abstracts of the 26th world congress of psychiatric...

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JID: NEUPSY [m6+; October 2, 2018;12:59 ] European Neuropsychopharmacology (2018) 000, 1–75

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Abstracts of the 26th World Congress of Psychiatric Genetics

(WCPG): Poster Abstracts: Sunday

Sunday, October 14, 2018

Poster Session III 4:00 p.m. - 6:00 p.m.

SU1

ANDROGEN RECEPTOR SIGNALING PATHWAYS IN- FLUENCE IN ATTENTION-DEFICIT/HYPERACTIVITY

DISORDER

Djenifer Kappel 1 , Bruna da Silva 1 , Renata B. Cupertino 1 , Diana Müller 1 , Vitor Breda 2 , Stefania Pigatto Teche 2 , Rogério Margis 1 , Luis Augusto Rohde 2 , Nina Roth Mota 3 , Diego L. Rovaris 1 , Eugênio H. Grevet 1 , Claiton Bau 1

1 Universidade Federal do Rio Grande do Sul 2 Hospital de Clínicas de Porto Alegre 3 Radboud University, Nijmegen Medical Centre

Background: The differential sex-based prevalence of ADHD

has long been subject to scrutiny. The role of sex-hormones, especially androgens during the neurodevelopmental period has been extensively demonstrated. Androgens regulate and interact with neurotransmitters and neuromodulators influencing developmental processes. Since androgenic disrup- tors modify these processes it has been suggested that its exposure during development was related to ADHD susceptibility. Also, it has been shown that women suffering from

the androgenizing polycystic ovary syndrome, have higher rates of ADHD, and so are their children. We hypothesize that one way by how exposure to androgens and its response network might affect susceptibility to ADHD is through the activation of androgen receptor (AR) function as a nuclear transcription factor. Methods: 407 adults with ADHD (53.1% males, mean age of 33.6 years) and 463 unrelated controls (47.9% males, mean age of 29.4 years) were genotyped with PsychChip array for > 5M SNPs. Annotation from human genome build 37 (hg19)

with a 2kb upstream and 1kb downstream region was considered for each gene. Gene-set analysis was conducted using MAGMA, with a principal components regression model for gene-based analyses. Sex, age, the 10 first and otherwise associated principal components were included as covariates in this step. We retrieved a “Hallmark Androgen response”gene-set from MSigDB to be tested in a case-control association study. This gene-set contains 98 curated genes involved in the response to androgen receptor signaling. Also, a list of 534 annotated genes with at least one occurrence of potential transcription factor binding sites (TFBS) for AR was created to investigate potential gene targets related to ADHD susceptibility. Results: No genome-wide association was observed at the SNPs or gene level. In the gene-set analysis, we found evidence that the “Hallmark Androgen response” gene-set was significantly associated with ADHD susceptibility in our sample (p = 0.039). We also observed that this gene-set seems to be associated with ADHD regardless of gender effects. When analyzed separately in both genders, the gene-set remained significantly associated, although with a larger effect in men (p = 0.024; p = 0.009, for women and men, respectively). In the secondary analyses, we observed that from the 534 genes expected to have a TFBS for AR, 14 have been associated with ADHD previously. Some are from the recent ADHD GWAS (FOXP2, TMEM161B), others are classical ADHD candidate genes as BDNF and SNAP25. Discussion: Our results add to the current knowledge that factors related to the influence of sex-hormones might play a role in ADHD susceptibility. The perspective of the involvement of such factors is interesting due to its influence during fetal development and also due to sex-hormones effects during puberty. These associations could be representing and underlying mechanisms related to ADHD development and differential sex-based prevalence in children and adults.

Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.365

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2 Abstracts

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JID: NEUPSY [m6+; October 2, 2018;12:59 ]

SU2

RECONCEPTUALIZING PSYCHOPATHOLOGY FOR GE- NETIC STUDIES USING HIERARCHICAL DIMENSIONAL

STRUCTURAL MODELS: THE EXAMPLE OF EXTERNALIZ- ING AND AVPR1A

Irwin Waldman

Emory University

Background: Recent trends in the psychopathology literature have reconceptualized psychopathology in terms of transdiagnostic or hierarchical dimensional perspectives. Despite these trends, the modal phenotypes used in psychiatric genetic studies (e.g., in GWASs of psychiatric disorders conducted through the Psychiatric Genetics Consortium) are single, specific psychiatric diagnoses. In this paper, I explore different conceptualizations of a higher-order Externalizing symptom dimension in children, as well as different analytic methods used to characterize this dimension, in its association with the Arginine Vasopressin 1a receptor gene (AVPR1a), a gene that was genome-wide significantly associated in a GWAS of aggression. Methods: In phenotypic analyses, data were available on parent ratings of DSM-IV symptoms of Attention Deficit Hy- peractivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD) from ∼2800 children whereas in genetic analyses data were available from ∼600 children, all aged 6-16 years old. These three disorders were divided into their constituent symptom dimensions. These included Inattention, Impulsivity, and Hyperactivity for ADHD, Negative Affect and Behavioral Dyscontrol for ODD, and Aggressive and Rule Breaking dimensions of Con- duct Disorder. In analyses of genetic association six SNPs in AVPR1a were used to characterize the gene in a series of gene-based tests. Results: I contrasted different models for characterizing the Externalizing symptom dimension with each other, as well as with models of its constituent diagnoses and symptom

dimensions. Comparisons of these phenotypic models used the percentage of variance explained and the relative fit of the alternative models to adjudicate among them. In phenotypic analyses, the best-fitting model contained a higher- order Externalizing factor on which the 7 symptom dimensions loaded, as well as residual correlations among the ADHD dimensions, the ODD dimensions, and the CD dimensions. This model fit better than a bifactor model in which a General Externalizing factor influenced all of the ADHD, ODD, and CD symptoms directly, as well as a model in which the 7 constituent symptom dimensions were correlated with each other. In gene-based analyses of AVPR1a the higher- order Externalizing higher-order factor was more strongly associated with AVPR1a than the 7 lower-order symptom dimensions, Conduct Disorder symptom scale composites, and the Conduct Disorder diagnosis. Discussion: Results of these analyses highlight the benefits of conceptualizing and operationalizing psychopathology in terms of hierarchical dimensional models, as well as which

conceptualizations of the externalizing spectrum and analytic methods for genetic associations are optimal.


doi: 10.1016/j.euroneuro.2018.08.366

SU3

DESCRIBING THE GENETIC ARCHITECTURE OF ADHD

USING LINKED-READ SEQUENCING: A CASE-CONTROL

STUDY FROM THE ISOLATED POPULATION OF THE

FAROE ISLANDS

August Gabriel Wang 1 , Noomi Odmarsdóttir Gregersen 2 , Ólavur Mortensen 2 , Marjun Biskopstø 3 , Julia Zachariasen 3 , Tórmódur Stórá 3 , Gudrun Andorsdóttir 2 , Ditte Demontis 4 , Anders Børglum

4

1 Copenhagen University Hospital 2 FarGen, Genetic Biobank of the Faroe Islands 3 National Hospital Faroe Islands 4 iSEQ, Aarhus University

Background: Attention-deficit/hyperactivity disorder (ADHD) is a mental disorder characterised by an ongoing pattern of inattention and/or hyperactivity-impulsivity. ADHD is highly heritable and genetic studies show substantia contribution of common variants to disorder susceptibility. Moreover, a reason meta-analysis show genome-wide significance of 12 independent loci comprising evolutionarily constrained genomic regions and loss-of-function intolerant genes. In this study the potential enrichment of ADHD risk variants will be explored based on whole-exome data from

linked-read sequencing of individuals from the isolated population of the Faroe Islands. The demographic history of the Faroese population may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for ADHD. Methods: Cases in this study comprises 56 patients with ADHD, recruited to the ADHD outpatient clinic at the De- partment of Psychiatry, General Hospital in Tórshavn, Faroe Islands. Diagnosis have been verified by a psychiatrist/child and youth psychiatrist, a psychologist and a ADHD special- ized nurse. Further, the diagnostics were verified with the diagnostic tools: ADHD-RS (Attention Deficit/Hyperactive Disorder-Rating Scale), TOVA (Test Variables of Attention), BRIEF (Behavioural Rating Inventory of Executive Function) and in some cases DIVA (Diagnostic Interview for ADHD in adults) and QbTest (Quantified Behaviour Test Plus). Cases have been reviewed by experienced psychiatrists and the diagnostic most solid/robust cases have been selected for genetic analyses. Healthy controls in this study comprises 200 individuals voluntarily recruited to the FarGen infras- tructure, at the Genetic Biobank of the Faroe Islands. Self- reported healthy status was confirmed by the diagnostic registry at the National Hospital of the Faroe Islands. High- molecular weight (HMW) DNA extracted from peripheral blood was barcoded by a gel-bead emulsion (GEM) process in the ChromiumTM controller. The 256 exomes were captured using the SureSelectXT Human All Exon kit and sequenced on the NextSeq 500. The linked-reads were aligned to the


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reference genome (GRGh37/hg19) and variants were called using GATK. Results: The exomes were sequenced with an average coverage of 56, > 98% of the reads were aligned to the reference genome. Due to the barcodes introduced to the DNA fragments in the GEM process we were able to perform

molecular phasing, which assign > 85% of the genes under 100 kb to a haplotype and phased > 75% of the SNPs. More- over, we will present results from single variant and gene- based association analyses, as well as possible structural variants will be presented. Discussion: To our knowledge this is the first study to use linked-read sequencing to identify susceptibility variants/genes for ADHD.


doi: 10.1016/j.euroneuro.2018.08.367

SU4

CHARACTERIZING THE GENETICS OF ADHD TRAITS WITH COGNITIVE DEFICITS USING A MULTIVARIATE

APPROACH

Elizabeth Corfield 1 , Christie Burton 1 , Lisa Strug 2 , Bowei Xiao 1 , Paul Arnold 3 , Jennifer Crosbie 1 , Russell Schachar 2

1 Hospital for Sick Children

2 Hospital for Sick Children, University of Toronto 3 University of Calgary

Background: Attention-deficit/hyperactivity disorder (ADHD) is a common, impairing and persistent disorder of children and youth. Genetic studies usually focus on univariate methodologies in clinical cohorts. However, simultaneously investigating correlated phenotypes using a multivariate approach could accelerate gene discovery by reducing phenotypic and genetic heterogeneity. Response inhibition (the ability to stop a speeded motor response) is a heritable and stable cognitive deficit that is correlated and co-heritable with ADHD. Therefore, this study aims to investigate the genetic architecture of ADHD by using a multivariate genome-wide association (GWA) approach in a pediatric community sample with a quantitative measure of ADHD traits and a cognitive deficit. Methods: The Spit for Science community sample includes 4,815 Caucasian children and youth (aged 6-17) with genotyping data and measured ADHD traits and response inhibition, which were used in all analyses. ADHD traits were measured by The Strengths and Weaknesses of ADHD Symp- toms and Normal Behavior Rating Scale, while response inhibition was measured by the stop-signal reaction time in the Stop-Signal task.

A multivariate GWA analysis of 8,786,567 SNPs ADHD

traits and response inhibition was conducted with the relevant covariates (age, sex, respondent, batch effects, and population stratification) using the MultiPhen approach. This approach uses a reverse proportional odds linear regression with the genotype regressed on each phenotype. The likelihood ratio test is then used to assess if the joint

combination of effects is significant. Results from the multivariate GWA analysis were used to identify specific genes associated with ADHD traits and response inhibition by con- ducting a gene-based association analysis in MAGMA. The biological relevance of the results was assessed by functional mapping and annotation using FUMA. Polygenic risk score analysis will be conducted to determine if the multivariate GWA results predict clinical ADHD. Results: No genome-wide significant risk loci or genes were identified, however, two variants and six genes reached suggestive p-value thresholds. The top risk loci from the joint analysis of ADHD traits and response inhibition were common intron variants rs12497498 in SSUH2 (p = 5.76 × 10-7) and rs56373513 in GLIS3 (p = 8.13 × 10-7). If two separate univariate GWA analyses were conducted only rs12497498 would have been identified as a risk variant of interest for ADHD traits. The top genes (with p < 0.0001) from the gene-set analysis were RNF148, RNF133, ZMIZ1, FAM163A, PDZRN4, and FGF22. Discussion: Although no genome-wide significant risk variants were identified the regions of interest identified from

this study warrant further investigation as they will increase our understanding of the biological mechanisms of with ADHD with cognitive deficits. Furthermore, it is hoped that the use of multiple phenotypes in GWA analyses increases the variance explained in clinical ADHD.


doi: 10.1016/j.euroneuro.2018.08.368

SU5

A RARE VARIANT ANALYSIS ON ATTENTION-DEFICIT

HYPERACTIVITY DISORDER

Kalle Leppälä 1 , Tetyana Zayats 2 , Ditte Demontis 1 , Anders Børglum

1

1 Aarhus University 2 Bergen University

Background: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neuropsychiatric condition that often persists into adulthood. The adult form of ADHD is associated with high rate of unemployment, incar- ceration, accidental deaths and suicide. Nonetheless, the biology underlying ADHD as well as its genetic architecture is not fully understood. Several twin studies have estimated ADHD heritability to be 70-80%, while the heritability estimated from the common SNPs varies between 10-28%. The discrepancy in these estimates is often attributed, among other factors, to rare variants (MAF < 1%) as well as the polygenic nature or phenotypic heterogeneity of the condition. Thus, in this work, we aim to study the genetic architecture of ADHD by focusing on rare variants and address the question of polygenicity by examining those associated with ADHD in light of common neuropsychiatric disorders. Methods: This study is based on the iPSYCH2012 sample consisting of all the Danes born between 1981 and 2005 and diagnosed with either schizophrenia (SCZ), autism, ADHD



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or affective disorder (about 57000 individuals), as well as 30000 randomly selected individuals. The participants were genotyped using a custom Illumina PsychChip that contains about 250000 rare variants. We performed a strict quality control of the genotyped data and excluded variants with low genotyping rate or out of Hardy-Weinberg equilibrium

as well as individuals revealing low genotyping quality, high levels of relatedness or heterozygocity, sex mismatch or non-European ancestry. We will perform genome-wide association analyses to assess the contribution of rare variants to ADHD. The association will be tested in form of regression by grouping the rare variants by (1) their location within known genes, (2) their missense status within known genes, (3) their loss of function status within known genes and (4) their location within constrained regions of the genome. We will also examine ADHD associated loci in light of SCZ, autism and affective disorder. Results: The results are not ready yet. Discussion: This study will address the question of missing heritability as well as aid our understanding of genetic architecture and biological processes underlying ADHD.


doi: 10.1016/j.euroneuro.2018.08.369

SU6

HYPERACTIVITY SYMPTOM IS PREDICTED BY AGE- OF-MENARCHE POLYGENIC RISK SCORE IN ADHD

CHILDREN

Hyo-Won Kim

1 , Tetyana Zayats 2 , Keejeong Park 1 , Raymond Walters 3 , Benjamin Neale 4

1 University of Ulsan Asan Medical Center 2 Bergen University 3 Massachusetts General Hospital, Broad Institute 4 Massachusetts General Hospital

Background: Early puberty has been reported to be associated with a number of attention-deficit/hyperactivity disorder (ADHD) symptoms and severity of its impairment, including inattention, difficulties in emotion regulation and risky behaviour. In addition, age at menarche was also reported to be inversely correlated with performance IQ. However, little is known about the contribution of genetics to the association between puberty onset and ADHD. We investigated the possibility of such genetic effect by examining the influence of the polygenic risk score (PRS) of age-at- menarche on diagnosis of ADHD and its two main symptoms, inattention and hyperactivity. Methods: The PRS of age-at-menarche was calculated in 324 Korean children (208 cases and 116 controls) utilizing the PRSise software and summary statistics from a large- scale (N = 370,000) genome-wide association study on age at menarche. ADHD was diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and confirmed with the Kiddie–Schedule for Affective Dis- orders and Schizophrenia–Present and Lifetime Version (K- SADS-PL). Hyperactivity and inattention scores were derived from the K-SADS-PL ADHD supplement (clinician-rated) and

ADHD Rating Scale (parent-rated). ADHD symptoms were examined in cases and controls separately. As genetics of age at menarche in women highly correlate with those of voice breaking in men, males and females were analysed together. Permutation was applied to correct for multiple testing. Em- pirical p-value (pemp) of 0.05 was considered statistically significant. Results: The age-at-menarche PRS was not associated with ADHD diagnosis (pemp = 0.495). Among ADHD symptoms, parent-rated hyperactivity symptom score showed significant association with the examined PRS in ADHD

cases (pemp = 0.047), but not in controls (pemp = 0.968). Clinician-rated hyperactivity symptom was not associated with the examined PRS both in cases (pemp = 0.184) and controls (pemp = 0.157). Discussion: These results suggest that genetics of puberty onset may play an important role in the development of symptoms of hyperactivity in children with ADHD.


doi: 10.1016/j.euroneuro.2018.08.370

SU7

ASSESSING THE CONTRIBUTION OF NEURODEVEL- OPMENTAL RISK ALLELES TO MATERNAL BEHAVIOURS AND LIFE-STYLE FACTORS

Beate Leppert 1 , Alexandra Havdahl 2 , Lucy Riglin 3 , Hannah J. Jones 1 , George Davey Smith 1 , Kate Tilling 1 , Ted Reichborn-Kjennerud 4 , Anita Thapar 3 , Evie Stergiakouli 1

1 University of Bristol 2 Norwegian Institute of Public Health and Nic Waals Insti- tute, Lovisenberg Diaconal Hospital 3 Cardiff University 4 Norwegian Institute of Public Health

Background: Exposures to adverse maternal behaviours and lifestyle factors prenatally have long been considered as potential risk factors for neurodevelopmental disorders and are biologically plausible because they impact during a sensitive time in development. However, maternal genetic factors could be confounding the association between prenatal factors and neuropsychiatric risk in the offspring leading to apparent associations which have no causal relationship. Methods: Here, we test whether maternal polygenic risk scores for attention deficit/ hyperactivity disorder (ADHD), autism and schizophrenia are associated with maternal behaviours, lifestyle factors and health during pregnancy within the population-based cohort study ALSPAC. Addi- tionally, we tested for associations of adverse birth outcomes, like preterm delivery ( < 37 week of gestation) and low birth weight ( < 2500g) with maternal and child genetic risk scores. Polygenic risk scores were derived using the risk alleles identified by the most recent GWAS from Demontis et al. (2017) for ADHD, Grove et al. (2017) for autism and Ripke et al. (2014) for schizophrenia. Results: Maternal polygenic risk scores for ADHD were associated with a range of adverse maternal behaviour and



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health traits, including maternal smoking during pregnancy (OR:1.27, 95%CI:1.18-1.36), lower maternal age at delivery (OR:0.66, 95%CI:0.59-0.73) and infections during pregnancy (OR:1.11, 95%CI:1.04-1.18). There was little evidence of association with autism and schizophrenia polygenic risk scores. Adverse birth outcomes, including low birth weight and preterm delivery, were not associated with either maternal or child neurodevelopmental risk scores. Discussion: We conclude that some of the previously reported prenatal risk factors for ADHD may not be causally linked to the development of ADHD as the associations could be driven by maternal genetic confounding. However, this didn’t seem to be the case for autism or schizophrenia in our study. Our results also show no evidence of genetic confounding of other often reported risk factors like low

birthweight and preterm delivery with neurodevelopmental disorders. This highlights the need for causally-informative study designs and statistical approaches.


doi: 10.1016/j.euroneuro.2018.08.371

SU8

EXOME SEQUENCING IN FAMILIES WITH SEVERE MENTAL

ILLNESSES

Suhas Ganesha 1 , Husayn Ahmed 2 , Ravikumar Nadella 1 , Ravi More 2 , Manasa Sheshadri 1 , Biju Viswanath 1 , Mahendra Rao 3 , Odity Mukherjee 3 , Sanjeev Jain 1

1 National Institute of Mental Health & Neurosciences 2 National Centre for Biological Sciences 3 Institute for Stem Cell Biology and Regenerative Medicine

Background: Severe Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs. We present describe the analysis of WES in 8 multiplex pedigrees with schizophrenia and BD phenotypes. We aimed to identify rare, damaging, exonic variants that co-segregated with SMI; and to examine the disease relevance and pathway enrichment of the genes which genes that harboured these variants. Methods: As part of a longitudinal study ‘Accelerator Pro- gram for Discovery of Brain disorders using Stem Cells’ (ADBS) (Viswanath et al., 2018) aimed at understanding the developmental trajectories and basic biology of SMI, we describe in this study, the results of WES (Whole Exome Se- quencing) in 8 multiplex pedigrees with SZ and BD phenotypes from a well characterized Indian cohort. We analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n = 26; schizophrenia, n = 4; schizoaffective disorder, n = 1 schizophrenia like psychosis, n = 1); and 33 healthy individuals by WES. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the con-

trols and rarity in South Asian sample of Exome Aggregation Consortium. Results: We identified a total of 42 unique rare, non- synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a private mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype. Discussion: NGS approaches in family-based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.


doi: 10.1016/j.euroneuro.2018.08.372

SU9

PATIENT-SPECIFIC MICROGLIA CELLULAR MODELS FOR SCHIZOPHRENIA STUDY

Jingchun Chen , Travis Mize, Xiaogang Wu, Xiangning Chen

University of Nevada, Las Vegas

Background: Schizophrenia is a devastating and prevalent psychiatric illness. Progress in understanding the basic pathophysiological processes underlying this disorder has been hindered by the lack of appropriate models or tissues. Methods: In this study, we generated a cellular model of microglia-like cells (iMGL) in vitro induced from peripheral blood cells of live human beings, following the procedure of Ohgidani et al. Results: Our results indicated that the iMGL cells have mi- croglial characterizations, such as a ramified morphology; expressing microglia specific surface markers; and phago- cytic activity. To further confirm the similarity of iMGL with the microglia from human brain, we conducted RNA-seq from the iMGL cells, and compared with RNA-seq data from

microglia from human brain. Our results showed that iMGL most closely resemble with microglia from brain, following with induced macrophage. Discussion: Further function identification of this patient unique iMGL model will be warranted to study many psychiatric or neurodegenerative diseases, such as schizophrenia and Alzheimer’s disorder.


doi: 10.1016/j.euroneuro.2018.08.373




6 Abstracts

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SU10

THE DNA METHYLATION PROFILE IN BDNF EXON 1

PROMOTER REGION IN DRUG DEFAULT PATIENTS OF

BIPOLAR AFFECTIVE DISORDERS: AN INDIAN STUDY

Sydney Moirangthem , Sanjeev Jain, Meera Purushottam, Biju Viswanath

National Institute of Mental Health and Neurosciences

Background: Bipolar Affective Disorders (BPAD) are complex heritable multifactorial psychiatric disorders in which epigenetic misregulations play a significant role and may be responsible for monozygotic twin discordance, parental origin effects, and fluctuating course of BPAD. A hypermethylation of brain derived neurotrophic factor (BDNF) and subsequent decreased levels of serum BDNF are seen in both phases of BPAD. The study will investigate the methylation status of the exon 1 promoter region of the BDNF gene in drug default patients. Methods: After taking informed consent 50 patients of BPAD

(ICD-10 based) are evaluated by a semi-structured interview

and tools like Young’s Mania Rating Scale (YMRS) & Hamil- ton’s Depression Rating Scale (HDRS). The assessments will also include the collection of the following demographical and clinical variables. Patients in both phases of BPAD, depression & mania, & who had defaulted on treatment are taken for the study. The study has been approved by the ethics committee of the National Institute of Mental Health and Neuro Sciences, Bangalore, India. The participants will be recruited from the out-patient, emergency unit & the in- patient units of the department of Psychiatry at NIMHANS.

DNA methylation mRNA expression & assay for serum

BDNF levels: DNA and total RNA are extracted from peripheral blood mononuclear cells (PBMC) following standard pro- cedures. DNA is then subjected to bisulphite conversion and PCR with specific primers to amplify the BDNF promoter region. The extent of methylation at the chosen CpG sites are assayed by pyrosequencing. The isolated RNA are then converted to cDNA and real-time PCR was used to determine expression levels using Taqman assay. BDNF levels in the serum

were assayed using appropriate kits. Results: Will be discussed. Discussion: Will be discussed.


doi: 10.1016/j.euroneuro.2018.08.374

SU11

THE MACROPHAGE MIGRATION INHIBITORY FACTOR

(MIF) AND STEM CELL FACTOR (SCF) LEVELS IN SERUM

OF ADOLESCENT AND YOUNG ADULTS WITH MOOD

DISORDERS: A 2-YEAR FOLLOW-UP STUDY

Pawel Kapelski , Aleksandra Rajewska-Rager, Maria Skibinska, Monika Dmitrzak-Weglarz, Natalia Lepczynska, Piotr Sibilski, Joanna Hauser

Poznan University of Medical Sciences

Background: Inflammation and cytokines have emerged as a promising target in mood disorders research, however there are still very limited numbers of study regarding inflammatory alterations among adolescents and young adults with mood disorders. The Macrophage Migration Inhibitory Fac- tor (MIF) and Stem Cell Factor (SCF) are the pleiotropic cytokines which may play an important role in mood disorders pathophysiology. The aim of this study was to investigate levels of these factors in serum of adolescent and young adults with mood disorders compared to healthy controls. Methods: We involved 79 patients aged 12-24 years in 2- year follow-up study with a primary diagnosis of mood disorders: bipolar disorder (BP) and unipolar disorder with BP spectrum. Study group includes: 23 males (mean age 19.08, SD 3.3) and 56 females (18.39, SD 3.28). Control group consisted 35 persons: 7 males (20.43, SD 4.23) and 28 females (21.25, SD 2.11). Clinical diagnoses according to DSM-IV-TR criteria were assessed using Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) and Structured Clinical Interview for the Di- agnostic and Statistical Manual (SCID) in young adults respectively. Clinical assessment includes evaluation of clinical factors and symptoms severity (rated using the Hamil- ton Depression Rating Scale and Young Mania Rating Scale). Clinical and biological evaluations were made at control visits respectively at baseline (week 0), euthymia (at month 3 or 6) and after 12 and 24 moths. Serum protein concentration was determined by Enzyme-Linked Immunosorbent Assays (ELISA) method. Human MIF and SCF DuoSet ELISA kits were used. In the analyses non-parametric tests were used: Mann-Whitney U test, Kruskall-Wallis ANOVA, Fried- man’s ANOVA, Wilcoxon signed rank test, Spearman correlation. We defined statistical significance as p < 0.05. Results: Comparing MIF and SCF levels between acute episode of depression/hypo/mania at baseline and euthymia (at month 3 or 6) we did not find any statistical differences. At baseline patients with age above 18 years old had decreased MIF level compared to patients younger than 18 years. MIF level at baseline positively correlated with age (p = 0.004). Positive correlations of SCF level at month 3 and 6 with depression or mania occurrence at month 24 (p = 0.03 and p = 0.04, respectively) was detected. Strong correlations between MIF and SCF levels at baseline (p = 0.0005) and month 3 (p = 0.03) were observed. Discussion: Our results did not show any differences in MIF and SCF levels between acute episode of depression/hypo/mania and euthymia in young patients. Further studies on larger groups are recommended.

Grant was founded by National Science Center in Poland no 2011/03/D/NZ5/06146.


doi: 10.1016/j.euroneuro.2018.08.375



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SU12

BEHAVIOURAL EFFECTS OF DEVELOPMENTAL EX- POSURE TO THE SYNTHETIC CANNABINOID JWH-018

IN WILD TYPE AND DISRUPTED IN SCHIZOPHRENIA 1

(DISC1) MUTANT ZEBRAFISH

Judit García-González , Bruno De Quadros, Maroua Akkari, Caroline Brennan

Queen Mary, University of London

Background: Cannabinoid abuse and addiction is an establish risk factor for psychiatric disorders and represents a public health issue. The increase in risk for psychiatric disorders is stronger for individuals at genetic risk or when consumption happens while the brain is still developing. How- ever, the underlying mechanistic role for the association between cannabinoid consumption and psychiatric disorders remains poorly understood. Recent advances in genetic manipulation and behavioural research make zebrafish (Danio rerio) a suitable model to study the short and long-lasting effects of developmental exposure to cannabinoids.

The aims of this study are (1) to investigate whether the developing central nervous system is susceptible to the effects of the psychoactive ingredients of synthetic cannabinoids, namely JWH-018, using zebrafish as an animal model and (2) to test whether the effects of JWH-018 in larvae and adult zebrafish are moderated by loss of function mutations in Disrupted In Schizophrenia 1 (DISC1), a gene previously associated to psychopathology in humans and other animal models. Methods: Zebrafish embryos were exposed to JWH-018 from

one to five days of age. This period corresponds to early development, equivalent to pre-natal stages in humans. At five days of age, fish locomotion and response to repeated startle stimuli was assessed. During adulthood, anxiety-like and social behaviours were investigated. Results: Zebrafish embryos exposed to JWH-018 showed increased locomotion levels at high doses and reduced their response to startle stimuli at lower doses. During adulthood, zebrafish exposed to JWH-018 showed decreased anxiety compared with controls but no changes in social behaviour were observed. Larvae with loss of function in DISC1 presented no differences in their response to startle stimuli compared to wild type controls. During adulthood, they showed increased anxiety levels and were less social. No interaction between drug and loss of function mutant zebrafish were observed. Discussion: This is the first study that has looked at the behavioural effects of early developmental exposure to JWH- 018. Our results suggest that exposure to this drug during early-development leads to short and long term behavioural changes in zebrafish. Although further studies in human populations are needed to confirm the harmful effects of synthetic cannabinoids during pregnancy, these results add further evidence to the increased risk for psychiatric disorders after exposure to cannabinoids during pregnancy.


doi: 10.1016/j.euroneuro.2018.08.376

SU13

GENETIC VARIATION IN ’CALCIUM VOLTAGE-GATED

CHANNEL SUBUNIT ALPHA1C (CACNA1C): INTERAC- TIONS WITH PREPUBERTAL STRESS AND IMPACT ON

HIPPOCAMPAL DEPENDENT LEARNING

Anna Moon , Nichola Brydges, Kerrie Thomas, Jeremy Hall

Cardiff University

Background: Genome-wide association studies have consistently demonstrated that variation in the gene calcium

voltage-gated channel subunit alpha1C (CACNA1C) increases risk for bipolar disorder, schizophrenia and major depressive disorder across diagnostic borders. CACNA1C encodes the Cav1.2 subunit of L-type voltage-gated calcium channels (LTCCs), which have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Although this finding has been replicated robustly, the mechanisms as to how

calcium channel dysfunction affects risk for several different psychiatric disorders is largely unknown. Therefore, the effects of Cacna1c genetic variation on associative learning, with a particular emphasis on the formation and expression of contextual representations within the hippocampus, were analyzed using a novel rat model.

It should also be understood that these disorders are largely polygenic and CACNA1C variation only contributes to a small amount of risk in isolation. Environmental factors also contribute to potential risk and may interact with genetic variants to modulate disorder manifestation. There- fore, the developmental influence on the expression of Cacna1c within the hippocampus and how this gene might be susceptible to environmental regulation in terms of early life stress was also examined using a rat model of prepubertal stress (PPS). Methods: PPS male and female rats (PND 25-27, 3- day unpredictable mild stressors) and control littermates (n = 9/group) were analyzed for Cacna1c mRNA and Cav1.2 protein expression within the hippocampus by in-situ hy- bridization and western blot analysis. Human post-mortem

tissue from subjects who had suffered ELS was also investigated using similar methods. Cacna1c + /- male rats (n = 8/group) and PPS male rats (n = 12/group) were also both subject to both delay and trace auditory fear conditioning paradigm and tested for conditioned responses by assessing context and cue-elicited freezing in recall ses- sions. Results: Cacna1c mRNA expression is reduced in the CA1 and CA3 of the hippocampus of male PPS rats (CA1: p = 0.002, CA3: p = 0.04), with no changes in females. There was also a trend to a decrease in Cav1.2 protein level (p = 0.06). Human ELS sufferers also have a trend to decreased Cacna1c mRNA expression in the hippocampus (p = 0.098). Cacna1c + /- rats subjected to trace fear conditioning showed increased freezing to cue (p = 0.0257), whereas those subjected to delay fear conditioning showed increased contextual freezing (p = 0.0331). PPS rats showed a decreased freezing to cue following trace conditioning (p = 0.047). Discussion: Cacna1c mRNA and protein levels were decreased following stress in early life suggesting that this


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gene may interact with stress to facilitate disease development. Both Cacna1c + /- rats and PPS rats also show a deficit in associative learning, highlighting the importance of both Cacna1c and stress in hippocampal-dependent learning. Trace and delay associative learning have been seen to be altered in schizophrenia and affective disorders, suggesting a translational aspect of this model.

