron,Barcelona Universitat Autònoma de Barcelona3Addiction and Dual Diagnosis Unit, Psychiatric Services,Hospital Universitari Vall d’Hebron-ASPB, UniversitatAutònoma de Barcelona4Addiction and Dual Diagnosis Unit, Psychiatric Services,Hospital Universitari Vall d’Hebron-ASPB, Biomedical Net-work Research Center on Mental Health (CIBERSAM), Insti-tuto de Salud Carlos III5Hospital Universitari Vall d’Hebron, Centro de Investiga-ción Biomédica en Red de Salud Mental (CIBERSAM), Insti-tuto de Salud Carlos III, Psychiatric Genetics Unit, Group ofPsychiatry, Mental Health and Addiction, Vall d’HebronResearch Institute (VHIR), Universitat Autònoma de Barce-lona, Universitat Autònoma de Barcelona6Psychiatric Genetics Unit, Institut Recerca Hospital Uni-versitari Vall Hebron (VHIR), Biomedical Network ResearchCenter on Mental Health (CIBERSAM), Instituto de SaludCarlos III, Hospital Universitari Vall d’Hebron7Hospital Universitari Vall d’Hebron, Biomedical NetworkResearch Center on Mental Health (CIBERSAM), Instituto deSalud Carlos III, Universitat Autònoma de Barcelona

Background: Drug addiction is a neuropsychiatric disor-der where long-lasting changes in gene expression withinparticular regions of the brain play an important role. Workover the past decade has demonstrated a crucial role forepigenetic mechanisms in driving stable changes in geneexpression in several tissues, including the brain. Allele-specific methylation (ASM) is a common epigenetic mechan-ism consisting on SNPs that correlate with differential levelsof methylation at CpG sites. The aim of our study is to assessthe possible contribution of ASM in different brain regions todrug dependence susceptibility.Methods: We performed a SNP selection based on twoprevious studies that reported thousands of ASM SNPs indifferent brain regions of post-mortem human samples. By

combining both studies, we obtained a total of 43,132 SNPsCpG pairs that include 33,944 SNPs and 5,036 CpG islands.From those, we obtained a sub-list of 184 SNPs using thefollowing selection criteria: cis associations between SNPsand CpG sites, correlation (R2) of DNA methylation withgene expression Z0.5 and selection of only one SNP perCpG site, the one showing the best correlation (R2).Subsequently, we evaluated the possible contribution ofthese SNPs to drug dependence predisposition through acase-control association study in a sample of 577 drug-dependent patients and 655 sex-matched controls fromSpain, and then we followed-up the significant associationsin an independent sample of 1,192 cases and 1,256 sex-matched controls.Results: In the discovery sample, we obtained five asso-ciations (po0.05) under the additive model after correctingby age. One of them was replicated in the follow-up sample.Discussion: To conclude, we detected a potential associa-tion between drug dependence and a SNP that correlateswith differential levels of methylation at one CpG site. Boththe SNP and the CpG site are located in the first intron of agene encoding an integral protein of the spliceosome.Further research is needed to understand its potential rolein the susceptibility to drug dependence.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.421

M115. ASSOCIATION OF THE PLCB1 GENE WITH DRUGDEPENDENCE

Judit Cabana-Domínguez1, Elena Martín-García2,Carlos Roncero3, Laura Pineda1, R. Felipe Palma-Álvarez4,Elena Ros-Cucurull5, Lara Grau-López3, Abderaman Esojo4,Miguel Casas6, Concepció Arenas7, Marta Ribases8,Rafael Maldonado9, Noèlia Fernàndez-Castillo1,Bru Cormand