These data point to the importance of the interaction of genetic and environmental effects impacting on the hippocampal circuity in psychiatric disorders.


doi: 10.1016/j.euroneuro.2018.08.377

SU14

MORPHOLOGICAL AND IMMUNOCYTOCHEMICAL CHAR- ACTERIZATION OF HUMAN-DERIVED ASTROCYTES FROM

SUBJECTS WITH THE NRG1 P.V266L GENETIC VARIANT

Daniela Ugalde Araya 1 , Laura Stertz 2 , Consuelo Walss-Bass 2 , Henriette Raventós 1

1 University of Costa Rica 2 University of Texas Health Science Center at Houston

Background: A valine to leucine variant (p.V266L) in the transmembrane domain of neuregulin 1 (NRG1) was associated with schizophrenia in the Central Valley of Costa Rica (CVCR) population. To determine its functional significance, we are studying its biological effects in different cell types. Due to the importance of the glial cells in the Central Ner- vous System, we have generated astrocytes derived from induced pluripotent stem cells (iPSCs) from unaffected CVCR subjects, with and without the p.V266L variant, to explore the role of this variant in these cells. Methods: Lymphoblastoid cells lines (LCLs) from 4 unaffected subjects were transformed into iPSCs using Episomal iPSC Reprogramming Kit. Neuronal Precursor Cells were generated using AggreWell methodology and cultured in N2B27 medium complemented with 5ng/mL CTNF, 10ng/mL BMP4 and 20ng/mL FGF2 for differentiation into astrocytes. Lipo- fectamine transfection was used to evaluate the morphology of the astrocytes (area) and the diameter of the nucleus was measure using DAPI. Immunocytochemistry was used to measure total corrected cell fluorescence (TCCF) of GFAP, CD44, S100B, and ALDH1L1 markers. The astrocytes with the NRG1 variant had larger areas than the non-mutated ones, whereas no significant differences between both groups were found when the diameter of the nucleus was compared. The TCCF of GFAP, CD44, and S100B was higher in cells with the variant; only ALDH1L1 did not present significant differences between groups. The TCCF was measured using ImageJ and the results were analyzed using R. Results: Astrocytes with the NRG1 variant have larger areas (p < 0.05), while no significant differences were found for the diameter of the nucleus (p = 0.0545). The TCCF of S100B, GFAP and CD44 was higher in cells with the variant (p < 0.05); only ALDH1L1 did not present significant differences (p = 0.26) between groups.

Discussion: Studies in animal models have shown that the presence of this variant in III NRG prevents the cleavage of the intracellular domain by the enzyme β secretase, and the extracellular domain by the enzyme γ secretase. This gen- erates the complete reversal of the signaling pathway and an alteration in expression of genes involved in cell survival, growth and maintenance. Our cell model shows changes in the area and the expression of markers with the p.V266L variant, which might reflect both structural and metabolic alterations induced by this mutation also in astrocytes. We found larger astrocytes with larger nucleus in comparisons with studies in animal models. Our results are in agreement with previous research that show that human astrocytes are substantially larger and have more complex processes than rodent cells. Also, we show that the astrocytes in which the variant is present tend to be of a larger size. The explanation of this difference between astrocytes with and without the variant could be mediated by the differences in expression of markers used in this study. GFAP and CD44 participate in the dynamics of the cellular cytoskeleton while S100B and ALDH1L1 are involved with growth and proliferation processes. These results support a possible functional role for the p.V266L NRG1 variant in modulating as- trocytic morphology and activity, and may have implications for schizophrenia. In addition, these results prove the feasibility and utility of this cell model to functionally characterize the p.V266L NRG1 variant and other genetic mutations in human astrocytes derived from EBV LCL through the iPSC

technique.


doi: 10.1016/j.euroneuro.2018.08.378

SU15

USING GENETIC MODULATORS OF THE STARTLE RE- SPONSE TO INVESTIGATE ANXIETY ETIOLOGY

Julia Tomasi , Arun K. Tiwari, Clement Zai, Deanna Herbert, Anashe Shahmirian, Nicole King, Natalie Freeman, James L. Kennedy

Centre for Addiction and Mental Health

Background: Anxiety symptoms are frequently observed across several psychiatric disorders, with these symptoms often leading to worse prognosis. Anxiety disorders have a high worldwide prevalence rate of 12%. Given the extensive and detrimental influence of anxiety, it is crucial to understand the etiology of pathological anxiety. The presence of anxiety can be assessed through measuring the startle reflex, as this reflex is increased when an individual is in a state of anxiety. The presence of an exaggerated startle response is a strong indicator of anxiety disorder. Genes such as CRHR2 (corticotropin releasing hormone receptor 2), GLRB (glycine receptor beta), and GRIK3 (glutamate ionotropic receptor kainate type subunit 3) have been associated with elevated startle reactivity. This study aims to examine genes associated with alterations in startle reactivity to determine whether they are associated with anxiety symptom severity across psychiatric patients.



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Methods: The study sample consists of patients with a clinical psychiatric diagnosis from the pharmacogenetic IMPACT study (im-pact.ca) that have been administered the Gener- alized Anxiety Disorder 7-item Scale (GAD-7) and provided a saliva sample for the genetic analysis. We are currently progressing with Infinium Omni 2.5 chip typing on over 1000 patients. First, we conducted a small pilot investigation using 17 genes and 18 SNPs to determine the effect of startle- altering genes on anxiety symptoms in psychiatric patients (N = 46). Second, we conducted this same analysis, but in a subset of individuals with an anxiety disorder diagnosis. The GAD-7 quantitative score served as the phenotype, and the associations were analyzed using a linear regression under both additive and dominant genetic models. Results: In an initial small pilot analysis, rs6298 from HTR1B (serotonin receptor 1B; p = 0.01) was significant under a dominant genetic model. In patients with anxiety disorders, rs2159100 from CACNA1C (calcium voltage-gated channel subunit alpha1 C; p = 0.03, 0.02) was associated with anxiety symptoms in additive as well as dominant genetic models, respectively (all p values unadjusted). Discussion: The preliminary results of this small study thus far suggest that genes associated with alterations in startle reactivity may be associated with anxiety symptomatology present in psychiatric patients, including among those with anxiety disorders. The top SNPs that have been identified in this study have not previously been reported in the context of anxiety. Therefore, although very preliminary, the results outlined may have promise as biomarkers of pathological anxiety. We are currently investigating these SNPs in a much larger sample. Overall, this study provides initial support for the approach of exploring genes associated with startle reactivity to identify biomarkers of pathological anxiety. Hopefully this approach will be useful in identifying novel treatment targets for those suffering from anxiety.


doi: 10.1016/j.euroneuro.2018.08.379

SU16

MONOAMINE OXIDASE A (MAOA) GENE DNA METHY- LATION IN ACROPHOBIA: EPIGENETIC CORRELATE

OF RESPONSE TO COGNITIVE BEHAVIORAL THERAPY

(CBT)?

Christiane Ziegler 1 , Miriam Schiele 1 , Leonie Kollert 2 , Andrea Katzorke 2 , Daniel Gromer 2 , Paul Pauli 2 , Jürgen Deckert 2 , Martin Herrmann 2 , Katharina Domschke 1

1 University of Freiburg 2 University of Wuerzburg

Background: Specific phobias such as acrophobia, the extreme fear of heights, are the most frequent anxiety disorders. Exposure-based cognitive behavioral therapy (CBT)

is known to be highly effective in the treatment of specific phobias. DNA methylation patterns have already been shown to be altered in anxiety disorders and to mediate and correlate with treatment response. For example, dynamic changes in DNA methylation patterns of the monoamine oxidase A (MAOA) gene were identified during the course of CBT in patients with panic disorder. In the present study, we aimed at extending these previous findings in panic disorder to specific phobias and analyzed MAOA gene DNA methylation patterns in patients with acrophobia during the course of exposure-based CBT. Methods: DNA methylation at 13 CpG sites (MAOA promoter/exonI/intronI region) was analyzed via direct sequencing of sodium bisulfite treated DNA extracted from

whole blood in Caucasian patients with acrophobia (N = 28, female) at baseline (T0) and after (T1) a standardized two- week exposure therapy using virtual reality technology therapy. Acrophobia symptoms were assessed at T0 and T1 using the Acrophobia Questionnaire (AQ, Anxiety Subscale) and the Attitude Towards Heights Questionnaire (ATHQ). All analyses were controlled for potential confounding factors such as MAOA VNTR genotype. Additionally, the functional relevance of differential MAOA methylation was investigated via luciferase-based reporter gene assays. Results: Acrophobia symptoms (AQ-Anxiety and ATHQ) decreased significantly after therapy (all ps < .001). From T0 to T1, patients displayed a significant increase in average MAOA methylation (p = .040) and in methylation at CpG4 (p = .040), CpG6 (p = .036), CpG8 (p = .004), and CpG9 (p = .004). Furthermore, clinical symptom improvement was associated with a significant increase in average MAOA DNA methylation (AQ Anxiety: r = -0.465, p = .019; ATHQ Danger: r = -0.496, p = .012). Functional analysis revealed that non- methylated vector constructs led to a significantly elevated normalized Lucia luciferase activity as compared to methylated constructs (p < .001). Discussion: The present study serves as the first replication study of dynamic MAOA gene DNA methylation patterns to be associated with therapy response in anxiety disorders and suggests an increasing MAOA methylation as an epigenetic correlate of treatment response in acrophobia. The investigated MAOA gene region and its DNA methylation patterns were furthermore shown to be of functional relevance for gene expression. The emerging evidence of changing epigenetic patterns as a potential biological mechanism of fear extinction might lead to probing pharmacological treatment enhancers such as MAO-inhibitors as augmen- tation strategies for lasting extinction effects. This might further contribute to an individual and thus more effective treatment based on individual epigenetic information.


doi: 10.1016/j.euroneuro.2018.08.380



10 Abstracts

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SU17

TREATMENT-SEEKING FOR INTERNALISING SYMPTOMS: GENE-ENVIRONMENT CORRELATION ANALYSES IN THE

UK BIOBANK

Christopher Rayner 1 , Jonathan Coleman 1 , Kirstin Purves 1 , Rosa Cheesman 1 , Genevieve Morneau-Vaillancourt 2 , Gerome Breen 1 , Thalia Eley 3

1 King’s College London

2 Laval University 3 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

Background: The high prevalence of anxiety and depressive disorders (i.e. internalizing disorders) is not proportional to the level of service use and associated treatment-seeking behaviour. The decision to seek help is expected to be influenced by symptom severity. However, treatment-seeking may also depend on other genetically influenced characteristics and their impact on active treatment-seeking behaviour. Only those who seek treatment will receive it, which has considerable implications for studies investigating treatment efficacy and genomic studies of treatment response. For example, individuals who believe in treatment are more likely to have a positive response. Methods: We defined three treatment seeking phenotypes in the UK Biobank: treatment-seeking (from a professional), self-help (self-sourcing a remedy) and self-medication (using drugs or alcohol). Multivariate logistic regressions we used to examine the effects of the environment and individual characteristics (N ∼ 45,000). Genome-wide association and LD score regression analyses were used to examine SNP heritability in the whole sample (N ∼ 70,000) and then stratified by a diagnostic interview derived lifetime internalizing disorder diagnosis (Ncases ∼30,000; Ncontrols ∼20,000). We also tested for genetic correlations with psychiatric, behavioural and cognitive traits. Results: Several environmental and individual characteristics were associated with treatment-seeking. Of particular note, we found that men are considerably less likely to seek- treatment and are much more likely to self-medicate than women. The ability and frequency participants are able to confide in others increases the odds of treatment-seeking and decreases the odds of self-medicating. Each full logistic model explains ∼20% of the variance in treatment-seeking, ∼5% of the variance in self-help and ∼25% of the variance in self-medication. Findings from genomic analyses indicate that treatment-seeking is mildly heritable (h2 ∼ 7%; s.e ∼ 1%). Treatment-seeking has a high, positive correlations with depressive symptoms, MDD, and neuroticism (rG: 64 –84%). Discussion: The finding that men are less likely to seek-help but more likely to self-medicate, over and above the effects of symptoms is reflected in the higher prevalence of alcohol use disorder in men in the UK. The higher prevalence of alcohol use (and also suicide) in men is likely to be associated with differences in coping mechanisms for internalizing symptoms. Genomic analyses indicate that treatment- seeking is not substantially heritable and much of the ge-

netic variance is shared with symptoms. This suggests that treatment-seeking is unlikely to confound genomic studies of treatment response.


doi: 10.1016/j.euroneuro.2018.08.381

SU18

POLYGENIC RISK SCORES REVEAL SUBTYPES OF AUTISM

THAT DIFFER IN CODING DE NOVO MUTATIONAL LOAD

Brian Lohman, Hilary Coon, Gabor Marth, Aaron Quinlan, Anna Docherty

University of Utah School of Medicine

Background: The rapid advance of DNA sequencing is poised to revolutionize research and treatment of human disease, both at the population and individual levels. To this end, the Simons Foundation Autism Research Initiative (SFARI) has made a major contribution by generating whole genome sequence for 2076 individuals in 4-member family units; each family containing parents and both a child diagnosed with Autism Spectrum Disorder (ASD; proband) and an unaffected sibling. These data have provided a powerful opportunity to map the genetic basis of ASD and discover genome-wide de novo mutations. However, very large GWAS have confirmed a complex and highly polygenic architecture for all major psychiatric disorders. Such complex traits are the product of many common loci of small effect, and few rare variants. Polygenic risk scores (PRS), aggregating the effects of thousands of loci, have been used to successfully subtype individuals into latent genetic classes, and to predict clinical symptoms and prognosis, not only for many cancers but also for psychiatric disorders, including schizophrenia and major depression. Methods: Here, using polygenic risk scores for 35 physical and psychological phenotypes (e.g. coronary artery disease, HDL/LDL, schizophrenia and major depression), we trained a decision tree model on Phase1 of SFARI (n = 519 families) to predict case status and to classify probands into distinct subtypes. Our model identified two distinct subtypes of probands, driven by high- and low-ASD PRS. We then tested for differences in the number of de novo mutations between subtypes. Results: We identified significant enrichment for coding mutations in the low-ASD PRS subtype. This result is consistent with the hypothesis that larger effect, more penetrant de novo variants may require less burden of polygenic risk to result in expression of the ASD phenotype. Conversely, in cases with higher polygenic risk for ASD, such variants may be more elusive. Discussion: Our work demonstrates that successful genetic subtyping of individuals, while accounting for critical covariates like sex and ancestry, produces distinct groups with more homogenous genetic backgrounds, simplifying downstream analysis and revealing previously unseen patterns that would be missed by traditional GWAS. We will present our efforts to replicate both our subtyping method


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and enrichment of de novo mutations in the low ASD PRS subtype in SFARI Phases 2, 3, and 4 (n = 1,868 families).


doi: 10.1016/j.euroneuro.2018.08.382

SU19

A SEARCH FOR RARE GENETIC VARIANTS IN A FAMILY- BASED STUDY OF AUTISM

Fiana Ní Ghrálaigh , Elaine Kenny, Louise Gallagher, Lorna Lopez

Institute of Molecular Medicine, Trinity College Dublin

Background: Autism is a neurodevelopmental disorder with a population frequency of ∼1 in 88, often co-morbid with other psychiatric disorders. While it is accepted that autism

is a highly heritable disorder (h2 > 0.8), much of the effect of genetic variation on autism remains unclear. A major search is currently underway to seek out the variation underpinning this disorder. 40% of all autism cases are currently unexplained. It is predicted that these cases may be the result of so far unidentified de novo and rare inherited variants. Family studies are a key tool in gene discovery due to the control of background genetic variation and environmental factors to a certain extent. The aim of this study is to take a family-based approach to identify the rare variants resulting in autism. Methods: A family was ascertained comprising of unaffected parents and four autism-affected offspring. DNA was extracted from saliva samples using Perkin Elmer Prepito D

cytopure kit. All six samples were sequenced using SOPHiA GENETICS Whole Exome Panel, covering 26,000 genes. Cap- tured libraries were sequenced on the Illumina HiSeq 4000 (2 × 250). Quality control was performed as standard. Data analysis was carried out using SOPHiA DDM. Results: The identification and annotation of variants implicated in autism will be reported. Medical annotation will be carried out by predicting the functional effect of variants on their respective genes, overlaying the variants called with autism candidate genes and comparing variants with well-established autism databases. Family analysis will be carried out in interpretation of the variants through segre- gation analysis and observing genotype-phenotype correlations. We will then classify the variant-containing genes and seek to identify candidate risk genes. Discussion: This study will contribute to the autism genomics field with the most up to date technology in a clinically relevant family-based study. This multiplex family, which shows a definite clustering of autism, holds particular promise for revealing highly penetrant genetic risk factors for autism. The genes identified will add to those already associated with autism, giving a deeper understanding of the genomics of the disorder. In turn, this genomic understanding will bring a clearer picture of the mechanism of disease, both on an individual level and on a global level. This gives the opportunity to develop personalised therapies and management strategies, improving patient outcomes. Genomics

is certain to play a crucial role in the diagnosis and intervention of autism in the future.


doi: 10.1016/j.euroneuro.2018.08.383

SU20

AUTISTIC TRAITS AND COGNITIVE DYSFUNCTIONS IN

CHILDREN WITH PATOGENIC COPY NUMBER VARIANTS: A PILOT STUDY FROM SERBIA

Marina Mihaljevic 1 , Milica Pejovic-Milovancevic 2 , Hristina Janeski 3 , Vanja Mandic-Maravic 2 , Roberto Grujicic 2 , Danijela Drakulic 4 , Milena Stevanovic 4 , Goran Cuturilo 3

1 Clinic for Psychiatry, Clinical Center of Serbia 2 Institute of Mental Health

3 University Children’s Hospital 4 Institute of Molecular Genetics and Genetic Engineering

Background: Copy number variants (CNVs) have been reported to be associated with a broad range of neurodevelopmental disorders (NDDs), including autism spectrum

disorders and schizophrenia. Current knowledge regarding phenotypic outcomes and pathological mechanisms is in- sufficient to translate genetic findings of CNVs into clinical practice. Therefore, a pan-European network MINDDS (Maximising Impact of research in Neuro-Developmental Dis- orderS) creates large trans-national patient cohorts with pathogenic CNVs associated with high risk for NDDs, which aim is to increase understanding and facilitate research of pathogenic CNVs. Particularly, MINDDS will challenge this issue by combining multi-dimensional research approaches, including clinical deep phenotyping, imaging, animal models and patient-derived iPS cell studies. To the best of our knowledge, there are no research groups in Serbia who investigated psychiatric phenotype in patients with CNVs. Be- coming a part of MINDDS network, the first aim of Serbian research team will be to explore psychiatric phenotype in an already existing cohort of CNV carriers. Beside phenotype measures, we will collect biological samples which will be used for different genetic and iPS cell studies. Methods: A cohort of 41 children (age range: 4-14) with pathogenic CNVs for NDDs has been recruited through a medical genetics unit at University Children’s hospital. The cohort includes: 22q11.2 deletion (N = 28), 22q11.2 duplication (N = 2), 16p11.2 deletion (N = 1), 16p11.2 duplication (N = 2), 15q11.2 deletion (N = 6), 15q11.2 duplication (N = 2) and 7q11 deletion (N = 1). Phenotype measures, such as autistic traits and cognitive functions, are assessed by Autism Diagnostic Interview − revised (ADI −R) and psychological tests (The Wechsler Intelligence Scale for Children and Vineland II). Results: Results will be presented at the congress. Discussion: This is the first study to explore psychiatric phenotype of CNV carriers in Serbia. Currently there are around 200 detected children with pathogenic CNVs for NDDs, and they will be tested during next year. As a part of MINDDS network, Serbia has an important opportunity to implement



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integrative CNV research approach in this region and to further contribute to CNV investigation worldwide.


doi: 10.1016/j.euroneuro.2018.08.384

SU21

GEOGRAPHICAL VARIATION IN GENETIC AND ENVIRON- MENTAL INFLUENCES ON AUTISM SPECTRUM DISORDER

AND ATTENTION DEFICIT HYPERACTIVITY DISORDER IN

SWEDEN AND THE UNITED KINGDOM USING BOTH TWIN

ANALYSES AND POLYGENIC RISK SCORES

Zoe Reed 1 , Henrik Larsson 2 , Robert Plomin 3 , Claire Haworth 1 , George Davey Smith 1 , Paul Lichtenstein 4 , Oliver Davis 1

1 University of Bristol 2 Örebro University 3 King’s College London

4 Karolinska Institutet

Background: Our previous work has shown that geographical location affects the balance of genetic and environmental influences on many developmental disorders and traits. For example, we may find greater heritability for a disorder in a city Centre, suggesting that the urban environment draws out genetic influences. In this study we applied our spACE approach using twin data to estimate genetic and environmental influences on autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) at locations across Sweden and the UK. We also explored how polygenic risk for these traits varies across a single city region using data from Bristol in the UK. Methods: We first used twin data from Sweden’s Child and Adolescent Twin Study to estimate spatial patterns of genetic, shared environmental and non-shared environmental influences on symptoms of ASD and ADHD measured using the Autism-Tics, A/HD and other Comorbidities inventory at ages 9 and 12. We fitted spACE structural equation models at thousands of locations across the country, with each twin pair’s contribution weighted by their inverse Euclidean distance from each location. We compared the resulting maps to our previous analyses in the UK’s Twins Early Development Study using the Childhood Asperger Syndrome Test and the Conner’s Parent Rating Scale at age 12. For our single-city- region polygenic risk score analyses we used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) in weighted linear regression models to determine the association of published polygenic risk scores with symptoms of ASD and ADHD at multiple locations. Phenotype data in ALSPAC were collected at age 7 using the Skuse social score for ASD and the Strengths and Difficulties Questionnaire hyperactivity scale for ADHD. Results: We found geographical variation in genetic and non-shared environmental influences for both ASD and ADHD

in Sweden, paralleling our previous results from the UK. In our analysis of polygenic risk scores, we also found evidence of geographical variation on a local scale in the city of Bris- tol and surrounding areas.

Discussion: Our twin analysis results show different patterns of geographical variation in genetic and non-shared environmental influences on symptoms of ASD and ADHD. This indicates that where we grow up effects the aetiology of these traits. For example, it appears that more densely populated areas show greater heritability for ASD in both the UK and Sweden, while patterns for ADHD appear more complex. We also found geographic variation in polygenic risk score associations across the Bristol area, providing complementary evidence that where we live moderates the effect of known polygenic risk on these outcomes.


doi: 10.1016/j.euroneuro.2018.08.385

SU22

AN UNUSUAL HIGH FREQUENCY OF NATURAL FETAL

LOSS IN AUTISM SPECTRUM DISORDER

Claudia Lattig 1 , Diana Nuñez 1 , Andrea Lopez 2 , Yvonne Gomez-Maquet 1 , Roberto Chaskel 3

1 Universidad de los Andes 2 Hospital Universitario Fundacion Santa Fe de Bogota 3 Instituto Colombiano del Sistema Nervioso

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders that share difficulties in communication, social interactions and stereotyped behaviors. ASD has a heritability of 64 – 91% indicating a high genetic component. Clinically recognized pregnancy loss is relatively common in the population with an estimate between 12-20%. However, this risk increases substantially, frequencies between 58-65%, for genetic diseases such as Edwards and Patau syndromes. Here we describe an unusual high rate of previous natural fetal losses in a cohort clinically diagnosed with ASD. Methods: We have clinically ascertained 65 family trios of Colombian origin composed of mother, father and at least one child with autism. All individual met criteria for ASD by psychiatric and genetic evaluation as well as psychological (ADIR/ADOS) evaluation. Informed consent was approved by all the participating institutions and signed by all participants. Results: An unexpected number of mothers in our cohort which 26 mothers (40%) had previous natural fetal losses; 17 of them had one previous natural fetal loss, and 9 mothers had two or more previous natural fetal losses. Age of the mother was not a critical factor in our cohort. Discussion: Previous pregnancy losses have not been described in ASD. Here we present a small cohort with an unusual number of cases of clinically recognized pregnancy loss. In order to determine if this risk increases in families with at least on individual with ASD, a follow-up on these families is highly recommended.


doi: 10.1016/j.euroneuro.2018.08.386




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SU23

A MACHINE LEARNING FRAMEWORK FOR CROSS-OMICS PREDICTION

Junfang Chen , Emanuel Schwarz

University of Heidelberg

Background: Technological advances in molecular high- throughput techniques and the necessity of embracing systems-approaches to shed light on the etiology of complex illnesses have led to substantial interest in computational approaches. Integrative analysis of omics data has the potential to elucidate biological mechanisms underlying complex illnesses that are hallmarked by numerous subtle changes distributed across data modalities. The objective of this work was to develop a machine learning framework for predictive pattern transfer across omics data. Since the joint analysis of multiple modalities commonly requires data to be derived from an overlapping set of subjects, a specific aim of this study was to develop an analysis framework that was independent of this requirement. Methods: We present CrossP, a cross-omics prediction framework that does not require different modalities to be acquired on an overlapping subject cohort. CrossP uses machine learning to compress modality-specific data into pathway-level prediction scores that are then used for cross-modality prediction. We demonstrate the utility of this approach using genome-wide expression and DNA methylation data acquired from patients with schizophrenia. Results: Our results show that CrossP can be used to map omics signatures predictive of schizophrenia case control status from lymphoblastoid cell line derived gene expression to whole blood DNA methylation data. These predic- tions were illness-specific against three non-psychiatric conditions and driven by overlapping illness-associations across the broad set of KEGG pathways. Discussion: The present results demonstrate that the CrossP framework has utility for integrative analysis of multi-omics data, particularly when data is not available for the same set of subjects. Notably, the possibility to map predictive patterns across omics-modalities can also facilitate the ex- clusion of confounding effects present in individual modalities. By mapping omics data to pathway-specific latent variables, CrossP further facilitates systems-based exploration of factors underlying the signal shared across modalities. Therefore, CrossP may be a useful tool to elucidate systems- biological alterations underlying complex illnesses such as schizophrenia.


doi: 10.1016/j.euroneuro.2018.08.387

SU24

NEW COMMON GENETIC VARIANTS ASSOCIATED WITH

CHRONIC PAIN: CONDITIONAL FALSE DISCOVERY RATE

ANALYSIS WITH MAJOR DEPRESSIVE DISORDER

Keira Johnston 1 , Daniel Smith 1 , Mark Bailey 1 , Mark Adams 2 , Barbara Nicholl 1 , Andrew McIntosh 2

1 University of Glasgow

2 University of Edinburgh

Background: Chronic pain is defined as pain lasting longer than 12 weeks. It is highly prevalent worldwide, imposes a significant socioeconomic burden, and contributes to excess mortality. Chronic pain can be considered a complex trait phenotype with moderate heritability (Hocking et al 2012). To date, no common genetic variation has been associated with chronic pain via Genome Wide Association Studies (GWASs) (Zorina-Lichtenwalter et al 2016). An alternative strategy for variant discovery is Conditional False Discovery Rate (cFDR) analysis on existing GWAS outputs. This approach leverages pleiotropy with a related secondary trait. One trait which shares genetic and environmental risk factors with chronic pain is Major Depressive Disorder (MDD) (McIntosh et al 2016). Methods: Summary statistic data were collected from the MDD GWAS meta-analysis carried out by Wray et al (2018). Results from 23andMe and UK Biobank research participants were removed, to give a dataset with cases = 45, 591 controls = 97,674. Summary statistic data from the Pfizer- 23andMe GWAS of von Korff chronic pain grade (1-4) vs controls (von Korff et al 1992, McIntosh et al 2016) was obtained (cases = 10, 543, controls = 12, 758). SNPs with association data on both traits were LD pruned, to give a dataset of 774, 292 SNPs. cFDR and conjunctional cFDR (ccFDR) values for each SNP for MDD given CPG and vice versa were calculated as previously detailed (Andreassen et al 2013, Liley &

Wallace 2015) using the statistical software R. To examine genes in putative linkage with significant

SNPs, NCBI dbSNP search was performed using the R package ‘rsnps’ (Chamberlain et al 2016). The UCSC Genome Browser (build GRCh38/hg38) was searched within a window

of 0.5mbp around the position of each SNP. Results: Eleven SNPs were found to be associated with either CPG or MDD, or both, at cFDR < = 0.01. Six CPG- associated and nine MDD-associated SNPs were found at cFDR < = 0.01, in comparison with three and zero MDD

and CPG-associated SNPs respectively found via the original GWAS analyses. Four SNPs on chromosome 14 were found to be pleiotropic (ccFDR < = 0.01). SNPs associated with CPG

only were linked to SLC16A7 on chromosome 12, whereas SNPs associated with MDD only were linked to LINC01360, LRRIQ3, FPGT, FPGT-TNNI3K on chromosome 1 and to LRFN5 on chromosome 14. SNPs found to be pleiotropic were also linked to LRFN5. Discussion: SLC16A7 encodes MCT2, a predominantly neuronal metabolite transporter (Pierre et al 2002, Debernardi et al 2003). Pain chronification may involve structural and functional-connectivity changes in the brain (Baliki et al 2010, 2012, Hashmi et al 2013). SLC16A7 could therefore affect chronic pain development via MCT2 involvement


14 Abstracts

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in neuronal-cell energy use. LRRIQ3 encodes leucine-rich repeat (LRR) and IQ motif containing protein 3. LRR-domain containing proteins in general are involved in cell-cell communication, innate immunity and neuronal development (Bella et al 2008, Ng et al 2011). FPGT encodes fucose-1-phosphate guanylyltransferase, involved in fucose metabolism (reviewed by Becker & Lowe 2003) which is important for cell-cell communication and neuronal development (reviewed by Becker & Lowe 2003). Lrfn protein, including Lrfn5 encoded by LRFN5, assist in cell-cell interaction, and consequently in neuronal development (Morimura et al 2006, Nam et al 2011) and synapse formation (Choi et al 2016). Multiple hits found in the LRFN5 region are putatively independent, suggesting pleiotropic effects here may contribute to both MDD and CPG pathology.


doi: 10.1016/j.euroneuro.2018.08.388

SU25

USING POLYGENIC RISK SCORE APPROACHES TO

INVESTIGATE THE COMMON-VARIANT GENETIC AR- CHITECTURE OF COGNITION IN SCHIZOPHRENIA

John Hubert , Antonio F. Pardiñas, Alexander Richards, Sophie Legge, Amy Lynham, Andrew J. Pocklington, Michael Owen, Michael C. O’Donovan, James T.R. Walters, Valentina Escott-Price

MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University

Background: Schizophrenia is known to have a substantial common-variant polygenic component [1] . Polygenic risk scores [1] directly estimate common polygenic liability in individuals regardless of their affected status and have shown weak prediction of schizophrenia affected status in independent case-control datasets [2] . With the recent discovery of gene-sets associated with schizophrenia [3] , and others to cognitive ability [4] , we investigated whether limiting the polygenic risk score to relevant functional sections of the genome may improve our understanding of cognition in cases of schizophrenia. Methods: Polygenic risk score profiles were calculated for the CardiffCOGS cohort [5] (1024 samples total) by training on the CLOZUK + PGC2 GWAS meta-analysis [3] (independent from CardiffCOGS; 39,651 cases; 64,643 controls) and a GWAS of IQ [6] (78,308 individuals). Three types of polygenic risk scores were created for each training set on LD pruned SNPs: a risk score including the entire genome, a score limited to exonic regions (including regulatory regions; 10 kb downstream, 35 kb upstream), and a score limited to gene-sets associated in each training set. Identifica- tion of association-enriched gene-sets in each training set was derived from 134 central nervous system (CNS)-related gene-sets shown to capture the excess burden in schizophrenia for copy number variants [7] . Gene-set analysis in each training set was performed using MAGMA [8] . All three types of polygenic risk score profiles were tested for association with cognition within schizophrenia.

Results: Whole genome polygenic risk scores training on IQ predicted cognition better in schizophrenia cases over a polygenic risk score trained on schizophrenia. The FMRP targets [9] gene-set preferentially captured variance in cognition in schizophrenia over other previously associated schizophrenia gene-sets when the GWAS of IQ was used to define risk alleles. One important observation was in marked contrast to genome wide polygenic risk score analyses, many gene-set polygenic risk scores capture maximal variance when risk alleles are defined at the genome wide significant threshold. Discussion: Our results support the hypothesis that shared common genetic factors exist between the variance in cognitive ability in schizophrenia and intelligence in the general population. They also suggest that this is relatively enriched in particular functional gene-sets. The fact that optimal prediction for functional gene-sets was often obtained using genome wide significant risk alleles points to alleles within these gene-sets playing the most important roles and demonstrates the importance of testing multiple thresholds in functional gene-set analyses.


References

Darnell, J.C., et al., 2011. Cell 146, 247–261. International Schizophrenia Consortium, 2009. Nature 460, 748–

752. de Leeuw, C.A., et al., 2015. PLOS Computational Biology 11,

e1004219. Lynham, A.J., et al., 2018. Journal of Psychiatry and Neuroscience. Pardiñas, A.F., et al., 2018. Nature Genetics. Pocklington, A.J., et al., 2015. Neuron 86, 1203–1214. Ripke, S., et al., 2014. Nature 511, 421–427. Savage, J.E., et al., 2017. bioRxiv, 184853. Sniekers, S., et al., 2017. Nature Genetics 49, 1107–1112.

doi: 10.1016/j.euroneuro.2018.08.389

SU26

A WEIGHTED BURDEN TEST USING LOGISTIC RE- GRESSION FOR INTEGRATED ANALYSIS OF SEQUENCE

VARIANTS, COPY NUMBER VARIANTS AND POLYGENIC

RISK SCORE

David Curtis

University College London

Background: Previously described methods of analysis allow variants in a gene to be weighted more highly according to rarity and/or predicted function and then for the variant contributions to be summed into a gene-wise risk score which can be compared between cases and controls using a t test. However, this does not allow incorporating covariates into the analysis. Schizophrenia is an example of an illness where there is evidence that different kinds of genetic variation can contribute to risk, including common variants contributing to a polygenic risk score (PRS), very rare copy number variants (CNVs) and sequence variants.