n,1

1University of Barcelona, Centro Nacional de InvestigaciónBiomédica en Red de Enfermedades Raras (CIBERER), Insti-tuto de Salud Carlos III, Institut de Biomedicina de laUniversitat de Barcelona (IBUB), Institut de Recerca SantJoan de Déu (IR-SJD), Esplugues de Llobregat2Laboratori de Neurofarmacologia, Universitat PompeuFabra, PRBB3Universitat Autònoma de Barcelona, Addiction and DualDiagnosis Unit Clinic Vall Hebron, Psychiatric Services,Hospital Universitari Vall d’Hebron-ASPB, Biomedical Net-work Research Centre on Mental Health (CIBERSAM), Insti-tuto de Salud Carlos III, Hospital Universitari Vall d’Hebron4Addiction and Dual Diagnosis Unit Clinic Vall Hebron,Psychiatric Services, Hospital Universitari Vall d’Hebron-ASPB, Hospital Universitari Vall d’Hebron5Universitat Autònoma de Barcelona, Addiction and DualDiagnosis Unit Clinic Vall Hebron, Psychiatric Services,Hospital Universitari Vall d’Hebron-ASPB, Hospital Univer-sitari Vall d’Hebron

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6Universitat Autònoma de Barcelona, Biomedical NetworkResearch Centre on Mental Health (CIBERSAM), Instituto deSalud Carlos III, Hospital Universitari Vall d’Hebron7University of Barcelona8Psychiatric Genetics Unit, Group of Psychiatry, MentalHealth and Addiction, Vall d’Hebron Research Institute(VHIR), Universitat Autonoma de Barcelona, BiomedicalNetwork Research Centre on Mental Health (CIBERSAM),Instituto de Salud Carlos III, Hospital Universitari Valld’Hebron9Laboratori de Neurofarmacologia, Universitat PompeuFabra, PRBB

Background: Drug dependence is a complex neuropsychia-tric disorder that results from the interaction of genetic andenvironmental factors. MicroRNAs (miRNAs) are very abundantin the central nervous system and seem to play key roles in thedrug-induced plasticity of the brain that likely drives theemergence of addiction. Some studies suggest that SNPslocated in both miRNAs and miRNA target sites may alter themiRNA-mediated regulation of gene expression that underliesdisease and non-pathological phenotypes. Here we aimed atexploring the role of miRNAs in drug addiction by performing atwo stage case-control association study.Methods: We genotyped SNPs located in regions of miRNAbinding in a Spanish sample of 735 cases and 739 controlsand replicated the results in an independent follow-upsample of 663 cases and 667 controls. The possible func-tional impact of associated SNPs on the binding of differentmiRNAs was performed with a luciferase reporter assay.Finally, we evaluated alterations of gene expression undercocaine in a gene harboring associated variants usingdifferent in vivo and in vitro models.Results: We identified an association between rs1047383 inthe 3’UTR of the PLCB1 gene and drug dependence, particu-larly with cocaine addiction, that was replicated. Then wetested the effect of this SNP and rs1047381-rs708910 (in LDwith it) on the binding of 10 miRNAs. Hsa-miR-582 was foundto downregulate gene expression, without showing differ-ences between the two alleles at rs708910. Finally, weexplored the possibility that PLCB1 expression is altered bycocaine. We observed a significant upregulation of PLCB1 inthe nucleus accumbens of cocaine abusers and in humandopaminergic-like neurons after cocaine treatment. In orderto confirm the contribution of PLCB1 to cocaine dependencewe are currently assessing cocaine-seeking behavior inheterozygous Plcb1 knockout mice.Discussion: To our knowledge, this is the first studyassessing the effect of SNPs in miRNA binding sites in drugdependence, and we provide additional evidence for theparticipation of the PLCB1 gene in the vulnerability tosusceptibility to drug dependence.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.422

M116. SMOKING AND NEUROTICISM: USING MENDELIANRANDOMIZATION TO INVESTIGATE CAUSALITY

Hannah Sallisn

, George Davey Smith, Marcus Munafo

University of Bristol

Background: Smoking is one of the leading modifiable riskfactors for disability, disease and death. There is a well-documented association between smoking and neuroticism,with smokers reporting increased levels of neuroticism.However, much of this data comes from observationalstudies and we are unable to make any causal inferenceregarding this relationship.Methods: Mendelian Randomization (MR) is a method ofassessing causality using observational data through the useof genetic instrumental variables for modifiable risk factors.Recent GWAS have identified variants robustly associatedwith both smoking phenotypes and neuroticism. Thisenabled us to use a range of MR methods to attempt tounpick this relationship. We use publicly available summarystatistics from these studies in addition to data from UKBiobank to investigate whether there appears to be a causallink between smoking and neuroticism.Results: We found evidence of a modest genetic correla-tion between smoking initiation and neuroticism (rG=0.124,p=0.0078). However, we found no strong evidence of acausal relationship in either direction when using 2-sampleMR or when looking at individual level data in UK Biobank.