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Methods: A logistic regression approach has been implemented to compare the gene-wise risk scores between cases and controls while incorporating as covariates population principal components, the PRS and the presence of pathogenic CNVs and sequence variants. A likelihood ratio test is performed comparing the likelihoods of logistic regression models with and without this score. The method was applied to an ethnically heterogeneous exome- sequenced sample of 6000 controls and 5000 schizophrenia cases. Results: In the raw analysis the test statistic is inflated but inclusion of principal components satisfactorily controls for this. In this dataset the inclusion of the PRS and effect from CNVs and sequence variants had only small effects. The set of genes which are FMRP targets showed some evidence for enrichment of rare, functional variants among cases (p = 0.0005). Discussion: This approach can be applied to any disease in which different kinds of genetic and non-genetic risk factors make contributions to risk.


doi: 10.1016/j.euroneuro.2018.08.390

SU27

A GLOBAL VIEW OF GENETIC ARCHITECTURE AND

PLEIOTROPY IN HUMAN COMPLEX TRAITS

Kyoko Watanabe , Sven Stringer, Tinca Polderman, Danielle Posthuma

VU Amsterdam

Background: Despite more than a decade of genome-wide association studies (GWAS), the proportion of segregating variants that contribute to variation of complex traits, the degree of polygenicity and the extent of pleiotropy are still largely unknown. Here we curated 3,795 GWAS summary statistics for 2,822 traits in 28 trait domains and systematically analyzed these to investigate two main fundamental questions: what is the nature of the genetic architecture of complex traits, and what is the extent of pleiotropy. Methods: We compiled a database of 3,795 GWAS summary statistics (including 3,184 publicly available and 611 UK Biobank release 2 GWAS performed in this study) for 2,822 unique traits across 28 domains. For the purpose of comparing GWAS outcomes across traits, we selected GWAS’s with s sufficiently large sample size ( > 50,000) resulting in GWAS for 501 unique traits across 23 trait domains. Results: The nature of the genetic architecture was measured in terms of the polygenicity of traits. We used a univariate Gaussian mixture for GWAS summary statistics to estimate pi_1 (the fraction of causal SNPs) and sigma_beta 2 (variance of effect sizes of causal SNPs). Over 90% of traits showed high polygenicity (1e-4 < pi_1 < 0.01) with moderate discoverability (2e-7 < sigma_beta 2 < 1e-3), and most of these traits required over a million subjects to reach 90% of discovery.

We evaluated the extent of pleiotropy by counting the number of associated traits and trait domains at the risk lo-

cus, SNP and gene levels. Risk loci across 501 traits covered more than a half the genome. 10.2% of SNPs and 58.1% of protein coding genes in the genome reached genome-wide significance in at least one trait. Pleiotropy is ubiquitous across the genome; 59.6% (76.6%) of SNPs (genes) that are associated with at least one trait are pleiotropic (associated with more than one trait) and 31.0% (63.3%) of SNPs (genes) are highly pleiotropic (associated with traits from more than one domain). Pleiotropic risk loci showed higher gene density compared to genomic regions that are not associated with any trait.

The recently proposed omnigenic model postulates that any regulatory variant and gene that is active in a certain tissue is likely to be associated with many or even all traits that are modulated through the same tissue. Under this model, active regulatory variants and genes expressed in many or all tissues are more likely to have associations with more number of traits. Indeed, our results showed that SNPs and genes that are more pleiotropic are less tissue-specific. Discussion: We show widespread variation in genetic architecture across hundreds of complex traits and widespread pleiotropy. Our results provide novel insights into how genetic variation contributes to trait variation based on a vast amount of empirical results. Our results support the omnigenic model where genes widely expressed in a variety of tissues are more likely to be associated with multiple traits.


doi: 10.1016/j.euroneuro.2018.08.391

SU28

MODELLING GENETIC ASSOCIATIONS VIA THE INTE- GRATION OF GWAS AND EQTL DATA

Josefin Werme , Sophie van der Sluis, Danielle Posthuma, Christiaan de Leeuw

VU Amsterdam

Background: Genome-wide association studies (GWAS) have aided the detection of vast numbers of genetic variants associated with complex traits. Results from these studies have emphasized their complex genetic architecture, and high levels of polygenicity has all but facilitated any functional interpretation. Enrichment of non-coding regions and regulatory elements suggests that altered gene expression plays an important role, and thus, integrating regulatory information such as expression quantitative trait loci (eQTL) data may help elucidate their aetiology. A number of methods, such as PrediXcan and TWAS, have been developed for this purpose. However, whilst these methods may prioritize relevant genes, they do not allow for any inference regarding the involvement of genetically regulated expression (despite their results often being interpreted as such). With the aim of addressing this, we have developed a novel method that adopts a competitive hypothesis testing framework, akin to that in gene-set analysis, into the integrated analysis of GWAS and eQTL data. Methods: We obtained information on the genetically regulated component of gene expression using blood-eQTL data



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from the Framingham cohort. Integrating this with independent, user-provided GWAS summary statistics, our tool applies a Bayesian penalized regression model with spike and slab priors to simultaneously model the gene expression patterns that mediate the observed genotype–phenotype associations. The performance of our method is evaluated via simulation studies and subsequently applied to real data. Results: Results from our simulation studies show that our method can successfully identify genes whose genetically regulated expression plays an important role in phenotypic aetiology. It allows us to detect convergent effects from

multiple loci as well as detect trans-regulated genes that would have otherwise been missed. By contrast, existing methods were found unable to distinguish genetic association patterns that were due to expression regulation, functioning essentially akin to standard gene analysis. Discussion: There is a pressing need for statistical approaches that further aid the functional interpretation of GWAS findings. Integration of additional sources of biological information, such as eQTL data, may help attain this goal. Although there are existing methods that aim to ac- complish this, their statistical and conceptual foundations limit the conclusions that can be drawn. Here, we presented a novel tool that overcomes these limitations, thus allowing the detection of phenotypically relevant gene expression regulation and providing an additional layer of interpretation for GWAS results.


doi: 10.1016/j.euroneuro.2018.08.392

SU29

PREDICTING PSYCHOPATHOLOGY WITH POLYTRAN- SCRIPT RISK SCORES

Jonathan Hess , Stephen J. Glatt

SUNY Upstate Medical University

Background: Polygenic risk scoring (“the Purcell method”) has become a widely used technique for summarizing small risk-associated effects across thousands of genetic variants to predict liability for complex disorders. An analo- gous method has not yet been introduced for application in transcriptomic data. Here, we present a novel method called polytranscript risk scoring (PTRS) which measures transcriptome-wide changes in gene expression associated with a disorder or phenotype. Methods: PTRS is a single variable that can be easily computed and incorporated into standard machine learning models for objectives such as risk prediction. In this study, we constructed PTRS for bipolar disorder (BD) using our multi-site transcriptomic mega-analysis that compared peripheral blood gene expression profiles in a predominantly adult sample of cases affected with BD (n = 95) with non- affected comparison subjects (NCs, n = 111). Results: PTRSs explained a significant proportion of risk for BD and could accurately discriminate BD-affected cases from NCs with an average AUC of about 70% (p < 0.0001). We hypothesized that PTRS for BD may generalize to other

forms of the illness, thus we tested the association of PTRS with dimensional measures of behavioral functioning that are intimately related to pediatric BD (i.e., aggression, anxiety with depression, and attention problems). Regression analysis revealed that PTRS for BD was significantly predictive of aggression in a sample of school-aged children (n = 92). Discussion: Our study demonstrates the potential utility of PTRS for risk prediction, thereby enabling further molecular characterization of complex disorders and phenotypes.


doi: 10.1016/j.euroneuro.2018.08.393

SU30

ANALYSIS OF WGS DATA FROM 108 INDIVIDUALS OF 8

SPANISH FAMILIES AFFECTED WITH BIPOLAR DISORDER

Sascha Fischer 1 , Charlotte Ng 2 , Martin Fink 3 , Céline Reinbold 1 , Anna Maaser 4 , Fabian Streit 5 , Jose Guzman Parra 6 , Fabio Rivas 7 , Fermin Mayoral 7 , Stefan Herms 1 , Marcella Rietschel 5 , Markus Nöthen 4 , Per Hoffmann 1 , Andreas Forstner 4 , Sven Cichon 1

1 University of Basel 2 Institute of Pathology, University Hospital Basel 3 Novartis Pharma AG

4 Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn

5 Central Institute of Mental Health, University Medical Center Mannheim/University of Heidelberg 6 Institute of Biomedicine (IBIMA), University Hospital of Malaga 7 Carlos Haya Regional University Hospital

Background: Bipolar Disorder (BD) is a genetically complex neuropsychiatric disorder with an estimated heritability of approximately 70%. Recent GWAS have shown that common risk factors substantially contribute to the development of BD. Yet, common alleles cumulatively explain only 25-38%

of the phenotypic variance, suggesting that other so far unknown genetic factors must play a role. Rare variants with higher penetrance might explain some of the hidden heritability and may particularly be present in families with multiple individuals affected with BD. A research strategy to identify such rare variants is Whole Genome Sequencing (WGS) of promising multigenerational families with BD. In the present study we conducted WGS of 108 individuals in a set of 8 extended multigenerational and multiply affected families of Spanish origin. On average we sequenced 14 affected and unaffected individuals per family. Methods: Library enrichment was done PCR free with the KAPA HTP/LTP Library Preparation Kit and WGS was performed at 30X on an Illumina HiSeq2500v4 system. Variant calling files (VCF) were created for all individuals using an in-house developed pipeline based on GATK s best practice guidelines. For the visualization and data handling we set up an analysis workflow based on the CRAN package vcfR and in-house developed R-scripts. We conducted a gene set/pathway analysis for the resulting genes using Ingenuity



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Pathway Analysis and ConsensusPathDB. In addition to that we conducted Polygenic Risk Score analysis (PRS) in the subset of the 8 WGS analyzed families. Results: In our analysis we focused on rare variants with a minor allele frequency (MAF) below 1% (according to the ExAC database). Our first analysis is an “extended exome”analysis of WGS data. We applied a narrow analysis model to identify overlapping, rare, co-segregating variants in the affected individuals in one family which are not shared by healthy individuals within the same family. In addition, we also applied an analysis model in which we take into ac- count incomplete penetrance. All synonymous, missense, nonsense and frameshift variants were included. In total we identified 1 protein truncating and 9 missense variants. PRS analyses in the families show very diverse risk profiles for healthy and affected individuals among the 8 analyzed families. Discussion: Most identified variants are classified as not disease causing and are typically not carried by all affected individuals in one family. Gene set enrichment analyses (IPA and ConsensusPathDB) mainly highlight immunological genes suggesting a possible role of immunological processes in BD which has also been reported for schizophrenia. As a next analysis step we will include information on clinical subgroups, such as BDI and BDII and analyze the combined effect of PRS data and rare variants on clinical phenotype. Based on our results we plan re-sequencing of identified promising genes in an independent cohort of 1000 BD

cases and 1000 controls of German origin to further support their potential role in BD. We are currently working on the incorporation of other types of genetic variation (structural variation) and the establishment of analysis pipelines for intergenic regions.


doi: 10.1016/j.euroneuro.2018.08.394

SU31

METHYLATION ANALYSIS OF THE MOLECULAR CLOCK

AND BACTERIAL DIVERSITY IN BIPOLAR DISORDER

Susanne Bengesser 1 , Sabrina Mörkl 1 , Jolana Wagner-Skacel 1 , Frederike Fellendorf 1 , Martina Platzer 1 , Konstantin Bauer 1 , Tanja Kirchschlager 1 , Annamaria Painold 1 , Bettina Halwachs 1 , Eva Reininghaus 1 , Carlo Hamm

1 , Alexander Maget 1 , Andreas Waha 2

1 Medical University of Graz 2 University of Bonn

Background: The gut-brain-axis, which is an extensive bidirectional communication network between the gastroin- testinal tract and the brain, is in the spotlight of research nowadays. Nevertheless, little is known about the mechanisms of this gut-brain-axis. There are results, which suggest that metabolites of microbiota affect gene regulation in the human body. Thus, we investigated, whether bacterial diversity is interconnected with epigenetic changes in the peripheral blood.

Methods: Isolation of genomic DNA with the salting out technique from fasting blood of study participants with BD

(n = 32). Methylation analysis of the clock gene ARNTL (CG

site cg05733463) was performed with bisulfite treatment/ Epitect kit, PCR and pyrosequencing. The microbiome was analyzed with 16S rRNA gene analysis. Results: The methylation status of the cg05733463 site of ARNTL correlated significantly with bacterial diversity (Simpson Index: r = -0.389, p = 0.0238) and evenness (Simp- son evenness index: r = -0.358, p = 0.044). Discussion: If the methylation of the clock gene ARNTL was influenced by the gut-microbiome diversity, probiotics could putatively have an “antidepressant” effect, because the molecular clock is connected with mood regulation (the transcription of the clock gene ARNTL correlates positively with the transcription of the serotonin, noradrenaline and dopamine degrading enzyme MAOA). Probiotics are especially promising for those not benefitting from common antidepressant treatments or for patients suffering from side effects. Nevertheless, further research is necessary.


doi: 10.1016/j.euroneuro.2018.08.395

SU32

GENETICS OF SLEEP DURATION AND BIPOLAR DIS- ORDER

Katie Lewis 1 , Alexander Richards 1 , Ganna Leonenko 1 , Katherine Gordon-Smith 2 , Liz Forty 1 , Sarah Knott 1 , Lisa Jones 2 , Valentina Escott-Price 1 , Michael Owen 1 , Nick Craddock 1 , Ian Jones 1 , Michael O’Donovan 1 , Arianna Di Florio 1

1 Cardiff University 2 University of Worcester

Background: Bipolar disorder (BD) is associated with sleep disturbances independently of mood state, and has been proposed to be an endophenotype for BD. However, genome wide association studies have reported mixed results when calculating genetic correlations between sleep traits and BD. BD is a multifactorial and heterogeneous disorder; thus, sleep disturbances may play a more potent role in the aetiology of the disorder for some individuals and not others. We therefore hypothesized that polygenic risk scores for sleep phenotypes could be used to identify particular clinical strata of individuals with BD. Methods: Participants were 4863 individuals with BD recruited from the Bipolar Disorder Research Network (BDRN) and 5714 controls recruited from the 1958 British Birth Co- hort and UK Blood Services. All participants were white and recruited within the United Kingdom between January 1 2000 and December 21 2013. Clinical subphenotypes of BD

were ascertained via semi-structured psychiatric interview

(the Schedules for Clinical Assessment in Neuropsychiatry) and case notes. Polygenic risk scores (PRS) for sleep traits were derived from publicly available genome wide association study summary statistics. Binary and multinomial logistic regression analyses examining associations between



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PRS for sleep traits (at p value threshold ≤ 1) and outcome variables were adjusted for 10 population principal components. Results: After quality control, a maximum of 92,234 SNPs were used to generate PRS at a p value threshold ≤ 1 in 5714 controls and 4863 individuals with BD. Using multinomial logistic regressions, PRS for sleep duration were significantly associated with severe clinical phenotypes of BD compared to controls, but not less severe BD clinical phenotypes. Discussion: Sleep duration PRS may identify clinically meaningful substrata of individuals with BD, suggesting that per- turbations in the sleep-wake regulation systems play a more significant role in the aetiology of BD for these individuals. Our results also potentially explain the lack of significant genetic correlations found between BD and sleep duration in previous research.


doi: 10.1016/j.euroneuro.2018.08.396

SU33

ANALYSIS OF WHOLE EXOME SEQUENCING OF 1000

BIPOLAR PATIENTS

Weiqing Wang 1 , Tan Hoang Nguyen 1 , Shaun Purcell 2 , Mikael Landen 3 , Patrick Sullivan 4 , Eli Stahl 1

1 Icahn School of Medicine at Mount Sinai 2 Brigham & Women’s Hospital 3 Gothenburg University 4 University of North Carolina at Chapel Hill

Background: Bipolar disorder (BD) is a common, severe mood disorder that affects more than 1% of the worldwide population. Despite the high genetic component in the disorder, the genetic architecture of bipolar remains elusive. Meta-analysis of genome-wide association studies (GWAS) with over 20,000 BD cases reveals over 20 loci associated with BD. Despite GWAS’s success in uncovering robust associations between common variants and the BD trait, it is estimated that the total variance in liability to BD that can be explained by all common SNVs does not exceed 25%. Exome sequencing has revealed a significant burden of deleterious rare variants in patients with schizophrenia, which overlaps with bipolar disorder clinically and genetically. Therefore, rare variants may be expected to explain additional risk for BD. We present analysis of rare coding variation in bipolar disorder cases and controls from Sweden. We try to identify any burden of rare variants in genes, gene sets or exome- wide that are associated with bipolar disorder. Methods: 1169 blood-derived DNA samples from bipolar disorder patients were collected as part of the Sweden dataset, which also includes 4970 schizophrenia cases and 6245 controls. DNA samples were sequenced with Agilent SureSelect Human All Exon Kit and Agilent SureSelect Hu- man All Exon v.2 Kit in 12 waves. We performed rigorous quality control and removed individuals and variants based on covariates including sequencing metrics, principle components, genotype missingness and number of heterozygous sites. Nonparametric matching methods (MatchIt r package)

were used to choose a 1-to-1 case-control sample matched on selected covariates. The variants were annotated using variant effect predictor (VEP) and dbNSFP. Loss of function singletons are defined as variants that appear only once in the dataset and are annotated either as frameshift, essen- tial splice sites or nonsense. We will use Mendelian clinically applicable pathogenicity (M-CAP) score to define missense- damaging variants. We will use logistic regression to assess whether bipolar cases have more missense-damaging variants. In addition to exome-wide analyses, we will use large gene sets previously found to be associated with schizophrenia, including constrained genes and targets of fragile X mental retardation protein (FMRP), to test for enrichment of rare loss of function and missense damaging variants. Results: Loss of function singleton association results show

that bipolar cases have significantly more loss of function singletons than the controls (p = 0.0385, beta = 0.046). Av- erage numbers of loss of function singletons in each control and bipolar patient are 3.94 and 4.24, respectively. This difference is similar to results from exome sequencing study of schizophrenia (a difference of 0.12 variants per person). Discussion: Results from GWAS studies suggest a polygenic architecture for bipolar disorder. With ∼1000 bipolar cases, we remain underpowered to identify any significant rare variants or genes associated with the disorder. Neverthe- less, we are able to detect a nominally significant rare variant burden exome-wide in bipolar disorder cases. We expect multiple rare variants that may converge in specific pathways contribute to the risk of bipolar.


doi: 10.1016/j.euroneuro.2018.08.397

SU34

CSMD1 GENETIC VARIANT IS ASSOCIATED BOTH WITH

ALZHEIMER’S DISEASES AND SCHIZOPHRENIA IN A

RUSSIAN POPULATION

Anna Bocharova 1 , Kseniya Vagaitseva 1 , Oksana Makeeva 1 , Andrey Marusin 1 , Natalya Zhukova 2 , Irina Zhukova 2 , Valentina Alifirova 2 , Maria Matveeva 2 , Vadim Stepanov 1

1 Research Institute of Medical Genetics 2 Siberian State Medical University

Background: Common neuro-psychiatric disorders including Alzheimer’s disease (AD) and schizophrenia (SHZ) are the subject of intensive genetic research. The genetic etiology of AD and SHZ is heterogeneous. Genetic variants associated with impairments in language, memory and executive functions, which are an important endophenotypes for AD

and SHZ, have been revealed by GWAS. Potentially, the increased prevalence of AD and schizophrenia may be related to a shared genetic liability. The aim of this study was to analyze associations of 42 SNPs reported in GWAS with AD

and SHZ in Russian population. All SNPs had been previously identified by GWAS as genetic susceptibility factors for AD, SHZ or cognitive impairments. Methods: 190 patients with AD, 711 healthy controls, and 350 SHZ patients, 670 healthy controls matched



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to the patients by age, gender, and ethnicity were included in the study. 42 SNPs were genotyped by MALDI- TOF mass-spectrometry using MassARRAY Analyzer 4 (Agena Bioscience TM ). Allele specific ORs and associated p-values were calculated. Results: Three susceptibility loci for AD were identified in our study in Russian patients: rs12989701 at LOC105373605 locus (OR = 1.46, p = 0.0459), rs2616984 at CSMD1 gene (OR = 1.33, p = 0.02) and rs1532278 at gene CLU (OR = 1.28, p = 0.04). Seven loci was found in association with the SHZ in Russian patients: rs2247572 at KCNB2 gene (OR = 1.276, p = 0.0468), rs2616984at CSMD1 gene (OR = 1.73, p = 0.0337), rs12807809 at intergenic region SPA17-NRGN (OR = 1.33, p = 0.0337), rs11064768 at CCDC60 gene (OR = 1.79, p = 0.001), rs16887244 at LSM1 gene (OR = 1.31, p = 0.0221), rs7004633 at intergenic region LOC100129100-LOC100509857 (OR = 1.34, p = 0.0134), rs7561528 at LOC105373605 gene (OR = 1.85, p = 0.0231). Discussion: We observed the common association of the genetic variant in the CSMD1 gene with AD and SHZ in the Rus- sian population. The CSMD1 gene encodes an important cell adhesion molecule which plays pivotal roles in the development, connection and plasticity of brain circuits. The CSMD1 might be an important factor in susceptibility to both AD and SHZ.

This work was supported by the Russian Science Founda- tion (project # 16-15-00020).


doi: 10.1016/j.euroneuro.2018.08.398

SU35

GENOME-WIDE SEQUENCING AND DATA-DRIVEN NEU- ROANATOMICAL MRI ANALYSIS SUGGESTS SHARPIN

MISSENSE VARIANT FOR ALZHEIMER’S DISEASE

Sourena Soheili-Nezhad 1 , Emma Sprooten 1 , Christian F. Beckmann 1 , Sebastian Guelfi 2 , Reza Khosrowabadi 3 , Andrew J. Saykin 4 , Neda Jahanshad 5 , Paul M. Thompson 5 , Mojtaba Zarei 6

1 Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen

2 University College London (UCL) Institute of Neurology 3 Institute for Cognitive and Brain Sciences, Shahid Beheshti University 4 Center for Neuroimaging, Indiana University School of Medicine 5 Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC

6 Institute of Medical Science and Technology, Shahid Be- heshti University

Background: Alzheimer’s disease is a heritable neurodegenerative disorder, but much of the responsible underlying molecular and system-level brain mechanisms remain elusive. Hippocampal volume loss is commonly used as an imaging biomarker of AD. Data-driven source separation methods are emerging as a promising tool for capturing more com-

plex patterns of brain MRI phenotypes less susceptible to a priori assumptions. In this regard, independent component analysis (ICA) may provide sensitive neuroimaging biomarkers for finding genetic influences on selectively vulnerable brain structures. Methods: We extracted a data-driven signature of structural brain covariation in 1,100 participants of the ADNI cohort using MRI data, ICA and Tensor-Based Morphometry (TBM). Brain morphometry maps of the population were fed into ICA to extract spatial components of anatomical brain variation with informative power in AD discrimination. After ex- tracting the most sensitive 3D signature of AD by a computational whole-brain search, which robustly mapped to the neuroanatomy of the memory limbic system, it was used in a whole-genome-sequencing based association study (read depth = 30-40x) to identify genetic polymorphisms with significant correlation with volume deficits in this brain component. The top-hit variant was subsequently explored in the UK Biobank dataset for potential association with maternal and paternal history of AD in more than 290,000 participants. Results: Logistic regression showed that the most promi- nent imaging predictor of AD is a neuroanatomical component which performed better than hippocampal volume measure in predicting subjects with AD and mild cognitive impairment from the cognitively normal group. This component was bilaterally symmetric, and spanned voxels of amygdalae, hippocampi, entorhinal cortex, insula, mammil- lary bodies, and fornix with a network-like topology in 3D.

Whole-genome association revealed that a missense variant in SHARPIN, coding for a synaptic scaffold protein, is correlated with brain volume deficits in this critical component (rs34173062, p = 2.1 ×10 −¹0 ). The same variant was also correlated with parental history of AD in the UK BioBank cohort (p both parents = 2.3x10 −6 ; p maternal = 0.0012; p paternal = 5.1x10 −4 ), with a biologically consistent effect direction of the risk allele (A) across the ADNI and UK BioBank datasets. Discussion: Our exploratory search reveals that AD is correlated with deficits in a unified anatomical structure spanning regions of the limbic system engaged in memory formation and retrieval. We report a new locus in SHARPIN as a genetic modifier of this limbic-specific MRI signature and also show its strong correlation with a positive family history of AD. SHARPIN codes for a SHANK scaffold synaptic protein and links the postsynaptic density neurotransmit- ter receptors with the actin cytoskeleton. SHARPIN is also a known modulator of the NF- κB signaling pathway with roles in learning and memory. Our findings show that exploratory imaging measures aid in discovering novel genetic risk loci of AD with significant influence on pathways of disease predisposition.


doi: 10.1016/j.euroneuro.2018.08.399



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SU36

THE ASSOCIATION OF GENETIC RISK FOR ALZHEIMER’S DISEASE WITH COGNITIVE MEASURES, EDUCATIONAL

ATTAINMENT AND BEHAVIOURAL OUTCOMES IN CHIL- DREN

Roxanna Korologou-Linden, Emma L. Anderson, Hannah Jones, George Davey Smith, Laura Howe, Evie Stergiakouli

MRC Integrative Epidemiology at the University of Bristol

Background: The lack of effective therapies for Alzheimer’s disease has placed added importance into the identification of modifiable risk factors prior to disease onset. Lower educational attainment is the only risk factor to have been consistently associated with Alzheimer’s disease. Recent studies have identified genetic variants associated with Alzheimer’s disease, but it is not currently known how they increase the risk of disease. One possibility is that genetic risk influences cognitive development early in life. We used polygenic risk scores (PRS) to examine whether a genetic risk for Alzheimer’s disease is associated with cognitive, educational attainment and behavioural outcomes through childhood and adolescence without the selection bias present in late-life studies. Methods: PRS were computed for children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort based on the summary statistics from the genome- wide association study (GWAS) of Alzheimer’s disease by the IGAP consortium. A PRS was calculated for each participant with genetic data using PLINK (version 1.9). Each score was calculated from the effect size logarithm odds- weighted sum of associated alleles within each participant. PRS were created for the following significance thresholds: 5x10-8 (genome-wide significance threshold), 5x10-2, and 5x10-1 (and including/excluding apolipoprotein E (ApoE)). Results: The PRS at the most liberal p-value threshold examined (p ≤5x10-1) was associated with lower educational attainment at ages 14 and 15 years. One standard deviation increase in PRS was associated with 0.03 (95% confidence interval [CI]: -0.05,-0.003) lower standardized exam

points at Key stages 4 and 5. Additionally, one standard deviation increase in PRS (at p ≤5x10-2 and p ≤5x10-1) was associated with 0.03 (95% CI: -0.06, -0.01) and 0.04 (95% CI: -0.07, -0.02) lower standardized total IQ at age 8 years, respectively. No associations were observed for PRS at 5x10-8 or behavioural outcomes. Associations were similar including/excluding ApoE. Discussion: Our study is the first to examine the association between genetic risk of Alzheimer’s disease and both educational/cognitive and behavioural outcomes in childhood/adolescence. Our findings suggest that genetic overlap may exist between Alzheimer’s disease, educational attainment, and cognitive measures at liberal PRS thresholds.


doi: 10.1016/j.euroneuro.2018.08.400

SU37

INCREASED GENETIC RISK LOAD FOR MAJOR DEPRES- SION IN PATIENTS ASSIGNED TO ELECTROCONVULSIVE

THERAPY

Jerome Foo 1 , Fabian Streit 1 , Josef Frank 1 , Stephanie Witt 1 , Jens Treutlein 1 , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bernhard Baune 2 , Susanne Moebus 3 , Karl-Heinz Joeckel 3 , Andreas J. Forstner 4 , Markus Nöthen 4 , Marcella Rietschel 1 , Alexander Sartorius 1 , Laura Kranaster 1

1 Central Institute of Mental Health

2 University of Adelaide 3 University Clinics Essen, University Duisburg-Essen

4 University of Bonn

Background: Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression, but its underlying mechanisms remain poorly understood; unfavorable treatment response is thought to be influenced by genetic factors. Increasing evidence shows that severity of psychiatric disorder is associated with higher genetic burden for disorder; depression has been shown to be a highly polygenic disorder (i.e. the result of the contribution of many genetic variants). Methods: In this study, we tested whether ECT assign- ment and response/non-response were associated with an increased genetic burden for major depression (MD) using polygenic risk scores (PRS), which summarize the contribution of disease-related common risk variants. Fifty- two psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients, as well as a separate population-based sample (n = 3547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD working group (Cases: n = 59,851; Controls: n = 113,154). Results: Response to ECT was positively correlated with being male (rho = 0.332, p = 0.045), having a positive family history for affective disorders (rho = 0.358, p = 0.029) and negatively correlated with diagnosis of personality disorder (rho = -0.335, p = 0.029). In association analyses, MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = 0.022, R2 = 1.173%); patients showed significantly higher MD-PRS. MD-PRS in population-based individuals self-reporting depression were intermediate between ECT patients and controls (n.s.). Sig- nificant associations between MD-PRS and ECT response (50% reduction in Hamilton Depression Rating Scale Scores) were not observed. Discussion: Our findings indicate that ECT cohorts show an increased genetic risk load for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup characterized by an increased genetic risk for MD. Going forward, ECT should be should be given further consideration as a model to examine the etiology of antidepressant response by applying time-sensitive molecular


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methods to take advantage of its clear pre-post treatment design.


doi: 10.1016/j.euroneuro.2018.08.401

SU38

EARLY ONSET DEPRESSION: CHARACTERISING DE- VELOPMENTAL TRAJECTORIES AND THE ROLE OF

NEUROPSYCHIATRIC GENETIC RISK VARIANTS

Frances Rice 1 , Lucy Riglin 1 , Ajay K Thapar 1 , Jon Heron 2 , Richard Anney 1 , Michael O’Donovan 1 , Anita Thapar 1

1 Cardiff University 2 School of Social and Community Medicine, University of Bristol

Background: Depression often first manifests in adolescence. Thereafter individual developmental trajectories vary substantially but it is not known what shapes depression trajectories in youth. Recent evidence from adult genome-wide association studies suggests that schizophrenia genetic risk may contribute to earlier onset depression. Methods: A longitudinal sample of adolescents who reported on depression on multiple occasions between age 10.5 years and 18.5 years. Trajectories based on self- reported depressive symptoms dichotomized by the clinical cut-point for the scale. MDD, schizophrenia and Attention Deficit Hyperactivity Disorder (ADHD) polygenic risk score (PRS) were predictor variables. Results: Latent class growth analysis identified three distinct trajectory classes – a persistently low class (73.7%), a late-adolescent-onset class (17.3%), and an early- adolescent-onset class (9.0%). The late-adolescent class, which had features of a ‘typical’ post-pubertal-onset depression trajectory, was associated with an elevated genetic risk for depression as indexed by MDD PRS, but not with liability to neurodevelopmental disorders. In the early- adolescent onset class, depression had an onset by age 12, and was associated with the neurodevelopmental as well as MDD genetic risk, with the strongest association coming from genetic liability to ADHD. Discussion: We found evidence of distinct depressive trajectories, primarily distinguished by age-at-onset. The more typical depression trajectory with onset of clinically significant symptomatology at around age 16 was associated with MDD genetic risk. The less common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk. These findings are consistent with emerging evidence for a neurodevelopmental component to some cases of depression and suggest that this is more likely when onset is very early.


doi: 10.1016/j.euroneuro.2018.08.402

SU39

GENETIC VARIATION IN THE MAJOR HISTOCOMPATI- BILITY COMPLEX AND ASSOCIATION WITH DEPRESSION

Kylie Glanville 1 , Jonathan Coleman 1 , Ken B. Hanscombe 1 , Jack Euesden 1 , Shing Wan Choi 1 , Kirstin Purves 1 , Major Depressive Disorder Working Group 2 , Paul F. O’Reilly 1 , Cathryn M. Lewis 1


2 Psychiatric Genomics Consortium

Background: The prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - depression increases the risk of developing an autoimmune disease, and vice-versa – and shared genetic etiology is a plausible explanation. In this study, we tested whether genetic variation in the MHC region that increases risk of autoimmune disorders, also confer risk for depression.

Association between genetic variation in human leuko- cyte antigen (HLA) genes and autoimmune diseases is well established. Recent findings indicate that the HLA class III complement component 4 (C4) haplotypes are associated with schizophrenia. The Psychiatric Genomics Consortium

(PGC), which performed the largest GWAS of depression to date, found association in the MHC region. Highly polymorphic alleles and long-range linkage-disequilibrium in the HLA region complicate the interpretation of SNP associations. Methods: We fine-mapped the classical MHC region (chr6:29,640,000–33,120,000), imputing 216 HLA alleles and four C4 haplotypes in a PGC subsample and the UK Biobank (UKB) to investigate the role of these loci in the susceptibility to depression. In the PGC, 15,805 cases, 23,340 controls had genotype-level data available. Cases met a lifetime diagnosis of major depressive disorder, determined by a structured diagnostic interview. In the UKB, 29,344 cases and 63,358 controls were identified from an online mental health questionnaire, based on the Composite International Diagnostic Interview Short Form. The total sample size was 45,149 cases and 86,698 controls.

HLA alleles were imputed using SNP2HLA with the Type 1 Diabetes Genetics Consortium reference panel (n = 5,225). C4 haplotypes were imputed with the HapMap CEU reference panel (n = 110), assayed by the McCarroll Lab to capture structural variation (long and short alleles) and copy number variation in C4A and C4B genes. Imputed SNPs were already available for analysis in both the PGC and UKB.

We tested for association between depression status and imputed MHC variants in each study using additive models and controlled for six principal components. We then performed an inverse-variance weighted meta-analysis across the PGC and UKB samples. Results: No HLA alleles or C4 haplotypes were associated with depression in the PGC, UKB or meta-analysis. The meta-analysis revealed independent signal from one indel in the classical class I region at the level of region-wide significance (rs368739359, p = 1.05e06, OR = 1.03).



22 Abstracts

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Discussion: We investigated whether genetic variation in the MHC region that increases risk for autoimmune diseases, also increases risk for depression. We found no evidence that HLA alleles, which play a major role in the genetic susceptibility to auto-immune disorders, or C4 haplotypes, which are strongly associated with schizophrenia, harbor risk for depression. We found suggestive evidence for association of an indel, rs368739359, which mirrors results from

the full PGC MDD GWAS. Collectively, these results do not support the theory that comorbid depression and autoimmune diseases are driven by shared genetic etiology in the MHC region.


doi: 10.1016/j.euroneuro.2018.08.403

SU40

DNA METHYLATION AND INFLAMMATION MARKER

PROFILES ASSOCIATED WITH A HISTORY OF DEPRES- SION

Bethany Crawford 1 , Zoe Craig 1 , Georgina Mansell 1 , Isobel White 1 , Adam Smith 1 , Steve Spaull 1 , Jennifer Imm

1 , Eilis Hannon 2 , Andrew Wood 1 , Hanieh Yaghootkar 1 , Yingjie Ji 1 , Major Depressive Disorder Working Group 3 , Niamh Mullins 4 , Cathryn Lewis 4 , Jonathan Mill 1 , Therese Murphy 1

1 University of Exeter 2 University of Exeter Medical School 3 Psychiatric Genomics Consortium


Background: Depression is a common and disabling disorder, representing a major social and economic health issue. Moreover, depression is associated with the progression of diseases with an inflammatory etiology including many inflammatory-related disorders. At the molecular level, the mechanisms by which depression might promote the onset of these diseases and associated immune-dysfunction are not well understood. Methods: In this study we assessed genome-wide patterns of DNA methylation in whole blood-derived DNA obtained from individuals with a self-reported history of depression (n = 100) and individuals without a history of depression (n = 100) using the Illumina 450K microarray. Polygenic Risk Scores (PRS) were calculated using the P-values and log odds ratios from the most recent genome-wide association study (GWAS) from the PGC MDD working group (7), without ex- ternal meta-analysis study 23andMe. Finally, known biological markers of inflammation, telomere length (TL) and IL-6, were measured in DNA and serum samples respectively. Results: Our analysis identified 6 significant (Sidak corrected P < 0.05) depression-associated differentially methylated regions (DMRs); the top-ranked DMR was located in exon 1 of the LTB4R2 gene (Sidak corrected P = 1.27 x 10-14). Next, we employed a systems-level approach to identify networks of co-methylated loci associated with a history of depression, in addition to depression PRS, TL and IL-6 levels. Our analysis identified one depression-

associated co-methylation module (P = 0.04). Interestingly, the depression-associated module was highly enriched for pathways related to immune function and was also associated with TL and IL-6 cytokine levels. Discussion: In summary, our genome-wide DNA methylation analysis of individuals with and without a self-reported history of depression identified several candidate DMRs of potential relevance to the pathogenesis of depression and its associated immune-dysfunction phenotype.


doi: 10.1016/j.euroneuro.2018.08.404

SU41

GENETIC INFLUENCES ON SUICIDAL BEHAVIOR IN A

SAMPLE OF CHINESE WOMEN WITH MAJOR DEPRESSIVE

DISORDER

Alexis Edwards 1 , Murray Stein 2 , Anna Docherty 3 , Hilary Coon 3 , Jonathan Flint 4 , Kenneth Kendler 5

1 Virginia Institute for Psychiatric and Behavioral Genetics 2 University of California, San Diego 3 University of Utah School of Medicine 4 University of California Los Angeles 5 Virginia Commonwealth University

Background: Suicidal behavior (SB) is a leading cause of death and a critical public health issue worldwide. SB, including thoughts of death, suicidal ideation, or attempts, is a symptom of depression, and its prevalence among individuals with depression is substantially higher than among the population at large. Previous studies have implicated genetic factors in SB, but most research has been conducted in samples of European descent; the extent to which genetic risk is shared across ancestry is unknown. Further- more, the genetic relationship between depression-related SB and other psychiatric outcomes has not been fully characterized. Methods: We used data from the China, Oxford, and VCU Ex- perimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depressive disorder (MDD). Cases reported on suicidal ideation, plans, and attempts within the context of their worst depressive episode (N = 2591-5802). We conducted within-case genome-wide association studies (GWAS) on these three outcomes, controlling for age and principal components. We then submitted SNP-level results to Func- tional Mapping and Annotation of Genome-Wide Association Studies (FUMA) for gene-based tests and functional characterization of implicated loci. Finally, we examined whether polygenic risk for suicidal behavior, major depression, or risk-taking behavior in European-descent samples was associated with suicidal behaviors in CONVERGE. Results: No individual marker met genome-wide significance across the three GWAS, potentially due to limited statistical power. Aggregate genetic analyses were more fruitful. Two genes met the corrected significance threshold: FBXW8 (suicide plan) and SYK (attempt). Mutations in a mouse homolog of FBXW8 are associated with dendrite pat-



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terning. SYK is a putative modulator of epithelial cell growth that may be inhibited by selective serotonin reuptake inhibitors. Implicated gene sets included drug transmembrane transport, catecholamine metabolic process, odorant binding, CD40 pathway, and other immune-related processes. Polygenic risk score (PRS) analyses were inconsistent across discovery and outcome phenotypes: PRS based on suicide completion, suicide attempt, and risk-taking behavior were suggestively associated with suicidal ideation, plans, or attempts in CONVERGE, but PRS based on major depression showed no associations. Only a small proportion of variance was accounted for by any PRS ( < 1%). Discussion: Previous analyses indicate that the genetic correlation between MDD in CONVERGE and psychiatric disorders in European samples is modest to moderate; trans- ancestry differences may contribute to the current results as well. In addition, heterogeneity across individuals ex- hibiting SB – e.g., those experiencing a depressive episode, post-traumatic stress disorder, high levels of impulsivity, or no discernable psychiatric condition – likely corresponds to underlying genetic heterogeneity. Further research, both within and across ancestry groups, is necessary to clarify the extent to which diverse genetic risk factors contribute to SB liability under different conditions.


doi: 10.1016/j.euroneuro.2018.08.405

SU42

COMMONALITIES AND DIFFERENCES IN THE GENETIC

ARCHITECTURE OF NEUROTICISM AND DEPRESSION

Mark Adams 1 , David Howard 1 , Michelle Luciano 1 , Toni Clarke 1 , Gail Davies 1 , William Hill 1 , Daniel Smith 2 , Ian J. Deary 1 , David Porteous 1 , Andrew McIntosh 1

1 University of Edinburgh


Background: Historically, major depressive disorder had been classified into ‘neurotic’ and ‘endogenous’ forms. ‘Neurotic depression’ was diagnosed in the presence of preexisting emotional instability. ‘Endogenous depression’, in contrast, was characterised by melancholic symptoms, disrupted sleep, impaired appetite, diurnal variation of mood and impaired cognition. We tested for depression subtypes using genome-wide summary statistics of depression and neuroticism to identify shared and unique genetic associations and trait correlates. Methods: We performed a pairwise genome-wide association analysis using summary statistics on depression from

the Psychiatric Genomics Consortium and on neuroticism

from UK Biobank. Pairwise GWAS was conducted to cate- gorize each genomic segment as being associated with depression only, neuroticism only, both traits, or neither trait. We used MAGMA and FUMA to identify genes and GWAS catalogue results that were associated with depression but not with neuroticism. We then used LD Score regression to calculate genetic correlations among depression, neuroticism and other traits. We implemented a Bayesian model

to estimate the joint genetic correlation matrix between all traits and then calculated the partial genetic correlation between depression and each trait after removing the variance shared with neuroticism. Results: Using pairwise GWAS, we identified 9 genomic segments containing loci that influence depression but do not associate with neuroticism. Genes associated with MDD, but not with neuroticism, were associated with glycosylation and coronary heart disease. In contrast, there were 25 genomic segments containing genetic variants that have ap- parently pleiotropic effects on both depression and neuroticism. From the partial genetic correlation analysis, we found that the shared genetic architecture between depression and neuroticism explained most of the genetic correlation that depression has with attention deficit hyperactivity disorder, anorexia, psychological distress, schizophrenia, age of first birth, pubertal growth, and college completion. However, depression—independent of neuroticism—had specific genetic correlations with bipolar disorder, body mass index, chronotype (“morningness”), and triglycerides. Discussion: Our results confirm that the majority of specific genetic variants associated with depression are shared with neuroticism. However, we identified several genetic association signals and correlations that were specific to depression. While these findings do not support all the characteristics that were historically used to distinguish neurotic and endogenous depression, they suggest that there may be subtypes of non-neuroticism-related depression, with specific genetic associations with bipolar disorder, metabolic traits, and sleep patterns.


doi: 10.1016/j.euroneuro.2018.08.406

SU43

EXAMINING THE ROLE OF SEX HORMONES IN POST- NATAL DEPRESSION AND MAJOR DEPRESSIVE DISOR- DER: POLYGENIC RISK SCORES AND HIPPOCAMPAL

NEUROGENESIS

Demelza Smeeth , Timothy Powell, Sandrine Thuret

King’s College London

Background: Genetic variation accounts for up to 54% of postnatal depression (PND) liability and 40% of major depressive disorder (MDD) liability. Alterations to sex hormones have been associated with the pathophysiology of depressive disorders and may partly explain the higher rates of MDD amongst females. However, few studies have considered whether genetic variants associated with sex hormone levels directly increase risk for depressive disorders. This risk may be mediated by alterations in adult hippocampal neurogenesis (HN), a cellular process which has been associated with mood regulation. Here we consider: i. the effects of oestradiol, testosterone and prolactin on human HN, and ii. whether polygenic risk for higher sex hormone levels directly affect risk for MDD or PND. Methods: To better understand how sex hormones affect HN, human female hippocampal progenitor cells (HPCs)



24 Abstracts

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were cultured with biologically relevant concentrations of each hormone. Immunocytochemistry and high-throughput analysis were used to quantify a range of markers of cell fate. To understand how polygenic risk scores (PRS) for sex hormones moderate risk, we used the PRSice software and sex hormone genome-wide summary statistics from the Twins UK cohort (n = 2913). Our target dataset was the Eu- ropean RADIANT cohort consisting of 176 PND, 2772 MDD

and 1588 control subjects. Sex and seven ancestry principal components were included as covariates in all logistic regression analyses. Results: When examining the effect of sex hormones on HPC fate, prolactin increased the proportion of Map2- positive cells (N = 4, F(6,21) = 7.04, p = 0.0003) indicating an increase in neuronal differentiation, but had no effect on HPCs maintained in a proliferative state. Conversely, oestradiol and testosterone had no effect on HPC differentiation, but increased cell number (N = 3, F(6,14) = 3.42, p = 0.027 & F(5,11) = 5.378, p = 0.0096). Only the best-fit PRS for oestradiol levels was associated with a depressive disorder, specifically PND case-control status ( β = -1156.4, SE = 423.7, uncorrected p = 0.006), where genetic risk for lower levels predicted higher risk for PND. Discussion: Here we provide evidence that genetic risk for higher plasma oestradiol may explain a small amount of the variance in risk for PND, potentially lowering risk via its ability to increase HPC number. Furthermore, we provide evidence that prolactin possesses neurogenic properties, but that genetic risk for higher prolactin does not influence risk for depressive disorders. This work suggests that the relationship between sex hormones, HN and depression is complex, and that there may not be a clear-cut pathway for aetiology or risk moderation.


doi: 10.1016/j.euroneuro.2018.08.407

SU44

STRATIFYING MAJOR DEPRESSIVE DISORDER BY POLY- GENIC RISK FOR SCHIZOPHRENIA: DIFFERENCES IN

UNDERLYING NEUROBIOLOGY

Mathew Harris , Xueyi Shen, Simon Cox, Jude Gibson, Mark Adams, Toni Clarke, Ian J. Deary, Stephen Lawrie, Andrew McIntosh, Heather Whalley

University of Edinburgh

Background: Major depressive disorder (MDD) is a heritable, disabling psychiatric disorder, defined by the presence of an arbitrary number of symptoms. Such syndromal defini- tions likely group individuals with diverse aetiologias. MDD

shares symptoms, risk genes and neuroimaging findings with other disorders, such as schizophrenia (SCZ). We hypothesized that differences in neuroimaging measures between MDD cases and controls vary as a function of polygenic risk (PGR) for SCZ, indicating an MDD subtype. Methods: We assessed 7,536 UK Biobank subjects with genetic, clinical and neuroimaging data. Imaging measures included subcortical volumes, measures of white matter

microstructure and locally-derived cortical metrics for a smaller subset (N = 2,966). We used standard linear regression models to examine interactive effects between SCZ- PGR and MDD case/control status on all neuroimaging measures. Results: We observed significant SCZ-PGR by MDD interactions for mean cortical thickness (CT) of rostral anterior cingulate cortex (ACC; β= .191, q = .004) and fractional anisotropy (FA) in parahippocampal cingulum ( β= .141, q = .039). These were driven by positive associations between SCZ-PGR and CT/FA among MDD cases ( β= .098, p = .026; β= .148, p = .001), versus negative/zero associations among controls ( β= –.087, p = .002; β= –.002, p = .854). Maximal case-control differences occurred at lower SCZ- PGR, with convergence at higher SCZ-PGR. Discussion: While we demonstrated significant SCZ-PGR by MDD interactions in rostral ACC and parahippocampal cingulum, these results were driven by greater CT/FA among MDD cases at low SCZ-PGR. Such results could reflect com- pensatory/protective features among these subjects, or impairments in synaptic pruning. Either way, MDD with high SCZ-PGR may represent a neurobiologically distinct form of the disorder.


doi: 10.1016/j.euroneuro.2018.08.408

SU45

IDENTIFICATION OF DISEASE-RELATED SNP IN A MDD

SUSCEPTIBILITY GENE LHPP

Jing Li

Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences

Background: Depression is an affective disorder characterized by a long-lasting depressed mood or marked loss of interest or pleasure. There are ∼350 million patients worldwide. It has high clinical heterogeneity and lack of clear etiology. Genetic susceptibility plays an important role in the pathogenesis of depression. Our earlier genetic research, by low-coverage whole genome sequencing (EXL-WGS) identified one loci rs35936514 located in the intron of LHPP gene. Considering the rs35936514 may represent a genetic signal of causal SNPs, we resequenced the coding region of LHPP gene to find potential mutations. Methods: We resequenced the LHPP gene of 474 depression patients and 640 health controls. Each of the seven exons of LHPP gene was amplified by Polymerase chain reaction (PCR) and examined by Sanger sequencing. Results: Totally 21 SNPs was identified in our sequencing data. A missense mutation c.A281G is statistically significant after correction (R = 5.6572, corrected p = 0.0428, OR = 1.6142, 95%CI = 1.0157-2.5654). Discussion: LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase), a highly conserved phosphatase in evolution, exists in the form of homologous dimer and catalyzes pyrophosphoric acid hydrolysis with the help of magnesium ions. The missense mutation p. Glu94Arg was



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located within a highly conserved motif that belongs to HAD

like supefamily. The original Glutamate is replaced by arginine. Glutamate is changed into arginine by a missense mutation. Since glutamate is an acidic amino acid and arginine is a basic amino acid. Their characters vary widely. We start thinking whether this replacement affect the LHPP enzyme activity. According to the reports, LHPP has three main activities, including the hydrolysis of O-P bonds in PPI, the hydrolysis of N-P bonds in phosphorylated histidine, and the hydrolysis of N-P bonds in phosphorylated lysine. Based that, we will verify whether this misplaced mutation affect these activities of LHPP in the subsequent experiments. On the other hand, we will continue to test some other samples to verify the missense mutation in case of error judgment for small sample size.


doi: 10.1016/j.euroneuro.2018.08.409

SU46

USING MENDELIAN RANDOMIZATION TO TEST CAUSAL

BIDIRECTIONAL INFLUENCES BETWEEN PHYSICAL

ACTIVITY AND DEPRESSION

Karmel Choi 1 , Chia-Yen Chen 1 , Murray Stein 2 , Yann Klimentidis 3 , Meg Wang 4 , PGC MDD Working Group 5 , Karestan Koenen 4 , Jordan Smoller 6

1 Massachusetts General Hospital 2 University of California, San Diego 3 University of Arizona 4 Harvard T.H. Chan School of Public Health

5 PGC

6 Massachusetts General Hospital, Harvard Medical School

Background: Burgeoning evidence from randomized controlled trials and prospective cohort studies suggests that physical activity has protective effects on depression, point- ing to a potential modifiable target for prevention and treatment. However, it remains unclear whether this inverse association is due to the protective effect of physical activity on depression, and/or depression’s negative impact on physical activity. Here, we used bidirectional two-sample Mendelian randomization (MR) that leverages the random

assortment of genetic variants (i.e., SNPs) at birth to establish instruments free of usual sources of environmental or genetic confounding, to test causal influences between physical activity and depression. Methods: For genetic instruments, we selected independent top SNPs associated with depression and two physical activity phenotypes—self-reported and objective accelerometer-based—from the largest available, non- overlapping genome-wide association results. We used two sets of genetic instruments: (1) only SNPs previously reported as genome-wide significant (GWS; p < 5x10-8), and (2) top SNPs meeting a more relaxed threshold (p < 1x10-7). For each direction of influence, we combined SNP-exposure and SNP-outcome effects using an inverse variance weighted (IVW) approach, with other standard MR methods such as

weighted median, MR Egger, and MR-PRESSO as sensitivity analyses. Results: We found evidence for protective influences of accelerometer-based activity on depression (IVW odds ratio (OR) = 0.74 for MDD per 1 SD unit increase in average acceleration, 95% confidence interval (CI) = 0.59-0.92, p = .006) when using SNPs meeting the relaxed threshold (i.e., 10 versus only 2 GWS SNPs, which provided insuffi- cient data for follow-up analyses). In the other direction, we found no evidence for negative influences of depression on accelerometer-based activity (IVW b = 0.04 change in average acceleration per positive depression status, 95% CI = - 0.43-0.51, p = .87). Furthermore, we did not see evidence for causal influences between self-reported activity and depression, in either direction and regardless of SNP set. Discussion: We apply MR for the first time to examine causal influences between physical activity and depression. Inter- estingly, we discover that SNPs associated with objectively measured—but not self-reported—physical activity tend to show opposite effects on depression. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being more representative of actual movement. Our findings validate physical activity as a causal protective factor for depression and point to the importance of objective measurements of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the notion that enhancing physical activity is an effective prevention strategy for depression.


doi: 10.1016/j.euroneuro.2018.08.410

SU47

RISK FOR SCHIZOPHRENIA IN INDIVIDUALS WITH

EATING DISORDERS AND THEIR RELATIVES

Ruyue Zhang 1 , Ralf Kuja-Halkola 1 , Cynthia Bulik 2 , Sarah Bergen 1

1 Karolinska Institutet 2 University of North Carolina at Chapel Hill

Background: Eating disorders and schizophrenia are highly heritable psychiatric disorders with profound morbidity and elevated mortality risks. Although they have few symptoms in common, they have substantial shared genetic risk. How- ever, almost no research has been conducted into the co- aggregation of these disorders in individuals and families. Methods: To address this, we used the Swedish National Registers to identify people diagnosed with anorexia nervosa (AN) or other eating disorders (OED; bulimia nervosa, binge eating disorder and eating disorders not otherwise specified) who were born between 1977 and 2003. We then used Cox regression to calculate the risk for schizophrenia in these individuals and their family members compared to individuals without eating disorders and their relatives. Sex and birth year were included as covariates. Results: Individuals with AN or OED were more likely to also have schizophrenia than people without these diagnoses



26 Abstracts

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(OR = 6), and risk differed by sex with women being about twice as likely as men to receive an additional diagnosis of schizophrenia. Both fathers and mothers of children with OED had increased rates of schizophrenia, but no elevated risk was shown for parents of children with AN. Discussion: These results suggest that individuals with all types of eating disorders have increased risks for schizophrenia. Schizophrenia rates were also elevated for the parents of people with OED but not AN. Whether siblings, grandparents, aunts, uncles and cousins exhibit increased risk for schizophrenia will also be calculated and offer additional insights into the relationships between these disorders. Deeper analyses will explore whether family history and/or high genetic risk for schizophrenia influences eating disorder course, severity, and outcome.


doi: 10.1016/j.euroneuro.2018.08.411

SU48

MIRNA PROFILING IN A MOUSE MODEL OF EATING

ADDICTION

Judit Cabana-Domínguez 1 , Laura Domingo 2 , Laura Pineda-Cirera 3 , Aurelijus Burokas 2 , Rafael Maldonado 2 , Bru Cormand 1 , Elena Martín-García 2 , Noèlia Fernàndez-Castillo 1

1 University of Barcelona, Centro Nacional de Investigación

Biomédica en Red de Enfermedades Raras (CIBERER), Insti- tuto de Salud Carlos III, Institut de Biomedicina de la Uni- versitat de Barcelona (IBUB), Institut de Recerca Sant Joan

de Déu (IR-SJD), Esplugues de Llobregat, Catalonia 2 Universitat Pompeu Fabra 3 University of Barcelona, Institut de Biomedicina de la Uni- versitat de Barcelona (IBUB), Institut de Recerca Sant Joan

de Déu (IR-SJD), Esplugues de Llobregat

Background: Increasing evidence supports the idea that energy-dense food (high in refined sugars and fats) is addictive and leads to some forms of obesity. Addiction is a chronically relapsing disorder characterized by compulsiv- ity in the face of adverse consequences, persistence to seek the reward and high motivation to overconsume which is observed in only a subpopulation of individuals. MicroRNAs are very abundant in the central nervous system and play an important role in neuronal plasticity, memory and learning that underlie addiction. Here, we aimed to investigate changes in microRNA profiling in a mouse model of eating addiction. Methods: Genetically identical inbred mice were exposed to a recently validated animal model of eating addiction, and two extreme subpopulations related to the phenotypes of vulnerability and resilience to addiction were considered. Using smallRNA sequencing, we compared microRNA expression levels of addicted and resilient animals in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two key areas of the brain’s reward circuitry. Results: We identified six miRNA genes that are differentially expressed in mPFC (FDR 10%), two of them upregu-

lated and four downregulated in the addicted mice group compared to the resilient one. Gene network analysis revealed that these microRNAs may regulate multiple genes that are important for brain functions. For example: PTEN, involved in synaptic plasticity and long-term potentiation or FOXP1, which has a role in neuronal development, autism

and intellectual disability. Discussion: We highlighted novel miRNAs that might have an important role in the susceptibility to eating addiction. Fur- ther studies are required to understand their contribution to the disorder.


doi: 10.1016/j.euroneuro.2018.08.412

SU49

GENOME-WIDE ASSOCIATION META-ANALYSIS OF CO- CAINE DEPENDENCE IN SAMPLES WITH EUROPEAN

ANCESTRY

Judit Cabana-Domínguez, Anu Shivalikanjli, Noèlia Fernàndez-Castillo, Bru Cormand

University of Barcelona, Centro Nacional de Investigación

Biomédica en Red de Enfermedades Raras (CIBERER), Insti- tuto de Salud Carlos III, Institut de Biomedicina de la Uni- versitat de Barcelona (IBUB), Institut de Recerca Sant Joan

de Déu (IR-SJD), Esplugues de Llobregat

Background: Cocaine dependence is a complex neuropsychiatric disorder that is highly comorbid with other psychiatric traits. Association studies suggest that common genetic variants contribute substantially to cocaine dependence susceptibility. In the present work we performed a genome-wide association (GWAS) meta-analysis of cocaine dependence. Methods: Four cocaine dependence GWAS datasets were obtained from the dbGaP repository. For each dataset, quality control and imputation were performed using the ‘Ricopili’ PGC GWAS pipeline. Association analysis was run under the additive logistic regression model with PLINK v1.9 and the first 10 principal components were included as covariates. A total of 2,085 cases and 4,293 controls, all of them with European ancestry, were meta-analyzed using an inverse- weighted fixed effects model implemented in the software METAL. LD Score regression (LDSC) and polygenic risk score (PRS) analyses were used to identify shared genetic risk factors between cocaine dependence and comorbid conditions. Results: Although no genome-wide significant findings were found in the SNP-based analysis, the gene-based analysis identified HIST1H2BD as significantly associated with cocaine-dependence (10% FDR). This gene is located in a region of chromosome 6 that is enriched in histone- related genes, previously associated with schizophrenia (SCZ). The top associated SNPs of this region, rs806973 and rs56401801 (P = 3.14e-06 and 3.44e-06, respectively), are eQTLs for different genes in multiple brain areas. Further- more, we performed LDSC analysis with comorbid conditions and found significant genetic correlations between cocaine dependence and SCZ, attention deficit/hyperactivity



Abstracts 27

ARTICLE IN PRESS


disorder (ADHD), major depressive disorder (MDD) and risk- taking behavior. We also found that all tested phenotypes can significantly predict cocaine dependence status by performing a PRS analysis: SCZ (R2 = 2.28%; P = 1.21e-26), ADHD

(R2 = 1.39%; P = 4.5e-17), risk-taking behavior (R2 = 0.60%; P = 2.7e-08), MDD (R2 = 1.21%; P = 4.35e-15), children’s aggressive behavior (R2 = 0.3%; P = 8.8e-05) and antisocial behavior (R2 = 1.33%; P = 2.2e-16). Discussion: To our knowledge, this is the largest reported cocaine dependence GWAS meta-analysis in European- ancestry individuals. Despite the small sample size, we identified suggestive associations in regions that may be related to cocaine dependence. Furthermore, we found evidence for shared genetic risk factors between cocaine dependence and several comorbid psychiatric traits.


doi: 10.1016/j.euroneuro.2018.08.413

SU50

THE GENETICS OF COGNITIVE BIASES IN THE DE- VELOPMENT OF PSYCHIATRIC DISORDERS

John Vincent 1 , Charlotte Booth 2 , Annabel Songco 2 , Sam Parson 2 , Anne-Wil Kruijt 3 , Maud Grol 2 , Desiree Spronk 2 , Robert Keers 1 , Elaine Fox 2

1 Queen Mary University of London

2 University of Oxford

3 Stockholm University

Background: Cognitive biases in attention, memory and interpretation have been associated with several psychopathologies including anxiety and major depressive disorder (MDD). Twin studies have shown that the same genes that explain variation in cognitive biases also increase the risk of depression and anxiety in children.

Cognitive biases may therefore represent an important intermediate phenotype that explains how genetic risk in childhood develops into psychopathology in adolescence and could therefore be a potential target for the prevention of these disorders. Nevertheless, this hypothesis is yet to be tested using a genome-wide approach in a longitudinal design.

The current study aims to assess the genetic overlap between psychopathologies and cognitive biases and examine whether, and to what extent these cognitive biases mediate the relationship between genetic risk for, and an outcome of psychopathology using a longitudinal study design. Methods: We obtained whole genome data from 959 individuals tested at age 12 and 14 for a range of attention, memory and interpretation biases, as well as externalizing and internalizing disorders as part of the CogBIAS Longitudi- nal Study at The University of Oxford.

A genome-wide association study (GWAS) was conducted to identify genes associated with cognitive biases. We then tested whether polygenic scores of adult psychopathologies were associated with cognitive biases. Finally, using a phenome-wide approach to inform analysis, we exam-

ined how cognitive biases might mediate the association between genes and psychopathology. Results: The GWAS revealed no genome-wide significant hits which was expected due to low power resulting from a small sample size. However, polygenic scores, including those for MDD, significantly predicted cognitive biases, and depression and anxiety explaining up to 4% of the variance. Fur- thermore, significant evidence for mediation was found suggesting that cognitive biases may lie on a causal pathway from genes to psychopathology. Cross-lag mediation analysis further confirmed this for cognitive biases in interpretation and memory. Discussion: The lack of any significant hits from the genome-wide analysis is likely the result of inadequate power due to small sample size. However, findings regarding the polygenic scores suggest that genetic risk for MDD

explains individual differences in interpretation and memory bias in children. Furthermore, these biases appear to lie on a causal pathway between MDD risk and depression and anxiety symptoms in adolescence.

Replication of these effects in further longitudinal studies is required. Nevertheless, these findings highlight cognitive biases as important targets for treatments and interventions for children at a high genetic risk of psychopathology.


doi: 10.1016/j.euroneuro.2018.08.414

SU51

INTERACTIONS BETWEEN OBSTETRIC COMPLICATIONS AND GENETIC LOAD FOR PSYCHIATRIC DISORDERS IMPACT PSYCHOPATHOLOGY IN ADULTHOOD

Viktoria-Eleni Gountouna , Joeri Meijsen, Jonathan Hafferty, Archie Campbell, Caroline Hayward, David Porteous, Andrew McIntosh, Kristin Nicodemus


Background: Both genetic and environmental influences contribute to psychopathology, not always independently. We investigated the interaction between increased genetic liability for psychiatric disorders or related traits and obstetric complications (OCs), an early environmental factor known to influence later mental health, in the Generation Scotland cohort. Methods: OCs were obtained using medical record linkage and polygenic risk scores (PRS) were created using publicly available data (N = 2697). We used general linear models to test for interactions between OCs (birthweight, labor in- duction, Caesarean section, use of forceps, gestational age and neonatal care admission) and PRS for loneliness, extraversion, neuroticism, anxiety, major depression, bipolar and autistic spectrum disorders (ASD), schizophrenia and psychiatric cross-disorder. Outcomes were measures of psychopathology: General Health Questionnaire (GHQ), Schizo- typal Personality Questionnaire (SPQ), Mood Disorder Ques- tionnaire (MDQ) and personality (Eysenck Extraversion and Neuroticism).



28 Abstracts

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Results: Significant interactions for the GHQ were observed between PRS for anxiety and birthweight (p = 0.004) and ASD

and use of forceps (p = 0.002). In addition, we found significant interactions for the MDQ between PRS for bipolar disorder and gestational age (p = 0.001), for neuroticism between PRS for bipolar disorder and use of forceps (p = 0.003) and for extraversion between PRS for anxiety and gestational age (p = 0.003). All p-values reported are after Bonferroni correction. Discussion: This is to our knowledge the first study to show that interactions between OCs and increased genetic load for psychiatric disorders influence measures of psychopathology and related psychological traits in adulthood. These findings add to our understanding of the complex relationship between genetics and environment and highlight the potential impact of the early environment on personality and psychopathology in later life.


doi: 10.1016/j.euroneuro.2018.08.415

SU52

GENOME-WIDE ASSOCIATION STUDY OF RUMINA- TIVE RESPONSE STYLE HIGHLIGHTS GENES PREVIOUSLY

ASSOCIATED WITH INTELLECTUAL DISABILITY OR

RUMINATION-RELATED MENTAL DISORDERS

Nora Eszlari 1 , Andras Millinghoffer 2 , Peter Petschner 3 , Xenia Gonda 4 , Daniel Baksa 1 , John Francis William Deakin 5 , Peter Antal 2 , Gyorgy Bagdy 3 , Gabriella Juhasz 1

1 Semmelweis University 2 Budapest University of Technology and Economics 3 Hungarian Academy of Sciences, Semmelweis University 4 Kutvolgyi Clinical Centre, Semmelweis University 5 University of Manchester, Manchester Academic Health

Sciences Centre

Background: Rumination, or in other words, ruminative response style, means a perseverative and passive mode of thinking about the person’s own depressed mood, and about its possible causes and consequences. It is not only a significant risk factor for major depression, but, since it has a 21- 40% heritability, it is worth investigation by candidate gene studies as an endophenotype, with the future aim of target- ing molecular underpinnings of depression with preventive purposes. Methods: In the present genome-wide association study (GWAS), we aimed to reveal candidate common genetic variants in the background of rumination, measured by the 10-item Ruminative Responses Scale, among 1825 Eu- ropean white adults recruited in Manchester, United King- dom and Budapest, Hungary. Linear regression models were run on rumination score in Plink v1.9 ( https://www. cog-genomics.org/plink2 ), with each single nucleotide polymorphism (SNP) as predictor, controlling for gender, age and population structure. FUMA v1.3.1 ( http://fuma.ctglab.nl/ ) was used to define genomic risk loci by SNPs with a suggestive significance level ( ≤1x10-5), and to map protein-coding genes to SNPs of these loci, based on position, expression

quantitative trait loci (eQTL) databases, or chromatin interaction databases. Results: Our analyses revealed six genomic risk loci for rumination, on chromosomes 2, 3, 5, and 13. SNPs on chromosome 3 was found to regulate brain expression of SR- GAP3 and SETD5, genes important in intellectual disability. Moreover, this genomic risk locus has shown chromatin interaction with promoter region of the oxytocin receptor gene OXTR, which has been associated with many psychiatric phenotypes, such as autism, empathy, panic disorder, and, most importantly, major depression, alcohol abuse and eating disorder symptoms, for which rumination denotes a risk. Our genomic risk locus on chromosome 13 comprises SNPs regulating brain expression of KCTD12, which gene has been related to bipolar depression and intrinsic excitability of hippocampal pyramidal neurons. This chromosome 13 risk locus also has shown chromatin interaction with promoter region of C13orf45 (LMO7DN) in hippocampus, dorsolateral prefrontal cortex, and neural progenitor cells. Discussion: To conclude, our GWAS results on the endophenotype of rumination can open new perspectives in revealing the common molecular underpinnings of several different mental disorders, hence they can fruitfully fuel drug target research and / or screening and disease prevention by biomarkers.