Within UK Biobank it was possible to stratify on smokingstatus, which meant that in addition to smoking initiation,we were able to look at the association between smokingheaviness and neuroticism. We found some evidence of acausal relationship from neuroticism to increased smokingheaviness (β=0.198, p=0.014).Discussion: In conclusion, although much of the observedassociation between smoking and neuroticism appears to benon-causal, we found evidence of a modest genetic correla-tion, suggesting some shared genetic aetiology. We alsofound some evidence of a causal relationship from neuroti-cism to smoking heaviness, which would lend support to theself-medication hypothesis.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.423

M117. INFLUENCE OF GENOME-WIDE ASSOCIATEDGENETIC POLYMORPHISMS OF SCHIZOPHRENIAON THE VERBAL FLUENCY

Tobias Wustmannn,1, Ina Giegling1, Annette Hartmann2,

Bettina Konte2, Dan Rujescu1

1Martin Luther University Halle-Wittenberg2Ludwig Maximilian University of Munich

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Background: Schizophrenia is a serious psychiatric dis-order of multifactorial genesis, which can be associatedwith serious limitations in everyday life. In addition toenvironmental factors, genetic factors play a crucial etio-logical role. In 2014, the Psychiatric Genomics Consortium(PGC) carried out the largest GWAS to date. Significantassociations between schizophrenia and 128 linkage-dise-quilibrium-independent Single-Nucleotide Polymorphisms(SNP) were found in 108 conservatively defined loci (Ripkeet al. 2014). A neuropsychological deficit of schizophrenia,which has been widely described in the literature, is adisturbance of verbal fluency. The aim of this study was toexamine schizophrenia-associated SNPs for their associationwith verbal fluency.Methods: The PAGES sample includes 1000 schizophreniapatients who were diagnosed according to DSM IV, and 3000randomly selected psychiatrically healthy controls that per-formed a multi-stage selection procedure. Verbal fluency wasassessed by Regensburg word fluency test (RWT) in a subset of361 cases and 559 controls. Association analysis was per-formed applying linear regression using an additive modelcorrected for affection status, age, education and gender.Results: Several SNPs showed nominal significant associa-tion with verbal fluency measured with RWT. rs11191419(BLOC-1 related complex subunit 7, BORCS7) was associatedwith all tested domains (words, words switch, categories,categories switch), association of rs111294930 (LINC01470)was restricted to categories and categories switch, for bothSNPs association was reflected in the same direction ofeffect in cases and controls. Association in cases only couldbe detected for rs7523273 (MIR29B2) (all domains) andrs9636107 (transcription factor 4, TCF4) (categories, cate-gories switch), whereas association of rs3849046 (eukaryotictranslation termination factor 1, ETF1) (all domains) andrs12826178 (mitochondrial serine hydroxymethyltransfer-ase, SHMT2) (categories and word switch) were restrictedto controls.Discussion: Though no association survived multiple test-ing, the nominal associated variations are localized in or neargenes showing interesting features. Most genes are involved inregulatory processes either on the transcriptional or transla-tional level: Long non coding RNAs (i.e. LINC01470) and microRNAs (i.e. MIR29B2) are known to be involved in transcrip-tional and post-transcriptional regulation of gene expression,ETF1 is involved in termination of mRNA translation andnonsense mediated RNA decay. TCF4 activates transcription.This gene also plays a role in the initiation of neuronaldifferentiation. Another hit, BORCS7 has been shown to beupregulated during human stem cell differentiation towardneuronal fates in early brain development. The resultsindicate an influence of schizophrenia risk variants on verbalfluency performance in healthy subjects, thereby implicatingan underlying mechanism which might be involved in suchdeficits in schizophrenia. Functional relevance of the asso-ciated SNPs as well as replication in independent samplesremains to be determined.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.424

M118. PATHWAY-FOCUSED POLYGENIC RISK SCORESINVESTIGATE THE IMPACT OF A RARE, HIGHLY PENE-TRANT GENETIC RISK VARIANT FOR SCHIZOPHRENIA ONBRAIN STRUCTURE

Miruna Barbun

, Yanni Zeng, Xueyi Xueyi, Jude Gibson,Andrew McIntosh, Stephen Lawrie, Mandy Johnstone,Heather Whalley

University of Edinburgh

Background: Schizophrenia (SCZ) is a psychiatric disorderwhere genetic risk factors contribute to the majority (h2 =80%) of individual differences in risk. Here we examine theeffects of a promising rare mutation linked to SCZ, nucleardistribution E homolog 1 (NDE1). Duplications and deletionsin the 16p13.11 locus, where NDE1 is located, affectapproximately 0.30% and 0.12% of SCZ patients comparedto 0.09% and 0.04 healthy individuals, respectively. Follow-ing a study of affected NDE1 carriers within a family, weidentified potential cortical morphological differences (cor-tical thinning was found in one SCZ NDE1 carrier of interestcompared to 41 unrelated healthy individuals (M = 2.52, SD= 0.09) in an N of 1 statistical test (t = - 2.305, p = 0.013).While the study of rare mutations aids in informing mechan-isms due to their greater impact, it is more difficult togeneralize their effect to the wider population. Therefore,we derived pathway-focused Polygenic Risk Scores (PGRS) inorder to investigate the effect of common genetic variantswithin associated pathways on brain cortical measures.Methods: Due to NDE1’s implication in the mitotic phaseof cell cycle progression, the M Phase biological pathway,which implicates division and cytokinesis, was chosen as ameans of investigating NDE1 more closely. Four pathwayswere annotated with the program ANNOVAR, containing theinclusion of genes present in the M Phase pathway, eitherthrough experimental [N = 254] or experimental & compu-tational prediction evidence [N = 308]) or their exclusion[henceforth known as whole genome (WG)-experimental;WG-experimental & computational]. PGC:SCZ PGRS at fiveP-value thresholds (0.01, 0.05, 0.1, 0.5, 1) tailored for eachpathway were created for unrelated participants of Eur-opean ancestry in UK Biobank, and their association withbrain structure and connectivity was then determined(cortical thickness N = 425).Results: We found significant cortical thinning in theinferior parietal (β = -0.110, p = 0.010), lateral occipital(β = -0.143, p = 0.001), middle temporal (β = -0.083, p =0.048), paracentral (β = -0.102, p = 0.026), pericalcarine (β= -0.088, p = 0.039), precuneus (β = -0.090, p = 0.035),superior frontal (β = -0.089, p = 0.034), superior parietal (β= -0.114, p = 0.012), supramarginal (β = -0.100, p = 0.019)regions, as well as in the superior temporal gyrus (STG) (β =-0.114, p = 0.011) in the M Phase experimental pathway.Significant reductions in cortical thickness were also foundin the STG in the M Phase complete pathway (β = -0.101, p =0.025). We found significant reductions in the inferiorparietal (β = -0.131, p = 0.021) and lateral occipital (β =-0.125, p = 0.035) regions in the WG-experimental &computational pathway, while no significant cortical

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thinning was found for any of the measures within the WG-experimental pathway.Discussion: Schizophrenia is associated with structuralbrain abnormalities, such as cortical thinning, reduced greymatter volume and disrupted white matter integrity. Ourpreliminary findings on ~500 individuals indicate that somestructural abnormalities are associated with SCZ PGRStailored to specific biological pathways in which a gene ofinterest for schizophrenia is implicated, leading to implica-tions of this specific pathway in a more generalized context.Further studies are needed in order to investigate theassociation between the M Phase pathway and SCZ.& 2017 Published by Elsevier B.V.

Disclosure: Nothing to disclose.

http://dx.doi.org/10.1016/j.euroneuro.2017.08.425