(The study was supported by: KTIA_NAP_13-1-2013-0001, KTIA_13_NAP-A-II/14, KTIA_NAP_13-2-2015-0001, 2017- 1.2.1-NKP-2017-00002 (Hungarian Brain Research Program); MTA-SE Neuropsychopharmacology and Neurochemistry Research Group; Manchester Academic Health Sciences Centre, OTKA 119866; ÚNKP-16-3, ÚNKP-17-3-III-SE-2, ÚNKP-17-4-I-SE-8 (New National Excellence Program of The Ministry of Human Capacities); Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences.)


doi: 10.1016/j.euroneuro.2018.08.416

SU53

A CROSS-DIAGNOSTIC GWAS OF LONGITUDINAL EX- ECUTIVE FUNCTION PROFILE SCORES

Urs Heilbronner 1 , Bernadette Wendel 2 , Monika Budde 3 , Katrin Gade 4 , Kristina Adorjan 4 , Janos Kalman 4 , Fanny Senner 4 , Till Andlauer 4 , Ashley Comes 4 , Eva Schulte 4 , Sergi Papiol 4 , Heike Bickeböller 2 , Thomas Schulze 4

1 Institute of Psychiatric Phenomics and Genomics, Medical Center of the University of Munich

2 University Medical Center, Georg-August-University 3 Institute of Psychiatric Phenomics and Genomics, Univer- sity Hospital, LMU Munich

4 Planck Institute of Psychiatry Munich

Background: Executive functions, i.e. cognition involving control and coordination of mental processes, are impaired in severe mental disorders such as bipolar disorder and schizophrenia. It has also been reported that psychiatric patients suffering from these disorders differ from healthy


https://www.cog-genomics.org/plink2

http://fuma.ctglab.nl/


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ARTICLE IN PRESS


controls in their ability to profit from practice incurred by repeated test administration.

Here, we use data of the longitudinal PsyCourse study, a study of patients from the affective-to-psychotic continuum

(n = 1047) and healthy controls (n = 288), to research genetic underpinnings of patient individual differences in two core aspects of executive functions: set-shifting and updating. Methods: Data were collected at four measurement points across a period of 1.5 years. Healthy controls were collected to identify and correct for important phenotype variability and change over time.

Patients were genotyped with the Illumina PsychArray. We imputed common variants (MAF ≥0.01) using the 1000 Genomes Phase 3 reference panel.

The Trail-Making-Test and the Verbal Digit Span Back- wards, a subtest from the Wechsler Intelligence Test for Adults, are used as phenotypes of set-shifting and updating capabilities, respectively. Both executive domains are investigated using cognitive profile scores derived from data collected over the course of the study. These scores provide a combined measure of both individual longitudinal change and performance level.

We will perform a longitudinal genome-wide association analysis, using both summary statistics addressing the profiles as well as longitudinal modelling via general linear mixed models. This should enable us to gain further insights in profile shapes and their dependence on specific disease and genetic factors. Results: We will present results of this research at the meeting. Discussion: We will present the discussion of our findings at the meeting.


doi: 10.1016/j.euroneuro.2018.08.417

SU54

DEEP PHENOTYPING GENOME-WIDE ASSOCIATION

STUDY IDENTIFIES GENETIC MARKERS ASSOCIATED

WITH BRAIN VENTRICULAR ENLARGEMENT AS NEU- RODEVELOPMENTAL BIOMARKERS OF PSYCHOSIS

Ney Alliey 1 , Rebecca Shafee 2 , Jaya Padmanabhan 2 , Neeraj Tandon 2 , Tamar A Grey 3 , Danielle Rubin 1 , Brett A. Clementz 4 , J Sweeney 5 , Godfrey D. Pearlson 6 , Matcheri S. Keshavan 2 , C Tamminga 5 , Sarah Keedy 1 , Elliot Gershon 1

1 University of Chicago 2 Harvard Medical School 3 Massachusetts Institute of Technology 4 University of Georgia 5 UT Southwestern

6 Yale School of Medicine, Olin Research Center

Background: In order to explore the genetic components of major psychoses, the Bipolar and Schizophrenia Network for Intermediate Phenotypes (B-SNIP) collected a sample of individuals with psychotic disorders and healthy controls,

where a large number of phenotypes (deep phenotyping) were studied in each subject. Methods: Genome-Wide Association on 463 phenotypes from clinical and behavioral interview data, brain imaging structural MRI and DTI was performed on 754 Schizophrenia, Bipolar, or Schizoaffective disorder cases, and 361 healthy controls. Genotypes were assessed using the Illumina Psy- chChip microarray, followed by imputation for a total of 4.3 million common SNPs. Results: After Bonferroni correction, the volume of the Temporal Horn of Left Lateral Ventricle (THLLV) was associated with SNPs of gene NRXN1 (P = 1.156E-11), and the Cavum Septum Pellucidum (CSP) was associated with SNPs of gene LRP1B (P = 1.661E-11). Enlarged CSP is present in an important proportion of cases (26.29%, O.R. = 2.01). In- creased volume of the temporal horn was observed in 6% of patients (O.R. = 3.49), and its presence combined with the NRXN1 risk allele gives a disease odds ratio of OR = 7.41, with an attributable fraction in exposed of 86.4%. This feature is also associated with enlargement of other parts of the ventricular system and reduction of some adjacent brain structures. Discussion: Enlarged CSP and THLLV are two biomarkers associated with psychosis and with common SNPs. These results lend molecular support to the neurodevelopmental hypothesis of Schizophrenia and related disorders and may constitute risk factors for psychosis.


doi: 10.1016/j.euroneuro.2018.08.418

SU55

BALANCE AND GAIT ANALYSIS USING MICROSOFT

KINECT IDENTIFIES GENES IMPACTING LOCOMOTION

AND AUTISM LIABILITY

Kevin Vervier, Leo Brueggeman, Jacob Michaelson

University of Iowa

Background: While the core clinical phenotype of autism

always involves deficits in social communication and restricted and repetitive behaviors, there are also a wide variety of comorbidities that contribute to its immensely heterogeneous presentation. One of these domains of comorbidity is in disorders of movement and gross motor coordination. Despite this known relationship, little is understood about the genetic overlap in susceptibility to movement disorders and autism. A better understanding of this relationship will contribute to a more refined parsing of patient subgroups, which in turn will lead to more effective clinical trials. Methods: Here, we propose an affordable digital phenotyping solution, consisting of a single Microsoft Kinect camera to record gait in two balance activities: standard walk and heel-toe balancing while walking exercise. Among the outputs of the Kinect camera is a 25-point skeleton of the research participant tracked at 30 frames per second in 3-dimensional space. Our study of neurodevelopmental conditions, devGenes, includes nearly 600 gait profiles



30 Abstracts

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for ASD-affected and unaffected individuals. We converted these movement profiles into the frequency-domain using a Fourier transform. Random forests were then used to classify walking profiles as affected or unaffected. This machine learning approach allowed us to assign semi-quantitative scores to devGenes participants that described the extent to which their gait resembled affected individuals. Perfor- mance of the classifier was good, with an area under ROC

curve of 0.744 and an out-of-sample accuracy of 66%. Using these scores as a quantitative trait, we mapped the genetic determinants of ASD-related gait abnormalities via genotyping with the PsychArray. Results: Through this analysis, we were able to prioritize genes harboring genetic burden related to locomotion. A follow-up analysis revealed that these candidate genes were enriched for known autism genes, and specifically for synaptic pathways. Of particular interest was an association with the gene DMD (the causal factor of Duchenne Muscular Dys- trophy), potentially broadening the role of this gene to a subclinical locomotion phenotype in the context of autism. Discussion: This work illustrates the promise of using objective, semi-quantitative measures as a trait to facilitate mapping of genetic risk factors that ultimately lead to a better understanding of comorbidities in autism, such as motor coordination deficits.


doi: 10.1016/j.euroneuro.2018.08.419

SU56

EPIGENETIC REGULATION OF THE NOVEL EARLY

LIFE ADVERSITY RESPONSIVE GENE MORC1 IN MAJOR

DEPRESSIVE DISORDER

Mara Thomas 1 , Vanessa Nieratschker 2 , Nadine Provençal 3 , Andressa Coope dos Santos Botezelli 3

1 IMPRS for Cognitive and Systems Neuroscience 2 University Hospital of Tuebingen

3 Simon Fraser University Burnaby

Background: Early life adversity (ELA) is a risk factor for the development of psychiatric disorders later in life, among them major depressive disorder (MDD). It is believed that the increased susceptibility to MDD is caused by maladap- tation to the early stressful environment, potentially leading to a disturbed stress response. It has been proposed that DNA methylation, an epigenetic modification that influences gene expression, may be one mechanism by which early experiences are translated into permanent changes in cellular function. A recent genome-wide methylation analysis identified MORC1 to be differentially methylated in response to exposure to different early life stressors in three different species (human, rhesus monkey, rat), at different ages (birth, childhood, adulthood) and in different tissues (blood, brain). MORC1 is an epigenetic regulator protein that has in the meanwhile been implicated with the development of MDD via genetic association studies as well as genetic animal models of psychiatric disease.

Methods: We analyzed DNA methylation in the promoter region of MORC1 in a cohort of Caucasian adults with (n = 76) and without (n = 76) experience of early life adversity as assessed by the Childhood Trauma Questionnaire. 50% of the participants in each group had a current or lifetime diagnosis of moderate to severe major depressive disorder, whereas the other 50% had never experienced any psychiatric disorder. High accuracy methylation measurements via targeted bisulfite sequencing (HAM-TBS) were used to assess a region spanning 57 CpG sites in the MORC1 promoter. Influ- ence of methylation quantitative trait loci (mQTLs) was assessed via genotyping of relevant single nucleotide polymorphisms. Further, we will study interacting effects of early life stress, DNA methylation and major depressive disorder on self-reported stress reactivity as assessed by the stress reactivity scale (SRS). Results: Results will be presented at the congress. We hypothesize that MORC1 serves as a biomarker of early life adversity in adults and that this effect may be specifically linking ELA and depression later in life. Further, we hypothesize that there is an interacting gene-ELA effect on MORC1 promoter methylation and vulnerability to depression. Discussion: Our results will provide valuable information about the validity of MORC1 methylation as blood-based marker of early life stress in adults and its potential role in the development of major depressive disorder.


doi: 10.1016/j.euroneuro.2018.08.420

SU57

INCREASED BDNF METHYLATION IN SALIVA, BUT NOT

BLOOD, OF PATIENTS WITH BORDERLINE PERSONALITY

DISORDER

Vanessa Nieratschker 1 , Mara Thomas 2 , Nora Knoblich 1 , Annalena Wallisch 1 , Katarzyna Glowacz 1 , Friederike Gundel 1 , Julia Becker-Sadzio 1 , Christof Brueckmann 1

1 University of Tuebingen

2 IMPRS for Cognitive and Systems Neuroscience

Background: The importance of epigenetic alterations in psychiatric disorders is increasingly acknowledged and the use of DNA methylation patterns as markers of disease and therapy response is a topic of ongoing investigation. Re- cent studies suggest that patients suffering from Border- line Personality Disorder (BPD), display differential DNA methylation of various genes relevant for neuropsychiatric conditions. Among those is the gene encoding the brain- derived neurotrophic factor (BDNF). Studies report differential BDNF methylation in blood, but only little is known about BDNF methylation levels in tissues other than that. However, recent evidence indicates that saliva might be a better suited surrogate measure than blood for the study of DNA methylation in psychiatric disorders. Methods: 41 BPD patients and 41 healthy controls were included in the study. BPD patients were diagnosed according to the IPDE and met at least five diagnostic criteria of



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BPD. 26 BPD patients completed a 12-week program of Di- alectical Behaviour Therapy (DBT). DNA methylation status of the BDNF IV promoter in whole blood and saliva samples was analyzed by pyrosequencing. The pyrosequencing assay contained six CpG sites, but only four sites passed pyrosequencing quality control and were used for further analysis. Statistical analysis was performed with SPSS (IBM, Version 26). Group mean comparisons were performed using two-sided student’s t-test. Cohen’s effect size d was calculated from the z-score. Differences in percentages between groups were assessed with the Chi-Square-Test. Bivariate correlation analysis was performed using Pearson’s correlation coefficient and 95% percentile bootstrapping was performed. Results: In saliva samples, DNA methylation was significantly higher in BPD patients than in healthy controls at all four analyzed CpG sites within the BDNF promoter (p < 0.001 for all sites). Further, the average methylation level calculated from all analyzed sites was higher in BPD

patients than in healthy controls (M = 6.9 %, SE = 0.19 vs. M = 4.3 %, SE = 0.20, M = Mean, SE = Standard Error). This difference, −2.6 %, 95% CI [ −3.163, −2.061] was significant (t(80) = −9.431, p-value = 1.26 x 10–14) and represented a large effect (Cohen s d = 2.1). In DNA isolated from whole blood, BDNF methylation levels did not differ significantly between BPD patients and healthy controls neither for single CpG sites, nor for the average calculated from all sites (patient average 9.0 % vs- healthy controls average 8.9 %). We further compared BDNF IV promoter methylation of single CpG sites and the average calculated from all sites in saliva and blood samples of individual patients and controls and did not find any significant correlation.

Following psychotherapeutic intervention (N = 26 patients), salivary DNA methylation at the BDNF IV promoter decreased at all analyzed CpG sites, though the effect was significant only for CpG 1, CpG 3 and the average calculated from all sites, where BDNF methylation decreased from 7.2 % to 6.5 % (mean difference = -0.7 %, SE = 0.33, 95% CI [-1.370,-0.019], t(25) = -2.118), p-value = 0.044, Co- hen’s d = 0.4). Discussion: Our results speak in favor of the recently postulated hypothesis that saliva is a better surrogate tissue for the use in psychiatric studies than blood is. Particularly interesting is our finding of significantly decreasing BDNF IV methylation levels following DBT, since this points towards the usability of saliva BDNF methylation as a marker for therapy response.


doi: 10.1016/j.euroneuro.2018.08.421

SU58

STRESS VARIABLES AND METHYLATION OF THE DDR1

GENE IN EARLY INTERVENTION PSYCHOTIC PATIENTS

Elisabet Vilella , Lorena Moreno, Ángel Cabezas, Vanessa Sánchez-Gistau, Alfonso Gutierrez-Zotes, Gerard Muntané, Lourdes Martorell, Elisabet Vilella

Hospital Universitari Institut Pere Mata

Background: We previously observed an association between DDR1 genetic variants and schizophrenia [1]. Also we have reported that DDR1 is a myelin protein [2] and an increased expression of DDR1 isoform c in postmortem brains from schizophrenic patients [3]. DNA methylation at specific CpG sites is an important regulator of myelin genes [4]. Compelling evidence shows that life event stressing factors are able to modify gene methylation patterns [5].

Here we aimed to show that life event stressing factors modify the pattern of DDR1 methylation in early intervention psychotic patients (PP). Methods: We selected 60 patients attended at the Early intervention Program with a schizophrenia spectrum disorder diagnostic according to DSMV criteria, and 40 controls matched by sex and age.

Stress variables were measured using Childhood Trauma Questionnaire (CTQ), Holmes–Rahe Stress Scale (HRSS) In- ventory and Perceived Stress Scale (PSS). Neutrophil to lym- phocyte rate (NLR) and C reactive protein (CRP) were used as inflammatory markers. Severity of depressive and psychotic symptoms were measured by Hamilton Depression rating scale and PANSS respectively. Each dose of antipsychotic was transformed into chlorpromazine and diazepam

equivalent. Levels of methylation at 5 regions (45 CpG islands) were measured in peripheral blood DNA using Massar- ray EpiTYPER technologyR (Agena Biosciences).

After a bivariate analysis between dependent (methylation) and independent variables (all the rest) was conducted to explore associations between variables we carried out a linear regression analysis using CpG island as dependent variable and participant group (patient or control), CTQ dimensions, HR, PSS, NLR, PCR and benzodiazepine equivalents as independent variables. Results: PPs (sex ratio 1:1) had a mean age of 24.7 ±5.4 years and controls (sex ratio 1:1) 24.6 ±5.4 years. Sex, age, psychotic symptoms (PANSS), depression and chlorpromazine equivalents associations with methylation did not pass the significance filter for multiple correlations. The linear regression analysis carried out to measure which variables associate with the methylation level at each CpG DDR1 island studied showed that: 1/ Methylation at CpG AS5_16 inside the DDR1-AS1 gene which is located upstream the promoter region of DDR1, associates with benzodiazepine equivalent dose and physical neglect, but is not different between patients and controls; 2/ Methylation at CpGs 1_3, 1_5, 1_7, is statistically different between patients and controls and highly associated to NLR; 3/ Methylation at CpG

2_2 and 2_5 was different between patients and controls but not associated to NLR. Stress variables (CTQ, HRSS and PSS) show an indirect association (negative B and β values) with methylation levels. That is, the higher the score in the stress item the lower the methylation level. Conversely, the inflammation NLR parameter showed a direct relationship with CpG methylation levels. Discussion: We show for the first time that DDR1 CpG

methylation levels are increased in PPs compared to controls. In some regions the methylation levels are in part explained by stress and inflammation biomarkers but in opposite directions. Region 1 has a high association with inflammation, but region 2, which is also different between patients and controls is not associated with inflammatory markers. Our results suggest that DDR1 methylation levels


32 Abstracts

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could be used as a PPs biomarker, but further studies are needed to confirm the present results.


doi: 10.1016/j.euroneuro.2018.08.422

SU59

DNA METHYLATION ASSOCIATED TO PSYCHOPATHOL- OGY IN CHILDREN AND ADOLESCENTS: DETECTING

DIFFERENTIALLY METHYLATED REGIONS

Leticia Spindola 1 , Marcos Santoro 1 , Pedro Pan 1 , Fernanda Talarico 1 , Carolina Muniz Carvalho 1 , Giovanni Salum Junior 2 , Luis Augusto Rohde 2 , Euripedes Constantino Miguel 3 , Michael March 4 , Patrick Sleiman 4 , Renata Pellegrino 4 , Rodrigo Bressan 1 , Vanessa Ota 1 , Hakon Hakonarson 4 , Sintia Belangero 1

1 Federal University of Sao Paulo 2 Hospital de Clínicas de Porto Alegre 3 University of Sao Paulo 4 Children’s Hospital of Philadelphia

Background: Psychiatric disorders are genetically complex traits, and little is known about the causal genes involved their pathogenesis, and how their function is regulated. The study of epigenetics processes will help to better understand the role of genetic variation in health and disease. Al- though performing a probe-wise methylation analysis is useful and informative, knowing whether several proximal CpGs are concordantly differentially methylated could provide insights into different phenotypes. In the present study, we aimed to identify differentially methylated regions (DMRs) associated with psychopathology using subjects from a large prospective community school-based study in Brazil, the High Risk Cohort (HRC) for Psychiatric Disorders. For this purpose, we compared DNA methylation in children and adolescents before (baseline) and after (3 years of follow- up) develop high psychopathology. Furthermore, to confirm DMRs findings, we compared the methylation levels of CpGs within DMR between HRC subjects and healthy controls paired by age and sex. Methods: The HRC has clinical and genetic measures in two different time-points. In both points, psychopathology was assessed using Child Behavior Checklist (CBCL). For the present study, we selected 24 subjects with CBCL score < 30 at the baseline (HRC_B) that increased these score more than 16 (mean = 29, SD = 9) after 3 years of follow-up (HRC_F). Moreover, we selected 24 healthy controls paired by age and sex with HRC_B subjects and compared methylation levels of CpGs within DMRs. We used the same criteria to select other 24 healthy controls to compare to HRC_F subjects. To check for possible confounding, we verified if methylation levels within DMRs were associated to age and sex. The methylation data was generated using the Infinium

Methylation EPIC BeadChip. To find DMRs, DMRcate package was used. Results: Comparing time-points, we have found 1 DMR spanning 3 DNA methylation sites. This DMR overlap KCNAB3 promoter area on chromosome 17. We have found that

the promoter region of KCNAB3 gene was hypermethylated on HRC_B compared to HRC_F (Mean Beta FC = 0.055; Min adjusted p-value within DMR = 1.29 x 10-23). Comparing HRC_B to controls, we observed that the 3 CpGs within KC- NAB3 region were hypomethylated in HRC_B. We found the same pattern in the follow-up: all CpGs were hypomethylated in HRC_F compared to controls. No methylation levels were associated to age and sex. Discussion: The KCNAB3 gene encodes for a member of the potassium channel, voltage-gated, shaker related subfam- ily. The mRNA is expressed in some brain regions and the protein is strongly expressed in the brain, shows a weaker expression in the heart but seems absent in other tissues. Al- though we found a hypermethylation in HRC_B compared to HRC_F, all CpGs were hypomethylated in HRC subjects compared to controls in both time-points. Moreover, methylation levels were not associated to age, suggesting that there is a difference in KCNAB3 methylation between children before the developed high psychopathology and controls. Our results have identified a differentially methylated region in blood that might be a risk marker for psychopathology in children and adolescents.


doi: 10.1016/j.euroneuro.2018.08.423

SU60

GENOME-WIDE DNA METHYLATION INVESTIGATION

OF SYNTHETIC GLUCOCORTICOID EXPOSURE WITHIN

HUMAN BUCCAL SAMPLES

Patricia Braun 1 , Benjamin Hing 1 , Mai Tanaka-Sahker 1 , Aubrey Chan 1 , Yasunori Nagahama 1 , Lindsey Gaul 1 , Jonathan Heinzman 1 , Kumi Yuki 1 , Liesl Close 1 , Brian Dlouhy 1 , Hiroto Kawasaki 1 , Kyle Stein 1 , James Potash 2 , Gen Shinozaki 1

1 University of Iowa Carver College of Medicine 2 Johns Hopkins

Background: Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm

across a larger proportion of the genome is needed. Methods: Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of oral surgery. This included 30 minor tooth extraction surgery patients who received 10 mg of dexamethasone. Genome- wide DNAm was assessed with the Infinium HumanMethyla- tionEPIC array. Data were processed and analyzed with the R packages Minfi and RnBeads. Results: Five CpGs showed genome-wide significant change in DNAm that was > 10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438,



Abstracts 33

ARTICLE IN PRESS


KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Us- ing previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with FDR-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with FDR-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. In a replication cohort of patients with treatment refractory epilepsy, brain, blood, buccal, and saliva samples were obtained before and after dexamethasone treatment. A portion of the FDR-adjusted significant CpGs in the discovery cohort were also nominally significant in the replication cohort (13 CpGs in blood, 5 in buccal tissue, 58 in saliva, and 6 in brain), and one of the CpGs that replicated in saliva also withstood correction for multiple testing. Discussion: In conclusion, high-dose synthetic glucocorticoid administration in the setting of oral surgery was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.


doi: 10.1016/j.euroneuro.2018.08.424

SU61

METHYLOMIC ANALYSIS OF SCHIZOPHRENIA IN 22Q11.2

DELETION SYNDROME

Ehsan Pishva 1 , Therese van Amelsvoort 2 , Eilis Hannon 3 , Laurens JM Evers 2 , Jonathan Mill 1 , Emma Dempster 1

1 University of Exeter 2 Maastricht University 3 University of Exeter Medical School

Background: Central nervous system (CNS) manifestations of 22q11.2 Deletion Syndrome (22q11.2DS) are highly diverse including intellectual disabilities, attention- deficit hyperactivity and anxiety disorders, autism, and schizophrenia (SCZ). Up to date, 22q11.2DS is the strongest molecular genetic link with SCZ. While catechol- Omethyltransferase (COMT), a well-studied candidate gene for SCZ, maps to the deleted region on chromosome 22, no evidence for association between polymorphisms in COMT and SCZ has been found in individuals with 22q11.2DS. More- over, the hemizygosity of this region itself cannot fully explain the increased risk to SCZ in 22q11.2 deletion carriers due to variable penetrance. Therefore, other genetic, environmental or stochastic factors might contribute in such phenotype variation. In this study we investigated the role of DNA methylation in the phenotype heterogeneity in individuals with 22q11.2DS. Methods: Whole blood derived DNA Samples were obtained from 64 individuals from a Dutch cohort of 22q11.2DS (37 developed SCZ and 27 with no symptoms of psychosis) individuals. We also included 162 age and gender-matched individuals with no CNV (65 was diagnosed with first episode psychosis and 97 healthy controls). DNA methylation was

quantified in the samples at over 850,000 sites on the genome using the Illumina EPIC array. We then carried out two epigenome-wide association studies (EWASs) to identify (i) differentially methylated CpG positions and regions associated with the deletion (ii) to compare the genome- wide methylation profile of 22q11.2DS individuals with and without SCZ. Next, we performed a weighted gene co- methylation network analysis (WGCNA) in subjects with 22q11.2DS and we examined the association between the identified modules and a wide-range of clinical manifestations related to 22q11DS. Results: We found 486 differentially methylated positions (DMPs) P-value < 6.31e-08 and 26 differentially methylated regions (DMRs) associated with 22q11.2DS. Several identified DMPs and DMRs mapped to the deleted region on chromosome 22 (for example, COMT, DGRC5, ARVCF). The within 22q11DS analysis identified 2 hypomethylated DMRs mapping to RUFY1 and NBR2 genes which were associated with SCZ diagnosis. Co-methylation analysis revealed discrete modules of co-methylated loci associated with cleft palate and hypocalcaemia in the 22q11DS individuals. Discussion: This is, to our knowledge, the most extensive study of DNA methylation in association with 22q11DS. We present robust evidence for cis and trans effects of the 22q11 deletion on DNA methylation. Many of the DMPs and DMRs associated with the deletion mapped to the COMT gene. However, no significant changes in the methylation of the COMT gene in association with psychotic symptoms were found. Altered mRNA expression of the RUFY1 gene, a within 22q11DS SCZ-associated DMR, has been previously observed in early-onset SCZ.


doi: 10.1016/j.euroneuro.2018.08.425

SU62

THE ROLE OF ENVIRONMENTAL STRESS AND DNA

METHYLATION IN THE LONGITUDINAL COURSE OF

BIPOLAR DISORDER

Ashley Comes 1 , Kristina Adorjan 2 , Till Andlauer 3 , Monika Budde 2 , Franziska Degenhardt 4 , Andreas J. Forstner 4 , Katrin Gade 5 , Urs Heilbronner 2 , Janos Kalman 6 , Ivan Kondofersky 7 , Sergi Papiol 2 , Fanny Senner 2 , Sugirthan Sivalingam

4 , Peter Falkai 8 , Thomas Schulze 2

1 Institute of Psychiatric Phenomics and Genomics 2 Institute of Psychiatric Phenomics and Genomics, Univer- sity Hospital, LMU Munich

3 Max Planck Institute of Psychiatry 4 Life & Brain Center, University of Bonn

5 University Medical Center Goettingen

6 Institute of Psychiatric Phenomics and Genomics, Univer- sity Hospital, LMU Munich, International Max Planck Re- search School for Translational Psychiatry (IMPRS-TP) 7 Institute of Computational Biology, Helmholtz Center Mu- nich, German Research Center for Environmental Health

(GmbH) 8 University Hospital, LMU Munich



34 Abstracts

ARTICLE IN PRESS


Background: Stressful life events in either early stages of development or adulthood can have a profound influence on the course of affective disorders. However, the molecular mechanisms allowing these stressors to bring about phenotypic effects is not completely understood. Recently, emphasis has been placed on long-term alterations in gene expression mediated by epigenetic modifications. Specifically, DNA methylation has been proposed as an adaptive mechanism by which the interaction between gene and environment is integrated at the cellular level, influencing phenotypic expression. Methods: We explored signatures of DNA methylation associated with stressful life events (i.e. childhood trauma based on the Childhood Trauma Screener and stressful life events in the last 6 months based on the Life Events Ques- tionnaire) in 96 bipolar patients from the longitudinal Psy- Course study. Whole blood samples from two time points (baseline and 1-year follow-up) were used to measure DNA methylation using the Infinium methylationEPIC beadchips from Illumina. First, we conducted an epigenome-wide association study (EWAS), modeling the effect of both childhood trauma and the impact of stressful life events in the last six months on DNA methylation. Second, we interrogated variation in DNA methylation in the vicinity of candidate genes previously implicated in the stress response (BDNF, OXTR, IL6, and FKBP5). Third, an investigation of differentially methylated regions (DMRs) was performed. Results: In the analysis of differential methylation, a single CpG was significantly associated with stressful life events in the last six months (cg15212455; gene symbol POU6F2; FDR = 0.022). Hypothesis-driven analyses of four candidate genes regarding the stress response revealed a significant effect of the interaction between childhood trauma and stressful life events on DNA methylation for a CpG probe annotated to BDNF (cg09505801; FDR = 0.016). Investiga- tion of DMRs identified one region consisting of five CpGs in chr3:146,262,331-146,262,434 that significantly correlated with baseline stressful life events scores (overlapping PLSRC-1 promoters; min. FDR = 6.8x10-16). Discussion: Preliminary findings from this exploratory study support a role of epigenetic changes associated with stressful life events for bipolar patients. Future studies are needed with larger sample sizes to replicate these findings on DNA methylation.


doi: 10.1016/j.euroneuro.2018.08.426

SU63

DNA METHYLOMIC PROFILING OF PREFRONTAL CORTEX

SAMPLES FROM COMPLETED SUICIDE CASES

Ana Romero-Pimentel , Said Munoz-Montero, Mirna Morales-Marin, Humberto Nicolini, Claudia Rangel

National Institute of Genomic Medicine INMEGEN

Background: Suicide represents a global health challenge because the rates are increasing among the world, the majority occurring in low and middle-income countries. This

phenomenon is complex, heterogeneous and its contributing factors remain unclear. The molecular pathology of suicide remains poorly understood. It has been hypothesized that regulatory genomic processes are involved. Recent studies have started to examine the role of epigenetic processes including DNA Methylation. Nevertheless, to date, few studies have examined DNA methylation differences changes in the brains of suicide completers and non-has focused in Latino population. The aim of the study is to describe the suicide methylation variation in cortical brain samples. Methods: In this study, genome-wide patterns of DNA methylation were assessed in suicide completers (n = 38) and compared with sudden-death controls (n = 13) using tissue from Brodmann Area 9 brain region. Analyses focused on identifying differentially methylated positions (DMP) and methylated regions (DMRs) using the Infinium HumanMethy- lation450 BeadChip. All samples passed stringent quality- control measures. Microarray preprocessing, Quantile normalization and background correction were performed using minfi R package. Statistical Analyses for DMPs and DMRs were performed using R statistical package limma and DMR- cate, respectively. Results: We identified 92 DMPs and 14 DMRs, the top 10 most significative genes were; TMEM68, TGS1, TCP11L1, IER3IP1, SNX5, ANKH, MORN4, TMEM14A and B3GALT4-001 and RPS18-008, B3GALT4-002 located in the chr6:33245585- 33246488. We also identificated the most enriched genes networks implicating biological processes relevant to suici- dality, including nervous system development, mitochondria function, inflammation process and immune system. Discussion: Our data suggest that there are changes in DNA methylation associated with suicide that may offer novel insights.


doi: 10.1016/j.euroneuro.2018.08.427

SU64

EARLY EXPERIENCES OF THREAT, BUT NOT DEPRI- VATION, ARE ASSOCIATED WITH ACCELERATED EPIGE- NETIC AGING IN CHILDREN AND ADOLESCENTS

Jennifer Sumner 1 , Natalie Colich 2 , Monica Uddin 3 , Don Armstrong 3 , Katie McLaughlin 2

1 Columbia University Medical Center 2 University of Washington

3 University of Illinois Urbana-Champaign

Background: Recent conceptual models argue that early- life adversity (ELA) accelerates development, which may contribute to poor mental and physical health outcomes. Ev- idence for accelerated development in youth comes primarily from neuroimaging studies of circuits involved in emotional processing and learning. Further, ELA encompasses a wide range of experiences that do not have identical developmental consequences. Thus, it remains unclear whether any ELA is associated with a more global biological metric of accelerated development and whether this pattern emerges following specific adversity types.



Abstracts 35

ARTICLE IN PRESS


Methods: In 247 children and adolescents aged 8-16 years with wide variability in ELA exposure, we evaluated the hypothesis that early environments characterized by threat, but not deprivation, would be associated with accelerated development on a global biological aging metric: DNA methylation (DNAm) age relative to chronological age. We also examined whether accelerated DNAm age relative to chronological age explained associations of ELA with psychopathology, namely depression and externalizing behaviors. Youth and caregivers reported on ELA exposure and psychopathology, and youth provided saliva samples for DNAm. Results: Exposure to threat-related ELA (e.g., violence) was associated with accelerated DNAm age (ß= 0.17, p = .042), but exposure to deprivation (e.g., neglect, food insecurity) was not (ß= 0.10, p = .260). Older DNAm age was related to greater depressive symptoms (ß= 0.26, p = .004), and a significant indirect effect of threat exposure on depressive symptoms was observed through DNAm age [0.045, (95%

CI:0.001–0.125)]. Discussion: Early experiences of threat and violence were associated with accelerated development with respect to epigenetic age, whereas early experiences of deprivation were not. Advanced epigenetic aging may be one mechanism linking early threat exposure with risk for depressive symptoms. Our findings shed light on how ELA, particularly threat-related experiences, may get under the skin to contribute to negative health outcomes.


doi: 10.1016/j.euroneuro.2018.08.428

SU65

IMAGING GENETICS IN PSYCHOSIS STUDY: EPIGE- NETIC AGE ACCELERATION, TRAUMA, AND PSYCHOSIS OUTCOMES

Sarah Cohen-Woods 1 , Oliver Watkeys 2 , Nina Teroganova 3 , Yann Quide 3 , Janice Fullerton 2 , Murray Cairns 4 , Melissa Green 3

1 Flinders University, South Australia 2 Neuroscience Research Australia 3 University of New South Wales 4 University of Newcastle

Background: Schizophrenia (SZ) and bipolar disorder (BD) share cognitive and brain abnormalities, polygenic vulnerability, and common environmental risk factors such as childhood maltreatment. Childhood maltreatment has been associated with significant alterations in structure, function, and connectivity of the brain, as well as with advanced epigenetic age. Epigenetic processes (such as DNA methylation) function to regulate gene expression and may be important mediators on the path between childhood maltreatment and psychosis. Methods: The Imaging Genetics in Psychosis (IGP) cohort includes 240 individuals (n = 80 Schizophrenia/ Schizoaffective, 80 bipolar cases, 80 healthy controls) who have completed clinical, cognitive, imaging, genetic, and DNA methylation assessments. Clinical measures include

confirmation of diagnosis using the Diagnostic Interview

for Psychosis. The Positive And Negative Symptom Scale (PANSS) evaluated current symptoms in the case participants. The Childhood Trauma Questionnaire and the Stress- ful Life Events scale were administered to all participants. DNA was extracted from peripheral whole blood samples. Genomic data was assayed using the HumanCoreExome Psy- chChip (Illumina, San Diego), and DNA methylomic data was assayed using the Infinium HumanMethylation 450K Bead- Chip (Illumina, San Diego). Epigenetic age acceleration was calculated using the epigenetic clock developed by Steve Horvath. Results: We find no association between epigenetic age acceleration and psychotic diagnoses. However, marginal support for epigenetic age acceleration was associated with trauma exposure (t = 1.86, p = 0.06), which was attenu- ated when including standardized Imipramine and Chlorpro- mazine dosages in the model. There was also evidence of association between epigenetic age acceleration and negative symptoms in clinical cases from the PANSS (t = 3.05, p = 0.003), independent of schizophrenia or bipolar diagnosis when standardized medication dosages were included in the model. Additional findings in relation to structural and cognitive changes will be presented. Discussion: The strongest association with peripheral DNA epigenetic age acceleration was revealed for current negative symptoms in the clinical cases, regardless of diagnosis. This could reflect severity of psychosis, and potentially variation within individuals with a history of psychosis. The attenuation of associations with childhood trauma when accounting for medication dosages suggests that these clinical factors should be controlled as potential confounds in future methylation analyses of psychosis samples.


doi: 10.1016/j.euroneuro.2018.08.429

SU66

OPEN BOARD


doi: 10.1016/j.euroneuro.2018.08.430

SU67

POLYGENIC RISK SCORES DERIVED FROM A TOURETTE

SYNDROME GWAS PREDICT PRESENCE OF TICS IN

THE AVON LONGITUDINAL STUDY OF PARENTS AND

CHILDREN (ALSPAC) COHORT

Mohamed Abdulkadir 1 , Carol Mathews 2 , Jeremiah Scharf 3 , Dongmei Yu 4 , Jay Tischfield 5 , Gary Heiman 5 , PJ Hoekstra 1 , Andrea Dietrich 6

1 University Medical Center Groningen

2 University of Florida 3 Massachusetts General Hospital/Harvard Medical School 4 Massachussetts General Hospital 5 Rutgers, The State University of New Jersey 6 University of Groningen, University Medical Center Groningen




36 Abstracts

ARTICLE IN PRESS


Background: Tourette syndrome (TS) is a complex polygenic neuropsychiatric disorder. The authors investigated the role of polygenic risk scores (PRS) derived from a TS genome- wide association study (GWAS) in relation to the occurrence of tics and associated traits in a general population cohort. Methods: Using the most recent TS GWAS (N cases = 4,819; N controls = 9,488) as the discovery sample, PRS were calculated in ALSPAC participants (N = 8,941). Regression analyses were used to assess whether PRS predicted the presence and number of tics, and symptom severity of obsessive- compulsive (OCD), attention-deficit/hyperactivity (ADHD), and autism spectrum disorder (ASD) in ALSPAC participants. Results: Following correction for multiple testing for the number of P-value thresholds (10,921), the PRS significantly predicted presence (P = 0.005) and number of tics (P = 0.04) in the ALSPAC cohort. The TS based PRS did not predict severity of OCD, ADHD, and ASD. Discussion: The authors found a significant polygenic component of tics occurring in a general population cohort based on PRS derived from a GWAS of individuals with a TS diagnosis. This supports the notion that tics along a spectrum from non-clinical to clinical symptom levels share a similar genetic background.


doi: 10.1016/j.euroneuro.2018.08.431

SU68

NO ASSOCIATION OF MTHFR C677T VARIANTS IN

POSTPARTUM PSYCHOPATHOLOGY: A PROSPECTIVE

STUDY OF AT-RISK WOMEN

Jehannine Austin 1 , Emily Morris 1 , Catriona Hippman 1 , Caitlin Slomp 1 , Angela Inglis 1 , Prescilla Carrion 1 , Rolan Batallones 1 , Heather Andrighetti 1 , Arianne Albert 2 , Colin Ross 1 , Roger Dyer 1

1 University of British Columbia 2 BC Women’s Hospital

Background: Postpartum mental illnesses (PPMI) are urgent health concerns, but their etiology is not well understood. Low red blood cell (RBC) folate has been associated with psychiatric disorders, and demands for folate increase dra- matically during pregnancy, with one study suggesting that perinatal folic acid supplementation can improve maternal depression symptomatology. The MTHFR C677T variant influences folate metabolism, and some studies have implicated it in psychiatric disorders. Taken together, this suggests a strong rationale for exploring the interaction between MTHFR C677T and RBC folate in PPMI. Objective: To conduct a prospective longitudinal study to explore the relationship between MTHFR C677T genotype, RBC folate levels, and PPMI (depression, mania, and psychosis) in women with a history of mood or psychotic disorders. Hypothesis: In the first three months postpartum, TT homozygous women would have increased symptoms of depression, mania, and psychosis, compared to CC homozygotes. Methods: We recruited 365 pregnant women (psychiatric history confirmed by the Structured Clinical Interview for the DSM-IV (SCID-IV)). At 3 postpartum timepoints, we ad-

ministered the Edinburgh Postnatal Depression Scale (EPDS), Clinician-Administered Rating Scale for Mania (CARS-M) and the Positive and Negative Symptom Scale (PANSS, for psychosis) and drew blood for RBC folate/genotype analysis. We used linear regression to investigate the effect of the interaction between RBC folate and genotype on the highest EPDS and CARS-M scores, and logistic regression to explore the effect of the interaction on PANSS scores above/below

cut-off. Results: There was no significant interaction effect between RBC folate and MTHFR genotype on highest EPDS (p = 0.19), CARS-M (p = 0.09), or PANSS (p = 0.14). There was also no difference between genotypes for EPDS CARS-M or PANSS (all p > 0.05) controlling for RBC folate, and no relationship between RBC folate on its own and any of the scales (all p > 0.05). Discussion: Our data do not support a relationship between MTHFR C677T polymorphisms and folate in risk for postpartum psychopathology, at least in the context of food fortifi- cation/supplement use.


doi: 10.1016/j.euroneuro.2018.08.432

SU69

PERIPHERAL MITOCHONDRIAL DNA COPY NUMBER

IS INCREASED IN MAJOR DEPRESSIVE DISORDER

Jae Kyunng Chung 1 , Soo Young Lee 2 , Hee Yeon Jung 3 , Eun-Jeong Joo 4 , Soon Ae Kim

3

1 Eumsung-Somang Hospital 2 School of Medicine, Eulji University 3 SMG-SNU Boramae Medical Center, Seoul National Univer- sity College of Medicine 4 Eulji University, School of Medicine

Background: Mitochondrial dysfunction has been suggested as a promising pathophysiology of depression. Mitochondrial DNA (mtDNA) copy number is considered as a biomarker for mitochondrial dysfunction. It is also suggested that DNA methylation of genetic region such as the D-loop region of mitochondria DNA and peroxisome-proliferator-activated receptor γ co-activator-1 α (PPARGC1A) gene related to mitochondria biogenesis may have a regulatory role for mtDNA copy number change. In this study, we compared mtDNA copy numbers between mood disorder patients and controls in peripheral blood and investigated DNA methylation ratio in the D-loop region and PPARGC1A. Methods: One hundred eighteen patients with major depressive disorder and 116 sex and age matched healthy controls were investigated. The relative mtDNA copy number in peripheral blood cells was measured using quantitative polymerase chain reaction and the DNA methylation ratio was measured using methylation-specific PCR after bisulfite conversion. Results: The relative mtDNA copy number was significantly higher in patients than controls ((p < .0001). In the patients group, the metDNA/unmetDNA ratio was decreased in PPARGC1A promoter (p < .0001), but there are no differences in mitochondrial D-loop region. Increase of mtDNA



Abstracts 37

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copy number was strongly associated with decrease of DNA methylation status in PPARGC1A promoter (p < 0.05) but was not associated with DNA methylation status of mitochondrial D-loop region. Discussion: The elevated mtDNA copy number and decreased methylation ratio at the promoter of PPARGC1A in the patients with major depressive disorder suggest not only the role of mitochondrial dysfunction in depression but also the involvement of epigenetic control mechanism for this mitochondrial dysfunction.


doi: 10.1016/j.euroneuro.2018.08.433

SU70

ANTIDEPRESSANT RESPONSE IN MAJOR DEPRESSIVE

DISORDER AND RARE VARIANTS

Ma-Li Wong 1 , Mauricio Arcos-Burgos 2 , Julio Licinio 1

1 State University of New York Upstate Medical University 2 International Institute of Translational Medicine, Univer- sity of Rosario

Background: Approximately 12% of Americans are currently taking antidepressants; thus, the ability to predict antidepressant drug response may have significant public health impact. Rare genetic variants are thought to contribute up to 40% of functional variability in genes relevant to drug action. We investigated the contribution of rare functional genetic variants to antidepressant drug response by performing whole genome screening and performing rare functional variant analysis. Methods: We obtained whole exome genotyping data in Mexican-Americans individuals who met DSM-IV criteria of major depressive disorder and completed 8 weeks of double-blind treatment with desipramine or fluoxetine in a prospective randomized double-blind pharmacogenetics trial. Hamilton Depression Rating Scale was used to determine the primary treatment outcome. Results: Data from remitters and non-responders were analyzed using regression- and permutation-based kernel-based adaptive cluster (KBAC) analysis. We identified rare variants in several genes significantly associated with treatment remission (FDR < 0.05), and their pathway analysis were enriched for sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycle process. Discussion: Our results support the involvement of rare functional variants in antidepressant drug response, and enriched pathways were in sensory, immune mediation and growth processes.


doi: 10.1016/j.euroneuro.2018.08.434

SU71

MICROBIOTA FEATURES IN PARTICIPANTS WITH SEVER- ITY OF DEPRESSION AMONG THE BIPOLAR DISORDER

AND HEALTHY CONTROLS

Li-Chung Chuang 1 , Yu-Chu Ella Chung 2 , Wei-Liang Shih 3 , Po-Hsiu Kuo 4

1 Cardinal Tien Junior College of Health

2 College of Public Health, National Taiwan University 3 Institute of Epidemiology and Preventive Medicine, Col- lege of Public Health, National Taiwan University 4 Institute of Epidemiology and Preventive Medicine, Na- tional Taiwan University

Background: Depression episode in the bipolar disorder represents the function weakening in the most patients. In- stead of mania episode, several recent longitudinal studies indicated depression being the hallmark for bipolar disorder, demonstrating that depressive episodes may play the dominant role in the illness course. Recent research has suggested the gut microbiota could assist in understanding and be treating depression. In the present study, we observed the microbiota features for the severity of depression in the bipolar disorder and healthy control. Methods: We recruited 23 patients with bipolar disorder and 37 healthy controls, and the self-reported Beck Depression Inventory (BDI) was used to examine the severity of depression. The BDI score more than 14 was used as a cut-offpoint for depression. The fecal samples were examined by Illumina Miniseq or Miseq platform for 16s rRNA sequencing of microbiota features. Three approaches were applied to test associations between depression and microbiota, including Linear discriminant analysis effect size (LEfSe), correlation analysis and random forest. The area under the receiver operating characteristic curve was used to assess the discrimination capability of the microbiota features for depression. Results: In the LEfSe approach, the abundance of Novosph- ingobium significantly increased in the participants with depression. The abundances of class Alphaproteobacteria, Megasphaera, Candidatus Portiera, Odoribacter, and Aero- coccaceae were significantly different in the participants with depression in the correlation analysis. Random forest algorithm revealed the top 5 bacteria of index mean decrease in accuracy for classification, including Novosphin- gobium, Blautia, Odoribacter, Sutterella, and Leuconostoc. The abundance of Blautia was with discriminability for the severity of depression, and the area under the receiver operating characteristic curve was 0.7513 (0.6028–0.8998). Discussion: In conclusion, our study indicated the association between the severity of depression and the microbiota features among the patients with bipolar disorder and healthy participants.


doi: 10.1016/j.euroneuro.2018.08.435




38 Abstracts

ARTICLE IN PRESS


SU72

RNA-SEQUENCING OF THE SUBGENUAL ANTERIOR

CINGULATE CORTEX HIGHLIGHTS TRANSCRIPT-LEVEL

EXPRESSION DIFFERENCES BETWEEN MAJOR PSYCHI- ATRIC DISORDERS

Nirmala Akula 1 , Robin Kramer 1 , Qing Xu 1 , Kory Johnson 2 , Stefano Marenco 1 , Pavan Auluck 1 , Jose Apud 1 , Harker Rhodes 1 , Brent Harris 1 , Barbara K. Lipska 1 , Francis J. McMahon 1

1 NIMH/NIH

2 NINDS/NIH

Background: The subgenual anterior cingulate cortex (sgACC) has been implicated in both mood disorders and schizophrenia, but gene expression in this brain region has been little studied. Here we report the first large-scale study of the sgACC transcriptome in major psychiatric disorders. Methods: A total of 200 tissue samples were obtained post- mortem from sgACC of people diagnosed with bipolar disorder (BD, n = 39), major depression (MDD, n = 54), schizophrenia (SCZ, n = 46), or no mental illness (controls, n = 61). Stranded, paired-end sequencing of high quality RNA (RIN

³6) was performed on the Illumina HiSeq 2500. The resulting 125bp reads were mapped to the reference genome (hg38) using HISAT2. Gene-level and transcript-level analyses were performed using HTSeq and StringTie, respectively. DESeq2 was used for quality control, normalization, and differential gene expression, with correction for known covariates. Matrix eQTL was used to discover the eQTLs, which were then combined with SNPs identified by published GWAS using SMR. SMR results were compared with those from other brain regions reported by GTex and Common Mind Consor- tium (CMC). Results: Of the 21 billion total reads obtained, 98M reads per sample mapped to the reference genome and 70M reads were properly paired, providing about 3-fold greater sequencing depth than previous studies. A total of 67, 53, and 11 genes were differentially expressed at FDR < 10% in BD, SCZ, and MDD, respectively, but absolute log2 fold-change values were all < 0.5. Many of the same genes were differentially expressed in multiple disorders (mean overlap 42%). Compared to controls, the overlapping genes showed a consistent direction of differential expression in cases, with a significant positive correlation in fold-change values across all 3 disorders. Transcript-level analysis identified 336, 680, and 304 transcripts differentially expressed at FDR < 10% in BD, SCZ, and MDD, respectively, and many absolute log2 fold-changes exceeded 1. For some genes, multiple distinct transcripts were differentially expressed in the same disorder, but for other genes some of the same transcripts were differentially expressed in multiple disorders. The mean overlap of differentially-expressed transcripts across disorders was only 18%. At FDR < 10%, a total of 370 genes, 62 genes and 7 genes were implicated by SMR in SCZ, BD and MDD, respectively. Discussion: To our knowledge, this is the largest and deep- est study of the sgACC transcriptome in human brain. Differ- ential gene expression was modest, with substantial overlap across disorders. Greater differential expression and

disorder-specific differences were observed at the transcript level. Integration of eQTL and GWAS data implicated many genes, some of which showed clear brain-region specificity.


doi: 10.1016/j.euroneuro.2018.08.436

SU73

POLYGENIC RISK SCORES FOR CALLOUS-UNEMOTIONAL

TRAITS ARE LINKED TO BRAIN STRUCTURAL CONNEC- TIVITY: RESULTS FROM THE NEUROIMAGE-COHORT

Hyun Ruisch 1 , JC Glennon 2 , A Dietrich 1 , JK Buitelaar 2 , PJ Hoekstra 1

1 University Medical Center Groningen

2 Donders Institute for Brain, Cognition and Behaviour, Ni- jmegen

Background: Callous-unemotional (CU) traits describe potential psychopathic traits in youngsters with conduct problems and are assumed to result from both complex genetics and environmental risk factors. In the current study we investigated whether genetic overlap exists between aggressive traits in the population and CU-traits in our clinical sample, and whether genetic liability for CU-traits relates to structural connectivity in the brain. Methods: Our sample consisted of 780 subjects from the NeuroIMAGE-study, which is a Dutch follow-up of the IMAGE- project, and contains genotype, MRI and phenotypic data. First, we computed polygenic risk scores (PRS) based on a pediatric-aggression GWAS, across multiple gene-sets and SNP P-value thresholds in relation to callous, uncaring and unemotional subscores of the Inventory of Callous- Unemotional traits. Subsequently, identified best-fit PRS were analyzed in relation to brain fractional anisotropy (FA), radial diffusivity (RD) and mode of anisotropy (MO) using Tract-Based Spatial Statistics with threshold-free cluster en- hancement. Correction for multiple hypotheses was performed using permutation-based testing. Results: Best-fit PRS explained 1.09% of variance in callous scores (P = 5.37E-3, glutamate-set PRS), 1.84% of variance in uncaring scores (P = 2.28E-4, genome-wide PRS), and up to 1.55% of variance in unemotional scores (P = 8.57E-4, glutamate-, dopamine- and neuroendocrine-set PRS). Best- fit PRS related to brain MO (peak P = 7.20E-3, genome-wide PRS) and FA (peak P = 1.86E-2, dopamine-set PRS) in multiple, predominantly right hemisphere clusters across different white matter tracts. Discussion: Our results showed genetic overlap between aggressive traits in the population and CU-traits in our sample. In addition to genome-wide PRS, genetic liability for CU-traits emerged from glutamatergic, dopaminergic and neuroendocrine gene-sets, and was linked to structural connectivity across multiple nerve tracts, suggesting involvement of different biological pathways and white matter mi- crostructural abnormalities.


doi: 10.1016/j.euroneuro.2018.08.437



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SU74

THE POTENTIAL OF LOCAL GYRIFICATION INDEX

AS A NEUROPHENOTYPE

Samuel Mathias 1 , Emma Knowles 2 , Joanne Curran 3 , Laura Almasy 4 , Ravi Duggirala 3 , Rene Olvera 5 , John Blangero 6 , David Glahn 7

1 Yale School of Medicine 2 Yale University 3 University of Texas Rio Grande Valley 4 Children’s Hospital of Philadelphia 5 University of Texas Health Science Center San Antonio 6 University of Texas Rio Grande Valley School of Medicine 7 Yale University and Olin Neuropsychiatric Research Center

Background: Cortical surface area and thickness are two dominant neurological phenotypes (neurophenotypes) in imaging genetics. Both measures are generated from models comprising thousands of points along the surface of the cerebral cortex. Both are heritable, independent from one another at a given locus, and are differentially associated with cognitive abilities and psychiatric disorders. Recently, interest has grown in local gyrification index (LGI)—another heritable surface-based metric which quantifies the complexity of cortical folding at a given locus. LGI correlates with general cognitive ability and may dissociate individuals with some psychiatric disorders from healthy controls. However, a thorough investigation of the potential of LGI as a neurophenotype is lacking. For instance, it is unclear whether the genetic factors influencing LGI are distinct from those influencing surface area and/or thickness at any given point on the cortex, or even those influencing total intracranial volume (ICV). Methods: We calculated area, thickness, and LGI at 20,484 cortical surface points (vertices) via T1-weighted magnetic resonance images of 1,443 individuals from extended pedigrees (the Genetics of Brain Structure and Function [GOBS] cohort; 836 female; age range 18-85 years). We estimated the narrow-sense heritability of each metric at each vertex, with and without ICV as a nuisance covariate. For LGI, we additionally estimated heritability with local (i.e., at the same vertex) area and thickness as covariates. We also estimated phenotypic, genetic, and environmental correlations between area, thickness, and LGI at each vertex. Results: LGI was at least moderately heritable at almost every vertex (mean heritability = 0.48; interquartile range = 0.42-0.54). Heritability of LGI was reduced very slightly by controlling for ICV, but remained moderate at most vertices (mean = 0.46; interquartile range = 0.40-0.52). By contrast, controlling for ICV drasti- cally reduced the heritability of area. Phenotypically, LGI was not wholly independent from either area or thickness. LGI tended to correlate most strongly with either area or thickness on a region-dependent basis. Despite all three metrics being heritable, environmental correlations between the metrics tended to be much stronger than the corresponding genetic correlations. LGI remained heritable at most vertices when ICV, local area, and local thickness (as well as their interactions) were included as covariates (mean heritability = 0.43; interquartile range = 0.39-0.48).

Discussion: Some of the phenotypic variance of LGI is shared with ICV, area, and thickness. These relationships appear to be largely environmental in nature, suggesting that they may be driven, at least in part, by methodological factors (e.g., imprecision or bias in the estimation of subsets of metrics in certain cortical regions) rather than biological ones. Indeed, a significant proportion of the genetic variance of LGI is not shared with the other metrics, suggesting that it captures some unique genetic signal. The results suggest that LGI is a useful neurophenotype. However, future studies, including those using LGI as an allied phenotype of psychiatric disorders, should probably take care to control for other aspects of global and local cerebral morphology.


doi: 10.1016/j.euroneuro.2018.08.438

SU75

ASSOCIATIONS BETWEEN POLYGENIC RISK FOR LOW

CIRCADIAN AMPLITUDE AND RISK TAKING BEHAVIOUR

AND BRAIN STRUCTURE IN THE UK BIOBANK COHORT

Laura Lyall 1 , Amy Ferguson 1 , Rona Strawbridge 1 , Joey Ward 1 , Cathy Wyse 2 , Donald Lyall 1 , Breda Cullen 1 , Nicholas Graham

1 , Keira Johnston 1 , Daniel Mackay 1 , Mark Bailey 1 , Jonathan Cavanagh 1 , Jill Pell 1 , Daniel Smith 1


2 Royal College of Surgeons in Ireland

Background: Disrupted circadian rhythmicity and greater risk taking behaviour are common features of mood disorders. Bipolar disorder and major depressive disorder are associated with reduced brain white matter tract integrity and reduced volumes of several cortical and subcortical brain structures compared to healthy controls. Genetic contributions to these brain structural differences may overlap with genetic contributions to common risk factors for mood disorder, including circadian disruption and risk taking. Methods: We conducted GWAS of low relative amplitude (RA), an accelerometry-derived objective measure of circadian rhythmicity, and of self-reported risk taking (“Do you consider yourself a risk taker?”) in 71,500 and 328,339 participants of the UK Biobank, respectively. Polygenic risk scores (PRS) for low RA and risk taking were generated for distinct subsamples (not used in the GWAS) with available MRI data (n = 4,882 for RA; n = 9,249 for risk taking). For low RA, associations between top and bottom PRS quartiles and general components of common metrics of white matter integrity, derived using principal component analysis, were examined (fractional anisotropy (FA); mean diffusivity (MD), intracellular volume fraction (ICVF) and orientation disper- sion index (ODI)). For risk taking, we examined associations between the top vs. bottom PRS quintile and general components of FA and MD as well as total tissue volumes and volumes of ten cortical/subcortical regions that have previously been linked to risk taking. Results: There were no significant associations between polygenic risk for low RA and general components of measures of white matter integrity (FA, MD, ICVF, ODI) at any


40 Abstracts

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PRS threshold. At 3 of 5 PRS thresholds, higher PRS for risk taking was associated with greater white matter tract MD

(reflecting poorer integrity), and at 2 of 5 thresholds, with smaller middle frontal gyrus volume. Discussion: We provide evidence that genetic propensity towards risk taking behaviour is associated with structural brain differences. The middle frontal gyrus has been linked to inhibitory control, and poorer white matter integrity to risk taking behaviour and impulsivity: the current findings suggest these associations are linked to by genetic propensity for risk taking.


doi: 10.1016/j.euroneuro.2018.08.439

SU76

EXPLORING THE RELATIONSHIP OF BIRTH WEIGHT

ON CORTICAL BRAIN STRUCTURE IN UK BIOBANK USING

GENETIC INSTRUMENTS

Emma Neilson, Toni Clarke, Xueyi Shen, Simon Cox, Masoud Shirali, David Howard, Jude Gibson, Mark Adams, Mathew Harris, Gail Davies, Ian J. Deary, James Boardman, Stephen Lawrie, Andrew McIntosh, Heather Whalley


Background: Differences in the brain’s cortical organization are linked to common psychiatric disorders and differences in cognitive ability. Low birth weight (BW, < 2.5kg) is associated with alterations in cortical brain structure, reduced cognitive ability and psychiatric problems; suggesting that somatic fetal growth may be an important determinant of brain structure and function in later life. However, the relationship between BW within the normal range and adult brain structure in the general population is little understood, including whether a causal relationship exists. We therefore sought to test if there is a causal relationship between BW and brain cortical morphology in a general adult population using Mendelian Randomization (MR). Methods: The current sample included 1,680 individuals from the first release of brain imaging data from UK Biobank. Linear mixed effects models were first used to test for associations between BW and global and localized regions of brain cortical volume, surface area and thickness. Secondly, to test for causal relationships between BW and cortical metric phenotypes we used a Two-sample MR framework, applying the inverse-variance weighted method. Results: BW was significantly and positively associated with global cortical volume ( β = .104, p = 2.86 ×−07) and surface area ( β = .100, p = 3.58 ×−07), but not thickness ( β = −.054, p = .097). The strength of effects was regionally heterogeneous across the cortical mantle; including frontal, temporal and insular regions ( β range = .037 − .069, pcorr range = .037 - .010).

Using birth-weight associated SNPs as proxies for lifetime exposure to low birth weight, MR indicated significant causal links between lower BW and decreased cortical volume of the insular lobe ( β = .346, pcorr = .009), global surface area ( β = .281, p = .009), and surface areas of the in-

sular ( β = .371, pcorr = .005) medial orbitofrontal ( β = .417, pcorr = .006), middle temporal ( β = .287, p = .045), rostral anterior cingulate ( β = .266, p = .045) and IFG ( β = .512, pcorr = .009) parcels. Discussion: Our findings extend previous studies reporting associations between BW and adult cortical morphology. They provide evidence of a potential causal effect of BW

as indexed by genetic variants, on several measures of cortical volume and surface area. The current MR results may therefore also have relevance for links between increased risk of psychiatric and cognitive impairment in individuals with lower BW.


doi: 10.1016/j.euroneuro.2018.08.440

SU77

BRAIN CORTICAL TRAJECTORIES, POLYGENIC RISK

AND ENVIRONMENTAL INTERACTIONS IN A PROSPEC- TIVE LONGITUDINAL STUDY OF YOUNG PEOPLE AT-RISK

OF BIPOLAR DISORDER

Janice Fullerton 1 , Gloria Roberts 2 , Bronwyn Overs 1 , Rhoshel K. Lenroot 3 , Michael Breakspear 4 , Andrew Frankland 3 , Melvin McInnis 5 , Anne Glowinski 6 , Holly Wilcox 7 , Emma Stapp 8 , Leslie Hulvershorn 9 , Kelly Benke 10 , Peter Schofield 1 , John Nurnberger 9 , Philip B. Mitchell 3

1 Neuroscience Research Australia 2 University of New South Wales 3 School of Psychiatry, University of New South Wales 4 QIMR Berghofer 5 University of Michigan

6 Washington University School of Medicine 7 Johns Hopkins University 8 National Institute of Mental Health

9 Indiana University School of Medicine 10 Johns Hopkins Bloomberg School of Public Health

Background: ‘High-risk’ (HR) prospective studies of young people at increased risk of Bipolar Disorder (BD) are crucial for identifying risk profiles that underlie the development of psychopathology. Environmental exposures may interact with preexisting genetic vulnerabilities, to affect brain mat- uration and/or development of psychopathology. The Aus- tralian prospective BD HR study has rich phenotyping over 8 years, including annual clinical assessments, neuroimaging and genetic data. The sister study, with participants recruited from four Universities in USA, used identical recruitment criteria and clinical assessments, allowing joint genetic and clinical data analyses. Methods: Participants were aged 12-30 years, in two groups: 1) children/siblings of a proband with BD (type-I or -II) who had not yet developed BD (HR); and 2) controls (CON) with no family history of major mental illness. Peripheral blood DNA was genotyped (Aus-US combined cohort n = 392 HR, 239 CON, 80 young-BD), and polygenic risk scores (PRS) calculated based on Psychiatric Genomics Consortium BD-GWAS. Genome-wide methylation was assessed at baseline in 214



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Australian subjects, and biological age acceleration calculated using the Horvath calculator. T1-weighted magnetic resonance images (MRI) were acquired on the Australian sample at baseline (n = 170HR, 126 CON, plus 68BD), and 75%

were re-scanned ∼2.1 years later. MRI scans were processed using Freesurfer v5.3.0. For baseline analysis, vertex-wise cortical thickness and volume measures were analyzed in a General Linear Model (GLM) to examine effects of group and BD-PRS, including relevant covariates. For longitudinal analysis of cortical change over time, Linear Mixed Effects analyses were performed. Results: 35% of Australian subjects (n = 63) have now developed psychopathology since baseline, including threshold BD-I or -II (n = 14, 7.7%), and subthreshold BD (n = 29, 16%). HR subjects have higher mean BD-PRS than controls. Traumatic stress interacts with BD-PRS to increase risk for suicide attempts, independent of demographics, group status, and mood and substance use disorders (interaction p = 0.041). Familial risk (group) is associated with thicker cortex at baseline in several regions, including the inferior frontal gyrus. We find widespread cortical areas in which stress exposure or BD-PRS interacts with age, such that the thickest cortex was found in the youngest individuals with the highest PRS scores in the HR group, but a thinner cortex in controls. A repeated measures analysis found striking differences in rates of cortical thinning over time across large sections of the cortex: HR subjects, but not controls, showed cortical thinning in a number of right lateralized frontal regions (inferior frontal gyrus, lateral orbitofrontal cortex, superior frontal gyrus, and rostral middle frontal gyrus). Biological age acceleration does not significantly differ in this sub-sample of HR and CON, nor with broadly- defined conversion to BD. Discussion: Clear clinical and neurobiological differences are observable in BD HR subjects, before they develop BD. Significant interactions between age, polygenic risk and environmental risk factors, indicate that effects of BD risk factors on cortical development may follow a complex trajectory. Evidence of widespread accelerated thinning of the frontal cortex over time in HR suggests that the frontal cortical thinning observed in established BD appears to be developing early, even before BD manifests.


doi: 10.1016/j.euroneuro.2018.08.441

SU78

PROTEIN-PROTEIN INTERACTION (PPI) NETWORK

ANALYSES OF DE NOVO VARIATION IN OBSESSIVE- COMPULSIVE DISORDER REVEAL OVERLAP WITH

AUTISM RISK GENES

Carolina Cappi 1 , Euripedes Constantino Miguel 2 , Dalila Pinto 1 , Thomas Fernandez 3

1 Icahn School of Medicine at Mount Sinai 2 University of Sao Paulo 3 Yale University School of Medicine

Background: Obsessive-compulsive disorder (OCD) is a common debilitating developmental neuropsychiatric disorder with a genetic risk component, yet identification of high- confidence risk genes has been challenging. We performed whole-exome sequencing in 222 OCD parent-child trios and found strong evidence for the contribution of de novo likely- gene-disrupting and predicted damaging missense variants (RR 1.52, p = 0.0005) to OCD risk, identifying CHD8 and SCUBE1 as high-confidence recurrently mutated genes. Methods: To extract additional information about possible enriched pathways, biological processes, and potential candidate risk genes, we performed an exploratory gene-set network analysis of all 103 genes carrying at least one de novo damaging variant in our OCD trios using three separate methods. GeneMANIA and its Cytoscape plug-in were used to identify and visualize the resulting protein-protein interaction (PPI) network, and the CentiScaPe plugin was used to analyze the topological parameters of the network. A second method, GeNets was used taking advantage of InWeb PPI information and 853 expertly curated pathways from the Molecular Signatures Database. Finally, Ingenuity was used to “validate” the top expressed biological pathways found by GeneMANIA and GeNets. Results: Starting from 103 seed genes, we obtained a Gene- MANIA PPI network of shared functional relationships among 98 genes more directly connected than expected by chance (p value = 0.021), with at the least one connection and a total of 835 gene-gene interactions. The LRBA gene was found to be highly connected and classified as a significant hub in the directed network (p = 0.046). Topological analysis classified SEC24B, DOCK5, AP1G1 and LRBA as key connector genes. Among these, AP1G1 had lower missense and loss-of- function mutation rates than expected based on the ExAC

database. The GeneNets network was also more connected than by chance (p < 2e-03) and the most significant genes included LDB3, STARD13, TLN2, GOLGA3, CTCF, SEC24B and CHD8. Among these, CTCF, TLN2 and CHD8 are mutation- intolerant, further supporting their candidacy for OCD risk. The most significant pathway was negative regulation of fibroblast growth factor receptor signaling (p = 9.98e-06). Finally, Ingenuity identified the granulocyte-macrophage colony-stimulating factor, renin-angiotensin signaling (RAS) system, and neurotrophin/TRK signaling pathway as additional significant pathways. Discussion: PPI analyses confirmed CHD8 as a high- confidence OCD risk gene. Although SCUBE1 was not identified by the PPI analysis, it is part of the EGF family and interacts directly with LRBA that was highly connected in the network and plays an important role in immune response development. Finally, most of the resulting key network genes based on their network topology are also known ASD risk genes and are known to participate in brain development and immunological processes.


doi: 10.1016/j.euroneuro.2018.08.442



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SU79

GENETIC PATHWAYS INVOLVED IN THE SEVERITY

OF OBSESSIVE COMPULSIVE DISORDER: A FUNCTIONAL

GENOMICS APPROACH

María Alemany-Navarro 1 , Raquel Cruz 2 , Eva Real 3 , Cinto Segalàs 3 , Sara Bertolín-Triquell 4 , José Manuel Menchón 3 , Angel Carracedo 2 , Maria Del Pino Alonso 4

1 Instituto de Investigación Biomédica de Bellvitge (Barcelona) 2 Santiago de Compostela University 3 Instituto de Investigación Biomédica de Bellvitge, Hospi- talet de Llobregat, Barcelona 4 Hospital Universitari de Bellvitge

Background: Different evidences exist about the genetic risk for Obsessive Compulsive Disorder (OCD) from Genome- wide studies (Stewart, 2013; Matthiesen, 2015). However, no studies look into the genomic base of the severity of the disorder. Nowadays, the dimensional -as opposed to categorical- nature of the psychiatric disorders has been assumed (APA,2013). Knowing more about the genetic bases of the severity of OCD, in addition to OCD risk, would allow

developing more personalized treatments as well as prevention strategies for OCD patients. Methods: Three-hundred and seven patients diagnosed for OCD were genotyped with the Infinium PsychArray from Illumina. The severity of the disorder was evaluated through the Yale-Brown Obsessive-Compulsive Scale (Good- man, 1989). Individual variant analyses were carried out for single nucleotide polymorphisms (SNPs). Enrichment analyses were executed for rare and normal variants (minor allele frequency = 0.000000001 to 0.05) for those genes with a p- value < 0.001. Results: At the variant level, one single nucleotide polymorphism (SNP) was found to be associated with YBOCS score at GWAS significance level (2,08x10-08) under additive and dominant models: rs9955055, an intronic variant next to RPL31P9 (147 bp) and near from DSEL gene (368 kb). The most enriched genetic pathways were rich in splice variants (enrichment score = 1.59; FDR = 6.55x10-4) or involved in alternative splicing (enrichment score = 1.39; FDR = 0.006). Discussion: Given the proximity of rs9955055 to RPL31P9 and DSEL genes, the functional roles of these genes could be involved in the severity of OCD. In line with this, RPL31P9 has been associated to Mood Disorders and non-response to serotonine-reuptake inhibitors (Li, 2016). DSEL gene is a CpG-associated gene within a region linked to Bipolar Dis- order (Goossens, 2003).

Regarding the results from pathway analyses, a dysfunc- tional splicing has been observed in other neuropsychiatric disorders such as Schizophrenia, affective disorders, substance abuse disorders or neurodevelopmental disorders (Glatt et al.; 2011). Our results suggest that an altered splicing could be in the base for OCD severity.


doi: 10.1016/j.euroneuro.2018.08.443

SU80

OPEN BOARD

SU81

OPEN BOARD

SU82

AN ALGORITHM TO IDENTIFY PATIENTS WITH

OBSESSIVE-COMPULSIVE DISORDERS IN BIOVU US- ING NATURAL LANGUAGE PROCESSING, ICD- CODE

AND MEDICATION ADMINISTRATION RECORDS IN THE

SYNTHETIC DERIVATIVE

Takahiro Soda 1 , Evonne McArthur 2 , Patrick McGuire 2 , Angela Maxwell-Horn 2 , Celestial Jones-Paris 2 , Angelica Soto-Freita 2 , James Sutcliffe 3 , James Crowley 1 , Lea Davis 2

1 University of North Carolina at Chapel Hill 2 Vanderbilt University Medical Center 3 Vanderbilt University

Background: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder with a lifetime prevalence of 2.3%

and an annual prevalence of 1.2%. It causes a high burden of society. Additionally, patients commonly start to experience symptoms from childhood, with a mean age of onset at 19 years of age. Despite this disorder burden, OCD’s etiology is unknown and existing treatments are suboptimal. In order to improve clinical outcomes and to reduce morbidity and societal costs, we need a better understanding of the causal mechanisms implicated in OCD. Initial genome- wide association studies (GWAS) for OCD were underpowered, but clearly indicated that OCD is a complex genetic trait and that increased sample size will yield significant loci. The worldwide genotyped sample size for OCD cases is lagging behind other psychiatric disorders, despite the fact that OCD is prevalent and a major source of disability. Methods: Clinical data were obtained from the Synthetic Derivative (SD), which is a de-identified electronic medical record (EMR) data warehouse that contains clinical information extracted from heath records of over 2.2 million individuals in a searchable form covering the past 20 years. Available data types include (but are not limited to)structured data including: ICD9, ICD10, PheWAS, CPT codes, administered medications, laboratory values, vitals as well as unstructured data including clinical com- munications (including discharge summaries, H + P, progress notes, other communication between care providers, or between providers and patient, clinical reports including those from radiology, pathology, rehabilitation), problem lists, and family history). A combination of ICD9/10 codes, medication administration history, history of treatment/ diagnosis as ascertained by natural language processing was used to identify roughly 1500 samples within BioVU (Vanderbilt University’s biobank). These samples were genotyped and imputed for comparison to other available genotypes of patients with OCD.


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Results: The heritability estimates, polygenic risk scores, and comparison between this sample set and existing OCD

sample sets is ongoing and will be presented. Discussion: Recent studies (C-Y Chen et al 2018) have demonstrated that EHR based automated phenotyping to be an efficient method of collecting samples for inclusion into GWAS studies for psychiatric disorders. Our method demonstrates that this method is applicable to obsessive compulsive disorders as well.


doi: 10.1016/j.euroneuro.2018.08.446

SU83

PHENOTYPE HARMONIZATION METHOD IN THE WHOLE

GENOME SEQUENCING FOR PSYCHIATRIC DISORDERS CONSORTIUM

Whole Genome Sequencing for Psychiatric Disorders Consortium

1 , Nelson Freimer 1 , Annabel Vreeker 2

1 University of California, Los Angeles 2 UMC Utrecht

Background: Severe psychiatric disorders, including schizophrenia and bipolar disorder, are clinically heterogeneous with overlapping symptoms and substantially shared genetic risk. Discovering causal genetic variants contributing to these disorders has proven difficult, despite the identification of numerous loci associated with them. Phenotypic imprecision likely contributes to this difficulty, leading to growing interest in assaying specific clinical symptoms and dimensional traits that may be associated with disease risk across diagnostic categories. The NIMH Whole Genome Sequencing for Psychiatric Disorders (WGSPD) Consortium is analyzing such measures in individuals affected by severe psychiatric disorders for whom it has obtained whole genome sequencing data. As phenotype definition and assessments vary across languages, cultures, sites and instruments, the WGSPD has harmonized diagnostic, symptom-level data, to enable combination of measures across studies as a prelude to genetic association analyses. Here, we describe adaptation of a recently developed factor analytic technique for test equating (Alignment; Asparouhov & Muthén, 2014) to calculate factor scores for use in cross-study genetic analyses. Methods: The WGSPD includes ∼20,000 cases across multiple diagnostic categories, drawn from several countries worldwide. Across the different participating sites, there is great variation in used clinical diagnostic instruments. For the current analyses, we included individuals with schizophrenia, schizo-affective disorder, bipolar disorder and major depressive disorder. We used symptom-level data from six major clinical instruments (SCID, OPCRIT, CASH, DI- PAD, DIGS and MINI) to create factor scores for mania, depression and psychosis. After identifying harmonized item

sets, we used item response theory (Embretson & Reise, 2013) to calculate factor scores within each study site and diagnostic group. Lastly, we adapted the alignment method to place factor scores from the six instruments on a common

metric by estimating the mean and variance of the factor score distributions in each study site and diagnostic group. Results: We demonstrate that alignment is a flexible, scal- able method to create valid phenotype scores using different instruments across different sites. Using this approach, we were able to create factor scores for mania, depression and psychotic symptom dimensions and transform those scores to a common metric across study sites and diagnostic groups. After alignment, differences in factor scores across groups can be easily assessed and used to demonstrate the validity of the approach. Discussion: We show that the alignment method is a valid approach to create phenotype dimension scores using symptom-level data derived from a variety of clinical instruments measured in different samples. We are now evaluating the heritability of these phenotypes and examining their relationship with genetic variability.


doi: 10.1016/j.euroneuro.2018.08.447

SU84

FAMILIAL INFLUENCES ON NEUROTICISM IN UK BIOBANK

Rosa Cheesman 1 , Jonathan Coleman 1 , Genevieve Morneau-Vaillancourt 2 , Kirstin Purves 1 , Christopher Rayner 1 , Gerome Breen 1 , Thalia Eley 3


2 Laval University 3 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

Background: A key mechanism by which genes can come to shape our experiences is genotype-environment correlation, or genetic influence on exposure to environments. In other words, the environmental influences affecting an individual are not independent of their own behaviour. Recently, genomic methods have yielded evidence that common genetic variants influence experiences of psychopathology-related environments in adulthood such as life events. However, we can now go further in unpicking genetic and environmental influences on individual differences in experiences. Methods: The UK Biobank sample includes family members with different degrees of relatedness (23,197 couples, 22,665 siblings, 6273 parent-offspring pairs in the full sample). This offers an opportunity to estimate the extent that environments are influenced not only by common SNPs but by kin genetic effects, family environment, sibling environment and couple environment. This study separates these familial sources of individual differences in experiences of psychopathology-related environments: substance use, social deprivation, and trauma. We employ GREML-KIN, a quantitative genetic mixed-model method that makes use of matrices of genomic and environmental relatedness. Results: N/A: analyses underway. Discussion: This research contributes to a body of evidence supporting a move away from a passive model of imposed environmental influences, and the environment as just a residual element. As well as quantifying the contribution



44 Abstracts

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of specific domains of ‘missing environments’, we address the ‘missing heritability’ problem: exploiting the high LD

in family members to quantify the effects of variants not tagged in GWAS of unrelated individuals, e.g. rare variants, CNVs, and structural variants. These findings shed new light on why people differ in their exposure to risk factors for psychiatric disorder.


doi: 10.1016/j.euroneuro.2018.08.448

SU85

CLOCK CLICKS WITH FINANCIAL STRESS BEHIND MI- GRAINE

Daniel Baksa 1 , Xenia Gonda 2 , Nora Eszlari 1 , Peter Petschner 3 , Gyorgy Bagdy 3 , Gabriella Juhasz 4

1 Semmelweis University 2 Kutvolgyi Clinical Centre, Semmelweis University 3 Hungarian Academy of Sciences, Semmelweis University 4 Semmelweis University, University of Manchester

Background: Mood disorders have previously been connected to circadian dysregulation and are also frequently comorbid with migraine. CLOCK gene is a central component in the main circadian clock mechanism working as a transciptional activator, and the rs10462028 tagSNP of CLOCK has been connected to bipolar disorder, a disease with known comorbidity with migraine. The effects of circadian genes on common migraine have not been tested yet and recent meta-analyses of migraine GWASs have not identified any circadian genes as a susceptibility gene of migraine. However, environmental factors including stress and their interaction with genes are also important elements to address in migraine research. In our present study our goal was to test the main effect of rs10462028 and its interactions with stress factors on migraine. Methods: 2349 subjects (69.3% females) were recruited from Manchester (n = 1350) and Budapest (n = 999) (aged between 18 and 60). 27.6% was defined to show migraine symptoms according to the ID-Migraine Question- naire. The following stress factors were used: childhood adversity (Childhood Trauma Questionnaire), recent negative life events (List of Threatening Experiences) and financial difficulties (from our validated background questionnaire). The main effect of rs10462028 and the SNP x stress factors interaction effects were tested on migraine using logistic regression models with additive, dominant and recessive models in the total population and in both subpopulations. All statistical models were adjusted for population, gender and age, and confounding effect of lifetime depression (derived from our background questionnaire) was also tested. Sta- tistical analyses were made using PLINK 1.9 and IBM SPSS Statistics 23. Results: CLOCK rs10462028 showed no main genetic effect on migraine. Childhood maltreatment and recent negative life events showed no significant interaction with the SNP. Only financial difficulties were found to have a significant interaction with rs10462028 on migraine (pFDR = 0.025 in ad-

ditive and 0.017 in recessive models). This latter result sur- vived correction for lifetime depression and was replicated in both population subsamples. Discussion: Our results suggest that CLOCK rs10462028 might alter migraine risk in the presence of financial difficulties, a chronic persistent stress factor. Further investigation of potential roles of circadian genes in the pathophysiology of migraine, especially in patients with serious life stressors, may provide new treatment strategies. (The study was supported by: KTIA_NAP_13- 1-2013-0001, KTIA_13_NAP-A-II/14, KTIA_NAP_13-2-2015- 0001, 2017-1.2.1-NKP-2017-00002 (Hungarian Brain Re- search Program); MTA-SE Neuropsychopharmacology and Neurochemistry Research Group; ÚNKP-16-3, ÚNKP-17-3-III- SE-2, ÚNKP-17-4-I-SE-8 (New National Excellence Program

of The Ministry of Human Capacities); Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences.)


doi: 10.1016/j.euroneuro.2018.08.449

SU86

GENETIC INFLUENCES ON EIGHT PSYCHIATRIC DIS- ORDERS BASED ON FAMILY DATA OF 4,408,646 FULL

AND HALF SIBLINGS, AND GENETIC DATA OF 333,748

CASES AND CONTROLS

Tinca Polderman 1 , Erik Petterson 2 , Henrik Larsson 2 , Patrick Sullivan 3 , Danielle Posthuma 1

1 VU University Amsterdam

2 Karolinska Institutet Stockholm

3 University of North Carolina at Chapel Hill

Background: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. Methods: We assessed heritability based on data of Swedish siblings (N = 4,408,646 full and maternal half siblings) and based on summary data of eight samples with measured genotypes (N = 125,533 cases and 208,215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: 1) alcohol dependence, 2) anorexia nervosa, 3) ADHD, 4) autism spectrum disorder, 5) bipolar disorder, 6) major depressive disorder, 7) obsessive- compulsive disorder, and 8) schizophrenia. Results: Heritability estimates from sibling data varied from

0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from

0.10 for AD to 0.28 for OCD. The largest discrepancy between sibling-based and genotype-based estimates was observed for OCD which is probably due to the fact that the genotype sample is heavily ascertained from highly multiplex families and early age of onset cases and consists thus of the most severe and genetically loaded cases. Genotype-



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based estimates correlated positively (0.19) with sibling- based estimates. When removing OCD from the data this correlation increased to 0.50. Discussion: Heritability estimates for eight psychiatric conditions converge across sibling-based and genotype-based study designs and are comparable to estimates based on previously reported survey measures in twin studies, suggesting that heritability estimates are robust across different tools and designs. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.


doi: 10.1016/j.euroneuro.2018.08.450

SU87

PCSK9 GENETIC VARIANTS, LIFE-LONG LOWERING

OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL, AND

COGNITIVE ABILITIES

Donald Lyall 1 , Joey Ward 1 , Maciej Banach 2 , George Davey Smith 3 , Jason Gill 1 , Jill Pell 1 , Michael Holmes 4 , Naveed Sattar 1


2 Medical University of Lodz 3 University of Bristol 4 University of Oxford

Background: PCSK9 inhibitors lower low-density lipoprotein (LDL) cholesterol and are efficacious at reducing risk of vascular disease, however questions remain about potential adverse effects on cognitive function. We examined the association of LDL cholesterol-lowering genetic variants in PCSK9, with continuous measures of cognitive ability in UK Biobank. Methods: Six independent SNPs in PCSK9 scaled to a 50mg/dL lower LDL cholesterol were used in up to 337,348 individuals from UK Biobank who completed tests of cognitive ability: fluid reasoning, reaction time, trial making test A/B and digit symbol coding. Associations were adjusted for age, sex, GWAS array, and 10 principal components (as provided by UK Biobank). Results: The scaled PCSK9 allele score was associated with a lower risk of coronary heart disease (odds ratio 0.73; 95% CI: 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nominally associated with worse log reaction time (0.04 standard deviations per 50mg/dL lower; 95%CI: 0.00 to 0.08; P = 0.038). Although no strong associations of the PCSK9 allele score were identified with any cognitive trait, the imprecision around the estimates meant that we could not ex- clude a similar magnitude of effect of genetic inhibition of PCSK9 to that seen with established risk factors, including APOE e4 or smoking history, for any of the individual cognitive traits. Point estimates for the PCSK9 allele score and cognitive traits were all on the harmful side of unity. Discussion: Using currently available data in UK Biobank, we are not able to rule out meaningful associations of PCSK9 genetic variants with cognitive traits. These data

highlight the need for further large-scale genetic analyses and, in parallel, continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.


doi: 10.1016/j.euroneuro.2018.08.451

SU88

THE EXTERNALIZING CONSORTIUM: A NEW EFFORT

TO IDENTIFY GENES INVOLVED IN A SPECTRUM OF

PSYCHIATRIC AND SUBSTANCE USE DISORDERS CHAR- ACTERIZED BY BEHAVIORAL UNDERCONTROL

Danielle Dick 1 , Philipp Koellinger 2 , Paige Harden 3 , Richard Karlsson Linnér 2 , Travis Mallard 3 , Ronald de Vlaming 2 , Andrew Grotzinger 3 , Peter Barr 1 , Elliot Tucker-Drob 3 , Irwin Waldman 4 , Arpana Agrawal 5 , Abraham Palmer 6

1 Virginia Commonwealth University 2 VU Amsterdam

3 University of Texas at Austin

4 Emory University 5 Washington University School of Medicine 6 University of California San Diego

Background: The “externalizing spectrum” is a constel- lation of co-morbid disorders and behaviors that involve under-controlled or impulsive action. It encompasses multiple clinical diagnoses across development, including attention deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, antisocial personality disorder, alcohol use disorders, and other substance use disorders. Considered together, externalizing disorders impose an enormous public health burden. Multiple twin and family studies have found that much of the genetic influence on any one externalizing disorder is broadly shared with other externalizing spectrum disorders, and with personality traits that are characterized by behavioral disinhibition (e.g., Krueger et al., 2002; Hicks et al, 2004). For example, as much as 65% of the heritability of alcohol dependence is suggested to operate via a general externalizing disposition, rather than via genes specific to alcohol dependence (Kendler et al., 2003). This shared, latent factor underlying externalizing disorders and traits is highly heritable. Methods: Capitalizing on the known genetic overlap between externalizing traits and disorders, we have launched a new consortium that employs genome-wide association studies (GWAS) of externalizing phenotypes, with the goals of (a) estimating the genetic structure underlying externalizing phenotypes, (b) identifying genes involved in the shared underlying liability to externalizing versus genes unique to specific phenotypes, (c) boosting statistical power for GWAS of specific externalizing phenotypes that are currently available in only relatively small samples, and (d) understanding the extent to which genetic associations observed with individual outcomes are operating through a general predisposition to externalizing behavior. Results: We will present results from applying Genomic SEM, a new multivariate method, which applies structural equa-



46 Abstracts

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tion modeling to summary statistics from genetically correlated traits. With the method we perform exploratory and confirmatory factor analyses, allowing for sample overlap. Our initial analyses include GWAS summary statistics for addictive behaviors (n ∼ 157,000), ADHD (n ∼ 53,000), alcohol consumption (n ∼ 414,000), antisocial behavior (n ∼ 16,000), childhood aggression (n ∼ 19,000), lifetime cannabis use (n ∼ 32,000), impulsivity (N ∼ 20,000) and several risk behaviors (n ∼ 370,000 – 405,000). We present results from these initial analyses and our planned future directions. Discussion: We will conclude with details about the Exter- nalizing Consortium, in order to invite groups to participate in the next wave of analyses.


doi: 10.1016/j.euroneuro.2018.08.452

SU89

TRAFFIC-RELATED AIR POLLUTION, APOE ε 4 STA- TUS, AND NEURODEVELOPMENTAL OUTCOMES AMONG

SCHOOL CHILDREN ENROLLED IN THE BREATHE

PROJECT (CATALONIA, SPAIN)

Silvia Alemany 1 , Natàlia Vilor-Tejedor 1 , Raquel García-Esteban 1 , Mariona Bustamante 1 , Payam Dadvand 1 , Mikel Esnaola 1 , Marion Mortamais 1 , Joan Forns 1 , Barend van Drooge 1 , Mar Alvárez-Pedrerol 1 , Joan Grimalt 2 , Ioar Rivas 2 , Xavier Querol 2 , Jesús Pujol 3 , Jordi Sunyer 1

1 Barcelona Institute for Global Health

2 Institute of Environmental Assessment and Water Re- search (IDAEA-CSIC) 3 Hospital del Mar

Background: Traffic-related air pollution is emerging as a risk factor for Alzheimer’s disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD. We aim

to analyze whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOE ε4 status in children. Methods: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Question- naire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2–4 times during January 2012–March 2013), and APOE genotypes were obtained for 1,667 children aged 7–11 years attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pal- lidum) was measured in 163 of the children by MRI (October 2012–April 2014.) Average annual outdoor polycyclic aro- matic hydrocarbons (PAHs), elemental carbon (EC), and ni- trogen dioxide (NO2) concentrations were estimated based on measurements at each school (two 1-week campaigns conducted 6 months apart in 2012).

Results: APOE ε4 allele carriers had significantly higher behavior problem scores than non-carriers, and adverse associations with PAHs and NO2 were stronger or limited to ε4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC. Discussion: PAHs, EC, and NO2 were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOE ε4 allele carriers in our study population, while corresponding associations were weak or absent among ε4 non-carriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. Replication in other population settings is needed to establish the potential role of APOE gene in neurobiological susceptibility to air pollution.


doi: 10.1016/j.euroneuro.2018.08.453

SU90

USING MEDICATION DATA TO DEFINE PSYCHIATRIC

PHENOTYPES AND RECRUIT LARGE SAMPLES FOR

GWAS

Nick Martin , Sarah Medland

Queensland Institute of Medical Research

Background: It has become abundantly clear that the key to progress in psychiatric genetics is large samples for GWAS. How to collect these quickly and cheaply? Methods: We are using data from the Australian Pharma- ceutical Benefit Scheme (which centrally registers 99% of all prescriptions) to ascertain cases through their prescription information. Results: So far, we have collected DNA from > 15,000 people with > 4 prescriptions for SSRIs of whom 93% report depression as a first diagnosis; 60% also report anxiety. We have also found > 2000 ADHD cases through prescriptions for Ri- talin etc. Discussion: This year we are launching recruitment of bipolar cases via lithium prescriptions and schizophrenia via clozapine. We have applied for funding to extend this model to alcoholism [acamprosate, naltrexone] and Alzheimer’s disease [memantine].


doi: 10.1016/j.euroneuro.2018.08.454




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SU91

THE VALUE OF POLYGENIC RISK SCORES IN PRE- DICTING THE TRANSITION FROM CHILDHOOD AND

ADOLESCENT PSYCHIATRIC SYMPTOMS INTO CHRONIC

ADULT PSYCHOPATHOLOGY

Christel M. Middeldorp 1 , Omowonuola Akingbuwa 2 , Marjo-Riitta Jarvelin 3 , Paul Lichtenstein 4 , Sebastian Lundstrom

5 , Ralf Kuja-Halkola 4 , Marcus Munafo 6 , Robert Plomin 7 , Kaili Rimfeld 7 , Hannah Sallis 6 , Henning Tiemeier 8 , Eivind Ystrom

9 , Meike Bartels 2

1 Child Health Research Centre, University of Queensland

2 Vrije Universiteit Amsterdam

3 Imperial College London

4 Karolinska Institutet 5 University of Gothenburg 6 University of Bristol 7 King’s College London

8 Erasmus MC

9 Norwegian Institute of Public Health

Background: Adult psychiatric disorders can be preceded by a broad range of childhood psychiatric symptoms. Schizophrenia, for example, is associated to anxious, depressive, behavioural and ADHD symptoms in childhood. A critical need to be able to provide targeted treatment is the ability to identify the children at highest risk for this unfavorable trajectory. Earlier polygenic risk score analyses in the Netherlands Twin Register (NTR), the Avon Longitudi- nal Study of Parents and Children (ALSPAC) and Generation R have suggested that the association with schizophrenia is due to shared genetic risk factors. Fewer studies have investigated the association with Major Depressive Disorder and Bipolar disorder, as fewer genetic variants were identified for these disorders. For other adult traits associated with adult psychiatric disorders, such as wellbeing and neuroticism, genetic overlap with childhood psychopathology has not been analysed yet. Given the large increase in genetic variants associated with adult psychopathology and associated traits, together with the large increase in available genotypes in individuals with longitudinal data on psychiatric symptoms from birth or childhood, it is timely to test genetic associations, and, if present, to test whether these associations vary with age. Methods: Polygenic risk scores (PRS) will be based on the most recent results from Genome-Wide Association Meta-Analyses for schizophrenia, depression, bipolar disorder, wellbeing, neuroticism, BMI, height, educational attainment and insomnia. The associations with internalizing, ADHD and social problems measured between age 7 and age 18 will be analyzed in the cohorts participating in the CAPICE consortium: ALSPAC, Child and Adolescent Twin Study in Sweden (CATSS), Generation R, NTR, Norwe- gian Mother and Child Cohort Study (MoBa), Northern Fin- land Birth Cohort (NFBC), Twins Early Development Study (TEDS) and Twin Study of Child and Adolescent Development (TCHAD), total N = ∼40,000. Meta-regression analyses will show whether associations depend on age and type of psychiatric symptoms in the children.

Results: Preliminary analyses in the Netherlands Twin Reg- ister showed the strongest genetic associations in the expected directions with schizophrenia, MDD, neuroticism and wellbeing, although not always significant. Especially ADHD

was negatively associated with the educational attainment PRS. Discussion: The results show how childhood, adolescent and adult psychiatric symptoms are influenced by overlapping genetic factors explaining persistence of symptoms from

childhood into adulthood. Adding polygenic risk scores to models predicting which children are at high risk for chronic symptoms may improve prediction.


doi: 10.1016/j.euroneuro.2018.08.455

SU92

GENERAL COMMON POLYGENIC RISK IN PSYCHIATRIC

DISORDERS

Arija Jansen 1 , Tinca Polderman 1 , Philip Jansen 1 , Danielle Posthuma 1 , Frank Verhulst 2 , Gwen Dieleman 2

1 VU University Amsterdam

2 Erasmus Medical Centre

Background: Neurodevelopmental disorders such as autism

spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD) and anxiety disorders (AD) are at least partly, heritable. These disorders each have a unique genetic architecture consisting of common and rare genetic variants. Recent research pro- poses the existence of a general genetic underlying psychopathology factor with in addition a unique set of genetic risk variants resulting in a specific psychiatric disorder. We aim to investigate this common genetic signal by exploring the joint genetic contribution of five psychiatric disorders, and Insomnia to a clinical diagnosis in a unique clinical child and adolescent sample (N = 1591). Methods: We calculated polygenic risk scores (PRS) for ADHD, ASD, Schizophrenia (SCZ), MDD, anti-social behavior (ASB) and insomnia (INS) for individuals with a psychiatric disorder in a clinical child and adolescent sample (total N = 1591), and for an adult control sample (N = 943). The clinical sample is overrepresented with ADHD (N = 449), ASD (N = 428) and AD (N = 305). Other diagnoses vary from

Anorexia Nervosa, to TIC disorder, to depression and dis- ruptive behavior. We tested all PRS jointly, representing a common genetic signal, with logistic regression analyses for an association with disorder status. Follow-up analyses explored the specific contributions per PRS. Results: With our common variant model that included all PRS we observed an explained variance of 3,8% (Nagelkerke R2 = 0.038). Inspection of the single contributions showed that MDD (R2 = 0.021), and ADHD (R2 = 0.014) showed the largest effects, while ASB (R2 = 0.006), ASD (R2 = 0.001), INS (R2 = 0.001) and SCZ (R2 = 0.01) showed small contributions. Discussion: This is the first study that explored the joint and single genetic effects of five psychiatric disorders, and


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Insomnia in a large clinical sample of children and adolescents. Interestingly, our results indicate that the ADHD and MDD PRS explain the largest part of the variance between our cases and controls. Given the large group of ASD cases in our clinical sample we also expected a substantial effect of the ASD PRS but the explained variance by this PRS was limited. This might be due to the relatively small sample size of the discovery sample on which this PRS is based. The MDD PRS is based on a large discovery sample (N = 59.851 cases), however, this is also the case for the INS and SCZ PRS (respectively N = 386.533 cases and N = 40.675 cases) of which the genetic effect was small.


doi: 10.1016/j.euroneuro.2018.08.456

SU93

THE CONTRIBUTION OF PSYCHIATRIC RISK ALLELES TO A GENERAL LIABILITY TO PSYCHOPATHOLOGY IN

EARLY LIFE: INVESTIGATING ONE EXPLANATION FOR

PLEIOTROPY

Lucy Riglin 1 , Stephan Collishaw

1 , Ajay K. Thapar 1 , Beate Leppert 2 , Joanna Martin 1 , Alexander Richards 1 , Richard Anney 1 , George Davey Smith 2 , Kate Tilling 2 , Evie Stergiakouli 2 , Michael O’Donovan 1 , Anita Thapar 1

1 Cardiff University 2 MRC Integrative Epidemiology Unit at the University of Bristol

Background: Molecular genetic studies provide evidence of shared genetic risks across different psychiatric disorders. Using factor analyses, phenotypic overlaps between different disorders have been found to be best explained both by a latent factor that reflects general liability to psychopathology, as well as by specific factors representing constructs such as emotional/internalizing and behavioral/externalizing problems. In this study we examine the structure of psychopathology in childhood and early adolescence in a population-based birth cohort, including autistic and ADHD symptoms as well as emotional and behavioral items that have been used in previous studies. We tested the hypothesis that common psychiatric risk alleles, indexed by polygenic risk scores (PRS), are associated with a general psychopathology factor, providing an explanation for pleiotropy across disorders. Methods: We used data from a UK, prospective, population- based cohort (ALSPAC). The sample included individuals with data on psychopathology at ages 7 (N = 8161) and 13 years (N = 7017). Given the young age of the cohort, symptoms were parent-reported. PRS were derived from the largest available published genome-wide association studies of schizophrenia, major depressive disorder (MDD), autism

spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Results: ADHD PRS were associated with a general psychopathology factor at ages 7 and 13 and also with a specific neurodevelopmental problems factor at age 7 years. Schizophrenia PRS were associated with the general

psychopathology factor and MDD PRS with a specific emotional problems factor but only at age 13 years, not at age 7 years. We found no clear associations for ASD PRS. Discussion: Our results suggest that schizophrenia and ADHD

genetic risk may contribute to pleiotropy at least partly via association with a ‘general psychopathology’ factor in childhood, whereas genetic liability for MDD appears to contribute to a specific emotional factor indexing depression and anxiety symptoms. This further suggests that while the phenotypic structure of psychopathology is stable from

childhood to early adolescence, there may be developmental changes in the genetic architecture of psychopathology.


doi: 10.1016/j.euroneuro.2018.08.457

SU94

INVESTIGATING THE GENETIC ARCHITECTURE OF

PSYCHIATRIC DISORDERS AND THEIR MEDICAL COMOR- BIDITY FROM A DEVELOPMENTAL PERSPECTIVE

Alison Merikangas 1 , Rachel Kember 2 , Monica Calkins 2 , Kosha Ruparel 2 , Ruben Gur 2 , Raquel E. Gur 2 , Laura Almasy 1

1 Children’s Hospital of Philadelphia 2 University of Pennsylvania

Background: Mental disorders are a leading cause of disability worldwide. One of the major sources of disability is comorbidity between mental and physical conditions, which has been documented in both clinical and community samples of both adults and youth. Previous work on the Chil- dren’s Hospital of Philadelphia (CHOP)/University of Penn- sylvania Philadelphia Neurodevelopmental Cohort (PNC) has demonstrated pervasive comorbidity between physical and mental disorders in youth. Shared genetic etiology between some seemingly disparate mental and physical disorders has been identified. Establishing the loci underlying this comorbidity across development may provide insight into etiology and identify key pathways for treatment of both disorders. Methods: The sample included 9498 youth ages 8 to 21 years from the PNC identified through pediatric clinics in the CHOP health care network (mean age = 14.2; female = 51.7%; European American = 55.8%; African American = 32.9%; Other Ancestry = 11.4%). Measures were as follows: physical condition based on electronic medical records and interview data on 42 physical conditions of 14 organ systems/specialties, mental disorders were assessed with an abbreviated version of the structured Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS) psychiatric diagnostic interview, alcohol and other substance use were assessed with the Minnesota Twin and Family Study computerized substance use assessment or the K-SADS substance screener, and participants were genotyped and standard quality control measures employed. Patterns of medical/psychiatric comorbidity across development were established with traditional regression techniques, and empirically based phenotype groups were calculated using latent variable analysis. SNP-based heritabil- ities were calculated to estimate the degree of influence



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of common genetic variation on the established subtypes, and polygenic risk scores were calculated for disorders to establish if SNPs associated with medical conditions predict psychiatric phenotypes, and vice versa. Results: Models adjusted for sociodemographic correlates, other physical and mental disorders, and false discovery revealed broad patterns of associations between neurodevelopmental disorders with behavior disorders and attention deficit/ hyperactivity disorder (ADHD); neurologic/central nervous system conditions with mood disorders and ADHD; and autoimmune/ inflammatory conditions with mood disorders. Discussion: To our knowledge, our study is the first to examine the genetic architecture underlying comorbid medical/mental conditions in a large diverse sample of children. Our findings show strong overlap between physical and mental conditions and the specific patterns of comorbidity have important implications for etiology. Prospective tracking of cross-disorder morbidity will be important to establish more effective mechanisms for prevention and intervention since the order of onset cannot be determined from these data.


doi: 10.1016/j.euroneuro.2018.08.458

SU95

TRANSDIAGNOSTIC FAMILY HISTORY OF MENTAL ILL- NESS, EXPOSURE TO ENVIRONMENTAL ADVERSITY, AND

PSYCHOPATHOLOGY IN YOUTH

Alyson Zwicker 1 , Vladislav Drobinin 1 , Emily Howes Vallis 1 , Lynn Mackenzie 1 , Jill Cumby 2 , Lukas Propper 3 , Sabina Abidi 3 , Alexa Bagnell 3 , Barbara Pavlova 1 , Martin Alda 1 , Rudolf Uher 1

1 Dalhousie University 2 Nova Scotia Health Authority 3 Dalhousie University/Nova Scotia Health Authority

Background: Family history of mental illness strongly predicts psychopathology. Exposure to adversity, such as childhood maltreatment, bullying, or poverty also contributes to risk. However, each individual form of exposure is typically studied in isolation. We aimed to examine whether a cumulative measure of multiple adversities adds to family history in predicting youth psychopathology. Methods: We assessed family history of mental illness and exposure to environmental adversity in a cohort of 323 youth aged 8-26 years. We calculated family history scores as the proportion of relatives affected with mood or psychotic disorders weighted by biological relatedness. We constructed polyenvironmental adversity scores as mean of 10 indicators: physical, sexual, and emotional abuse, neglect, exposure to violence, bullying, parents’ education, income, and home ownership status. We defined psychopathology burden as sum of affective lability, anxiety, psychotic symptoms, and basic symptoms. Results: Transdiagnostic family history of mood and psychotic disorders significantly predicted psychopathology burden in children and youth (beta = 0.66, 95%CI 0.08-1.24,

p = 0.027). The polyenvironmental adversity score also significantly predicted psychopathology burden (beta = 1.25, 95%CI 0.75-1.76, p < 0.001). Family history and polyenvironmental adversity jointly explained 16% of variance in youth psychopathology burden. Discussion: Psychiatric family history and cumulative exposure to adversity can be combined to powerfully predict psychopathology.


doi: 10.1016/j.euroneuro.2018.08.459

SU96

PHARMACOGENETICS MAY IMPROVE THE SAFETY

PROFILE OF ANTIPSYCHOTIC TREATMENTS

MJ Arranz 1 , Alex Gonzalez-Rodriguez 2 , Josefina Perez-Blanco 3 , Rafael Penadés 4 , Blanca Gutierrez 3 , Ibañez Laura 1 , Barbara Arias 5 , Mercè Brunet 4 , Jorge Cervilla Ballesteros 3 , Juliana Salazar 6 , Rosa Catalan Campos 4

1 Fundacio Mutua Terrassa - Hospital Universitari Mutua Ter- rassa 2 Parc Taulí University Hospital, Sabadell 3 University of Granada 4 Hospital Clinic, Barcelona 5 Universitat de Barcelona/Institut de Biomedicina de la Universitat de Barcelona (IBUB) 6 Hospital de la Santa Creu i Sant Pau, Barcelona

Background: Antipsychotic drugs fail to achieve adequate response in 30-50% of treated patients and about 50% of them develop severe and lasting side-effects. Treatment failure results in poorer prognosis with devastating reper- cussions for the patients, caretakers and broader society. Hypothesis: Growing evidence indicates that genetic factors in Cytochrome P450 (CYP) enzymes play a critical role in determining the clinical outcome of antipsychotic treatment. The adjustment of clinical doses according to the CYP genetic profile of patients may improve the safety and efficacy of antipsychotic treatments. OBJECTIVES: The aim of this study was to evaluate the clinical benefits of a pharmacogenetic intervention for the personalization of antipsychotic treatment Methods: Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG + , N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG-, N = 167). Results: Patients who had their antipsychotic dose adjusted according to key polymorphisms (PharmG + ) had a bigger reduction in side-effects than those treated as usual (PharmG-), although the difference was not statistically significant (p > 0.05 for all comparisons). However, clearer differences were observed in the subgroup of patients carrying CYP functional variants. PharmG + patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improve-



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ment in global, psychic and other UKU side-effects than their PharmG- counterparts (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG + clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG- clozapine patients in general. However, those differences were not statistically significant. Discussion: Our results suggest that pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side-effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP metabolizing enzymes.


doi: 10.1016/j.euroneuro.2018.08.460

SU97

EFFECT OF PHARMACOGENETICS-GUIDED ANTIDE- PRESSANT TREATMENT ON SUICIDAL IDEATION

Sheraz Cheema 1 , Anashe Shahmirian 1 , Gwyneth Zai 2 , Arun Tiwari 1 , Deanna Herbert 1 , Nicole Braganza 1 , Sajid Shaikh 1 , Maria Tampakeras 1 , Natalie Freeman 1 , Clement Zai 1 , James L. Kennedy 1

1 Centre for Addiction and Mental Health

2 Centre for Addiction and Mental Health, University of Toronto

Background: Pharmacogenetic-guided treatment is being increasingly considered for improving psychiatric drug treatment. The effect of pharmacogenetic guidance on suicidal ideation (SI) has not yet been investigated. Methods: To test the feasibility and utility of pharmacogenetic testing, we conducted a multi-year study and provided pharmacogenetics-based guidance to clinicians in prescribing antidepressant and antipsychotic medications. This study, IMPACT, was cross-diagnostic and naturalistic, and included patients referred by primary-care physicians, allied health professionals, and psychiatrists. The IMPACT study uses a combinatorial pharmacogenomics test GeneSight (As- surex Health), which tests for variants in six liver enzyme genes (CYP1A2, CYP2D6, CYP3A4, CYP2C9, CYP2C19, CYP2B6) and two serotonin genes (HTR2A, SLC6A4). The patients are assessed for symptom severity and side effects at baseline and eight weeks.

As part of an interim analysis for the IMPACT study, we selected participants with Beck Depression Inventory (BDI) scores of at least 20 at baseline, and medication information available for their baseline (V0) and eight-week follow-up (V2) visits. We divided the patients into two groups: patients whose physicians considered the genetic information that was provided in prescribing were classified as ‘congruent’ group compared to patients whose medications were not guided by the GeneSight report (‘non-congruent’). In this pilot analysis, we included only patients of self-reported Eu- ropean ancestry.

Results: A total of 648 participants who reported SI at baseline were available for analysis. Among these SI patients, preliminary congruency was scored for 67 patients, of which 23 received congruent medication at V2 and 44 did not. We examined whether receiving congruent medications re- solved SI. Our preliminary analysis did not detect a statistically significant association between medication congruency and the resolution of SI (p = 0.89). Discussion: This exploratory analysis did not show a major effect of pharmacogenetic testing on suicidal ideation. However, our analysis is currently limited by the small sample size and naturalistic design of the study. We expect to have full congruency information for all 648 participants in our final analysis. Larger prospective randomized controlled studies will identify the contribution of pharmacogenetic testing in SI.

Disclosure: Patent applications - Patent, Self.

doi: 10.1016/j.euroneuro.2018.08.461

SU98

CONVERGENT ANALYSIS OF SEQUENCING AND MI- CROARRAY DATA SUGGEST THE INVOLVEMENT OF

MIRNAS AND THEIR TARGET MRNAS IN RESPONSE TO

LITHIUM TREATMENT IN BIPOLAR DISORDER

Alessio Squassina 1 , Claudia Pisanu 1 , Eleni Merkouri Papadima 1 , Carla Melis 1 , Stefano Calza 2 , Donatella Congiu 1 , Annalisa Loizedda 3 , Nicola Orrù 4 , Giovanni Severino 1 , Raffaella Ardau 5 , Caterina Chillotti 5 , Sandro Orrù 4 , Carlo Carcassi 4 , Maria Del Zompo 1

1 University of Cagliari 2 University of Brescia 3 Consiglio Nazionale delle Ricerche (C.N.R.), Istituto di Ricerca Genetica e Biomedica (I.R.G.B.) 4 Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS Sardegna 5 University Hospital of Cagliari

Background: After more than 60 years of use, lithium (Li) is still a first line treatment for bipolar disorder (BD). Clin- ical trials have shown that Li is effective in at least 60%

of patients but its use is characterized by high interindivid- ual variability and important side effects. These features have stimulated intensive research to identify genetic and molecular predictors of response and disentangle its complex biological mechanisms. Genetic studies have so far explained only a small proportion of the observed variability, suggesting that factors other than DNA variants could be implicated. Recent findings have shown that Li interferes with the expression of microRNAs (miRNA) and their targeted genes, suggesting that non-coding RNAs could play a role in modulating its clinical efficacy. Methods: We used next generation sequencing (NGS) to investigate genome wide miRNAs expression in lymphoblastoid cell liens (LCLs) derived from BD patients characterized as excellent responders (ER, n = 12) and non-responders (NR, n = 12) to Li with the “Retrospective Criteria of Long- Term Treatment Response in Research Subjects with Bipo-



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lar Disorder” (Alda scale). These data were matched with genome wide expression data obtained from the same LCLs. The lists of miRNAs and mRNA differentially expressed between ER and NR were analyzed with MiRComb to identify couples of miRNA/mRNA inversely and significantly correlated. This analysis was integrated with results from miRNA target prediction performed using 7 different databases. Results: In total, 24 miRNAs were significantly differentially expressed in ER vs NR and significantly, inversely correlated with genes showing significant differential expression between the two groups (FDR q < 0.05). The 24 miRNAs were involved in 146 negative correlations which included 125 unique genes. Two miRNAs (miR-320a and miR-155-3p) were selected for qRT-PCR validation based on the strength and p values of the correlations with mRNAs. Both miR- NAs were successfully validated. miR-320a and miR-155-30 were inversely correlated with 24 and 19 genes predicted by at least 1 database respectively. Four genes for miR-320a and three genes for miR-155-3p were selected for validation. CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regu- lator of G Protein Signaling 16) for miR-320a and SP4 (Sp4 Transcription Factor) for miR-155-3p were successfully validated. miRNA mimic experiments for functional analysis of the miRNA/mRNA interactions identified are currently ongoing. Discussion: miR-320a was previously suggested to be involved in major depression, Alzheimer disease and demen- tia. Its target gene CAPN1 is involved in dendritic branching, spine density, and hippocampal long-term potentiation, and has been reported to be hypermethylated in the prefrontal cortex of schizophrenia patients. RGS16 encodes for an in- dispensable protein for the circadian regulation of cAMP in the superchiasmatic nucleus. Circadian genes have been strongly suggested to be involved in BD and in Li response. miR-155-3p is involved in processes related to the immune system. Its target gene SP4 codifies for a transcription factor involved in the development of the hippocampus. It has been associated with schizophrenia, major depression, and BD in several studies, and its encoded protein was shown to be stabilized by Li in rat cerebellar granule neurons. Our data suggest that miRNAs and their targeted genes involved in key processes of neuronal functioning and circadian rhythm might be involved in Li response in BD.


doi: 10.1016/j.euroneuro.2018.08.462

SU99

COMBINING DIFFERENTIAL GENE EXPRESSION ANALYSIS AND GENETIC DATA TO PREDICT TREATMENT RESPONSE

IN FIRST-EPISODE PSYCHOSIS

Stephane Jamain 1 , Réjane Troudet 2 , Wafa Bel Haj Ali 3 , Caroline Barau 4 , Anne Boland-Auge 5 , Jean-François Deleuze 5 , Marion Leboyer 6 , OPTiMiSE Consortium

1 Inserm U955, Psychiatrie Translationnelle 2 Inserm U955, Psychiatrie Translationnelle, UniversitéParis Est

3 Inserm U955, Psychiatrie Translationnelle, UniversitéParis Est, Fondation FondaMental 4 AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme de Ressources Biologiques, Créteil 5 Commissariat à l’Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry 6 Inserm U955, Psychiatrie Translationnelle, UniversitéParis Est, Fondation FondaMental, AP-HP, Hôpital H. Mon- dor – A. Chenevier, Pôle de Psychiatrie, Créteil

Background: Despite nearly fifty years of pharmacological research, the treatment of schizophrenia remains a challenge and clinical outcomes are still far from optimal. One of the major shortcomings in the current treatment of schizophrenia is that we have no valid criteria in clinical practice to predict who will respond to antipsychotic treatment and how long the treatment should be maintained before changing therapeutic strategy. The identification of blood-based biological markers of drug response with a good sensitivity and specificity would enable physicians to use these tests prior to choosing the antipsychotic treatment and therefore help the practitioner in his daily clinical practice. Methods: Through a European consortium on Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE), we investigated treatment response in 188 individuals with first episode psychoses. Using RNA sequencing, we characterized changes in gene expression after 4- week treatment with amisulpride according to treatment outcome. In addition, we genotyped subjects with DNA array to identify eQTLs, and used this eQTLs to propose a polygenic score to predict treatment outcome. Results: Out of the 16,264 genes expressed in peripheral blood mononuclear cells, we showed an enrichment in differentially expressed genes in subjects who will be in remission after 4-week amilsupride treatment, when compared with non-remitted patients. We thus demonstrated that 10%

of differentially expressed genes had a change in the expression level, which was correlated with clinical outcome. We identified many eQTLs that may explain transcriptional variations between responders and non-responders to treatment. The combination of these eQTLs in a polygenic score allowed the prediction of clinical improvement with an accuracy of 0.7 on the discovery sample of 135 individuals and 0.6 on an independent sample of 129 subjects. Discussion: We demonstrated here that amisulpride treatment affects gene expression in peripheral blood mononuclear cells, mainly in patients who will be in remission after four-week treatment, and that gene expression was associated with symptom improvement. We also showed that combining transcription and genetic data might help in the identification of biological signature to predict treatment response in first episode psychosis.


doi: 10.1016/j.euroneuro.2018.08.463



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SU100

INTEGRATIVE ANALYSIS OF OMICS SUMMARY DATA

TO IDENTIFY GENES ASSOCIATED WITH LITHIUM RE- SPONSE AND RELATED PHENOTYPES IN PATIENTS WITH

BIPOLAR DISORDER

Claudia Pisanu 1 , Nirmala Akula 2 , Consortium on Lithium

Genetics, Maria Del Zompo 1 , Alessio Squassina 1 , Francis J. McMahon 2

1 University of Cagliari 2 National Institute of Mental Health, National Institute of Health

Background: Summary-data-based mendelian randomization (SMR) is a novel approach that integrates genome-wide association (GWA) data with expression (eQTL) or methylation (mQTL) quantitative trait locus data to identify genes whose expression/methylation levels are associated with a complex trait due to a shared genetic variant ( 1,2 ). Using data from the International Consortium on Lithium Genet- ics (ConLiGen, 3 ) and the Psychiatric Genomics Consortium

(PGC), we applied SMR to pinpoint functionally relevant genes involved in lithium response in patients with bipolar disorder (BD) as well as in shared heritability between lithium response and susceptibility to schizophrenia (SCZ), reported previously ( 4 ). Methods: We applied the SMR method to 1) ConLiGen only [GWA results for > 2,000 Caucasian BD patients characterized for lithium response on both a categorical (Li-categ) and a quantitative (Li-quant) scale], and 2) ConLiGen + PGC

2 SCZ summary statistics (36,989 cases and 113,075 controls). We used the Bioconductor package ASSET, which provides meta-analysis statistics as well as the "best subset" of studies contributing to the signal, to identify SNPs relevant for both lithium response and SCZ. In order to evaluate the association between genes and lithium response or lithium response + SCZ in different tissues, we used eQTL data from: 1) two large studies conducted on peripheral blood; 2) a meta-analysis of 13 brain regions from GTEx V7, corrected for sample overlap with the SMR Meta-analysis of cis-eQTL in Correlated Samples (MeCS) method; and 3) post-mortem dorsolateral prefrontal cortex (DLPFC) samples from the CommonMind Consortium. mQTL summary data from peripheral blood were obtained from a meta- analysis of the Brisbane Systems Genetics Study (BSGS) and the Lothian Birth Cohorts (LBC) data (2). Results: No gene was found to be associated with lithium

response in the ConLiGen only dataset after correction for multiple testing. ASSET identified 2,816 and 3,208 SNPs for which both SCZ and Li-categ or Li-quant, respectively, contributed to the signal. SMR showed that the same SNP (rs2002375) was significantly associated with the Li-categ + SCZ trait, blood expression (P = 6.44E-09), and blood methylation levels (p < 2.1E-10) of Neuromedin B (NMB). In DLPFC, expression levels of three pseudo- genes located on chr 15 were significantly associated with the Li-categ + SCZ trait (CSPG4P11, rs142959789, pSMR = 4.33E-08; CSPG4P12, rs35677834, pSMR = 6.09E-08, and GOLGA2P7, rs12906983, pSMR = 7.34E-08). Blood expression of five genes located on chr 6 (BTN2A1, BTN3A2,

HIST1H2BK, HIST1H2BD and ZNF322) and 40 methylation probes were associated with Li-quant + SCZ through the same SNP (rs2237234). Discussion: This study points toward functionally relevant genes whose expression or methylation levels are associated with a shared predisposition to lithium response and SCZ. NMB encodes a bombesin-like peptide whose receptor is highly expressed in various brain regions and has been suggested, among other functions, to be a potential therapeutic target in memory and anxiety disorders. Although the results were significant only in blood, this might be due to the more limited sample sizes of publicly available brain eQTL data, compared to peripheral blood. Further analyses on larger eQTL and mQTL datasets will be needed to validate and extend these results.


References

Hou, et al., 2016. Lancet. International Consortium on Lithium Genetics, 2018. JAMA Psych. Wu, et al., 2018. Nat Commun. Zhu, et al., 2016. Nat Genet.

doi: 10.1016/j.euroneuro.2018.08.464

SU101

EVALUATION OF GLUTAMATE RECEPTOR GENE (GRID2, GRIK2) VARIANTS IN OBSESSIVE-COMPULSIVE DISOR- DER RISK, SYMPTOM SEVERITY, AND ANTIDEPRESSANT

TREATMENT RESPONSE

Amanda Lisoway 1 , Gwyneth Zai 2 , Vanessa F. Goncalves 1 , Clement Zai 1 , Arun K. Tiwari 1 , Karen Wigg 3 , James L. Kennedy 1 , Margaret (Peggy) Richter 3

1 Centre for Addiction and Mental Health

2 Centre for Addiction and Mental Health, University of Toronto 3 Sunnybrook Health Sciences Centre

Background: Convergent evidence increasingly supports abnormalities in glutamate signaling to play an important role in the pathophysiology and treatment response of obsessive- compulsive disorder (OCD). In fact, genes within the glutamate system have consistently appeared among the top hits in genetic studies of OCD risk and treatment response. In- terestingly, a recent meta-analysis of two consortia level genome-wide association studies (GWAS) of OCD reported polymorphisms within the glutamate ionotropic receptor delta type subunit 2 (GRID2) and the glutamate ionotropic receptor kainate type subunit 2 (GRIK2) genes to be among the top hits associated with the disorder. As a result, we at- tempted to replicate these findings by investigating GRID2 and GRIK2 single-nucleotide polymorphisms (SNPs), or tag SNPs, in a well-characterized sample of OCD patients. We hypothesized that GRID2 and GRIK2 SNPs would be associated with OCD when compared to the general population. We also investigated associations with OCD symptom severity and with antidepressant treatment response.


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Methods: OCD patients of European Caucasian ancestry (n = 150) were selected from a large retrospective sample collected in Toronto, Ontario, Canada. Quality control pro- cedures, genotype extraction from the Illumina Human610- Quadv1_B SNP array, and statistical analyses were performed using PLINK1.9 and Rv3.3.2. OCD symptom severity was evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and patients were naturalistically treated with up to six different SRIs, including five selective SRIs (fluoxetine, fluvoxamine, sertraline, paroxetine, and citalo- pram) and one SRI (clomipramine). Each medication trial was evaluated retrospectively for response and was rated categorically as either responder or non-responder using the Clinical Global Impression – Improvement (CGI-I) scale. A Eu- ropean Caucasian comparison sample was selected from The 1000 Genomes Project Consortium (EUR, n = 503). Pearson’s chi squared or Fisher’s exact test was used to investigate the relationship between the GRID2 and GRIK2 variant genotype distributions and the 1000 Genomes sample, as well as SRI response, while linear regression was used to investigate the effect of genotypes on symptom severity. Results: A significant difference in genotype distributions between our OCD sample and the 1000 Genomes comparison sample was observed for GRIK2 rs2852615 (X2 = 6.12, p < 0.05). The minor T allele was more frequent in OCD patients than in the comparison sample. Furthermore, OCD

symptom severity was also associated with rs2852615. Pa- tients with the TT genotype reported more severe OCD

symptoms than either the CC or CT genotypes (p < 0.05). However, these glutamate gene variants were not associated with antidepressant response (p > 0.05). Discussion: Our targeted study provides further evidence in support of a role for the glutamate GRIK2 gene in OCD

risk and symptom severity. While our preliminary results were not significant for antidepressant response, our pharmacogenetic data sample size was limited at the time of this analysis. Our work is continuing to add coverage of additional glutamate system genes, a larger sample size, as well as additional pharmacogenetic antidepressant response variables.


doi: 10.1016/j.euroneuro.2018.08.465

SU102

META-ANALYSIS OF CLOZAPINE-ASSOCIATED NEU- TROPENIA AND AGRANULOCYTOSIS

Bettina Konte 1 , J.T. Walters 2 , I. Giegling 1 , S. Legge 2 , A.F. Pardiñas 2 , D. Cohen 3 , M. Pirmohamed 4 , J. Tiihonen 5 , A.M. Hartmann 1 , J.P. Bogers 6 , J. van der Weide 7 , K. van der Weide 7 , A. Putkonen 8 , E. Repo-Tiihonen 8 , T. Hallikainen 8 , E. Silva 4 , O. Ingimarsson 9 , E. Sigurdsson 9 , James L. Kennedy 10 , Gerome Breen 11 , Patrick Sullivan 12 , Marcella Rietschel 13 , Hreinn Stefansson 14 , D.A. Collier 15 , Michael O’Donovan 2 , Dan Rujescu 1

1 Martin-Luther-University Halle-Wittenberg 2 Cardiff University

3 Mental Health Care Organization North-Holland North, Heerhugowaard

4 The University of Liverpool 5 Karolinska Institutet 6 Mental Health Services Rivierduinen

7 St Jansdal Hospital 8 University of Eastern Finland, Niuvanniemi Hospital 9 School of Health Sciences, University of Iceland, Landspi- tali University Hospital 10 Centre for Addiction and Mental Health


12 University of North Carolina at Chapel Hill 13 Central Institute of Mental Health

14 deCODE genetics 15 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

Background: The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses including neutropenia and agranulocytosis. Agranulocytosis and neutropenia occur in about 1% and 3%

of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors.

The Clozapine-Induced Agranulocytosis Consortium

(CIAC) identified two independent loci in the major his- tocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR = 0.19, P = 4.7E −14) and an amino acid change in HLA-B (158T) (OR = 3.3, P = 6.4E −10).

A meta-analysis of CIAC and CLOZUK identified a genome-wide association with rs149104283 (OR = 4.32, P = 1.79E −08), located in the intergenic region between transcripts of SLCO1B3 and SLCO1B7.

We sought to confirm previous findings and to identify novel variants by performing the largest meta-analysis to date including individuals of European ancestry. Methods: The CRESTAR project aimed at the development of pharmacogenetic biomarkers for schizophrenia and collected individuals from sites of Finland, Germany, Iceland, the Netherlands and the UK. We combined genome-wide association summary statistics of CIAC, CLOZUK and CRESTAR and performed a meta-analysis. Moreover, we imputed HLA alleles, amino acid changes and SNPs and performed a meta- analysis of CIAC and CRESTAR.

This CRESTAR project was funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement #279227. Results: The genome-wide association analysis revealed 9 genome-wide hits in 2 independent regions, confirm- ing the most associated marker from CIAC and the meta- analysis of CIAC and CLOZUK. The first marker rs149104283 (OR = 3.96, P = 6.38E-09) is located in the intergenic region between SLCO1B3 and SLCO1B7. The second marker rs41549217 (OR = 3.96, P = 1.57E-08) is located in HLA-B.

Analysis of imputed HLA variants identified 17 genome-wide hits in 3 independent regions. Two markers, HLA_DRB1_1601 (OR = 0.15, P = 9.55E-18) and SNP_B_31431998 (OR = 3.29, P = 5.85E-11), are in linkage disequilibrium to the variants genome-wide associated


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in CIAC. We further identified a novel independent SNP, rs3129891 (OR = 1.87, P = 2.92E-08), located 2kb downstream

to HLA-DRA. Discussion: Our study gives further evidence for the implication of a variant located in the intergenic region between members of a family of hepatic transporter genes (SLCO1B3 and SLCO1B7) previously implicated in docetaxel- induced neutropenia. Moreover, our study gives further evidence for the contribution of the HLA region. We found genome-wide associated variants in three independent regions: HLA-DQB1/DRB1, HLA-B and HLA-DRA. This suggests the implication of immune function as contributing process to this severe adverse drug response.


doi: 10.1016/j.euroneuro.2018.08.466

SU103

A ZEBRAFISH MODEL OF CLOZAPINE EXPOSURE: DRUG-INDUCED TRANSCRIPTOMIC CHANGES IN THE

BRAIN

Joana Viana 1 , Nick Wildman 2 , Eilis Hannon 3 , Audrey Farbos 1 , Paul O’Neill 1 , Karen Moore 1 , Konrad Paszkiewicz 1 , Ronny van Aerle 4 , Gregory Paull 2 , Eduarda Santos 2 , Jonathan Mill 1

1 University of Exeter 2 University of Exeter School of Biosciences 3 University of Exeter Medical School 4 Centre for Environment, Fisheries and Aquaculture Sci- ence (CEFAS)

Background: Schizophrenia (SZ) is a severe neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. About 20% of SZ patients are resistant to the commonly-prescribed antipsychotic medications used to treat disease symptoms. Clozapine is an atypical antipsychotic drug often prescribed to treatment-resistant SZ patients, although the functional pathways mediating its action are not well understood. Importantly, 40-70% of patients treated with clozapine show an inadequate response and there are sever side-effects. Understanding the molecular pathways involved in antipsychotic response will help in the development of new improved therapeutics that act on pathogenicity rather than just treating the acute manifestations of SZ. Methods: We exposed wild type zebrafish to two doses of clozapine and performed RNA-seq analysis in the brain of these animals to identify transcriptional changes occurring in response to clozapine. Weighted gene co-expression network analysis was performed to identify modules of co- expressed genes sensitive to clozapine exposure and pathway analysis was employed to identify over-representation of gene ontology (GO) terms in each of the clozapine exposure-associated modules. Results: We identified five genes showing significant gene expression changes in response to clozapine, including odc1, a gene previously implicated in SZ which shows changes in expression during brain development, angptl4 and slc16a9b.

Using network analysis, we identified fifteen modules of co- expressed genes which show a striking shift in module connectivity in response to the drug. These modules show over- representation of key GO terms, implicating processes such as calcium ion transport, cell-cell signaling, G-protein cou- pled receptor activity, ribosomal activity, and the regulation of transcription. Discussion: Our study highlights the utility of zebrafish as a model for assessing the molecular consequences of antipsychotic medications. Our data show marked behavioural effects induced by clozapine and significant transcriptomic alterations in important functional pathways in the brain.


doi: 10.1016/j.euroneuro.2018.08.467

SU104

GESTATIONAL INFLUENZA INCREASES THE RISKS OF

PSYCHOSIS IN ADULTS

Lin He 1 , Lei Cai 2

1 Shanghai Jiao Tong University 2 Bio-X Institutes, Shanghai Jiao Tong University

Background: Psychotic disorders are complex and caused by interplay of genetic and environmental factors. Influenza is a common infectious disease in humans, and it has been suggested that maternal influenza is an estimated risk factor for psychotic disorders, especially for schizophrenia. Methods: In view of conflicting results of this association in literature, we performed the strict meta-analysis to examine whether maternal influenza is a risk factor for psychosis in the children. Four ecological studies and three birth cohort studies were included in our meta-analysis. Results: It has been observed that the Risk Ratio (RR) of maternal influenza on psychosis is 1.062 (95% Confidence In- terval (CI) = 1.004-1.123) for the analysis of ecological studies and the RR is 1.564(95%CI = 1.051-2.324) for the analysis of birth cohort studies. Furthermore, a survey of pregnant women and fetus’ health in Nanjing of China indicated that only 1.5% of women received the influenza vaccine before pregnancy, 0.4% received it during pregnancy, and 5.1% were willing to receive the influenza vaccine if necessary. Discussion: These results showed that gestational influenza could increase mental disorders risks in adult offspring be- sides its established harms for gravidas. Results suggest it might be effective to increase attention to gravidas to pro- tect them from influenza infection through encouragement of vaccinations.


doi: 10.1016/j.euroneuro.2018.08.468




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SU105

BRAIN CELL TYPE-SPECIFIC POLYGENIC RISK IN

SCHIZOPHRENIA: INFLUENCE ON CLINICAL PHENO- TYPES

Sergi Papiol 1 , Nirmal Raman Kannaiyan 2 , Kristina Adorjan 1 , Monika Budde 1 , Ashley Comes 1 , Katrin Gade 1 , Urs Heilbronner 1 , Janos Kalman 1 , Eva Schulte 1 , Fanny Senner 1 , Richard Musil 2 , Alkomiet Hasan 2 , Moritz Rossner 3 , Peter Falkai 2 , Thomas G. Schulze 1

1 Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig Maximilian University 2 Ludwig Maximillian University, Munich

3 Ludwig Maximillian University, Munich, Max Planck Insti- tute of Experimental Medicine, Goettingen

Background: Genome-wide association studies (GWAS) have just started to shed light on the polygenic architecture of schizophrenia (SCZ) (Ripke et al., 2014; Pardiñas et al., 2018). Polygenic risk scores (PRS) summarize the joint risk effect of such common risk variants. However, little is known about the biological processes, cellular pathways and/or cell types underlying such a polygenic risk. A recent study has been able to map genomic SCZ risk loci onto specific brain cell types (Skene et al., 2018). Here we lever- age the cell type-specific expression profiles derived from

this single-cell RNAseq study and from our own experimental work using primary cells (Sharma et al., 2015) to generate cell type-specific PRS in our sample of SCZ patients. Subsequently we have analyzed the association of these PRS with the rich clinical information available in our sample. Methods: The sample under analysis consists of 700 SCZ (or schizoaffective) patients of German origin (KFO241/PsyCourse, Exercise II, RESIS & RIE cohorts). All these patients were genotyped using the Infinium PsychAr- ray Bead ¬Chip (Illumina®) and imputed using the standard SHAPEIT2/IMPUTE2 pipeline. Cell type-specific gene- sets definition: 1) the 5% most specifically expressed genes in each mouse brain cell type as published in the aforementioned single-cell RNAseq study (Skene et al., 2018); 2) by high-throughput RNAseq or deep proteomic analyses of primary mouse brain cells differentiated in vitro into different cell types (Sharma et al., 2015). PLINK 1.90 (Chang et al., 2015), SPSS and R were used for PRS calculation and data manipulation/analysis. The most recent SCZ GWAS was used as discovery sample for these calculations (Pardiñas et al., 2018). The association of cell type-specific risk profile scores with relevant clinical variables (psychopathology, cognition, functioning) was studied using linear models. Results: Our preliminary analyses show that psychopathology (PANSS positive score) in our sample of SCZ patients might be influenced by polygenic risk associated to Neural Progenitors cell type (P = 0.006, R2 = 0.9%). Results also suggest that the risk derived from Hypothalamic Dopaminergic Neurons (HDN) is associated with the overall functioning of these patients as measured by GAF. The genetic risk associated to HDN also seems to influence cognitive functions measured by Trail-Making-Test-A (TMT-A) and TMT-B tests, although the full SCZ PRS shows the best results in TMT-B analyses (P = 0.008, R2 = 1%).

Discussion: Our results suggest that clinically-relevant domains of SCZ might be influenced by cell-type differential polygenic risk. Our study will be extended with longitudinal analyses given the availability of follow-up data in these SCZ samples. Taken together, our results suggest that different brain cell types may have distinct roles in the clinical expression of SCZ.

Funding: this research was funded by the Deutsche Forschungsgemeinschaft (Clinical Research Group 241, Grant number SCHU 1603/4-1 & SCHU 1603/5-1; PsyCourse, Grant number SCHU 1603/7-1); Lisa-Oehler-Foundation.


doi: 10.1016/j.euroneuro.2018.08.469

SU106

IS GENETIC LIABILITY TO SCHIZOPHRENIA MAPPING

TO THE PSYCHOSIS CONTINUUM MODEL?

Evangelos Vassos 1 , Diana Prata 2 , Vishal Bhavsar 1 , Gerome Breen 1 , Marta Di Forti 1 , Matthew Kempton 1 , Robin Murray 1 , Matthew Hotopf 1 , Philip McGuire 1 , Cathryn Lewis 1


2 iMM Lisboa

Background: Genetic studies of binary outcomes, such as mental disorders, are based on the liability threshold model (LTM), in which a large number of genetic risk factors are summed to yield an overall ’liability’ score. The observed outcome is determined by whether the latent score is smaller or larger than the threshold. Polygenic risk scores (PRS) can give an aggregate measure of the genetic liability and the PRS for schizophrenia, given its high predictive ability, would be ideal to test subthreshold expression of the liability, if the outcome could be presented as a continuous or ordinal variable. Our hypothesis is that genetic liability to schizophrenia is associated with a gradient of psychosis expression, from ‘mild’ psychosis phenotypes to fully diagnosed schizophrenia. Methods: For this analysis we used European individuals from three samples recruited in South London. The first is a clinical sample of first episode psychosis and controls (GAP, N = 333), the second was a sample of individuals at high risk of psychosis with two years prospective follow up to establish conversion to psychosis (OASIS, N = 108) and the third, a sample of general population assessed with the Psy- chosis Screening Questionnaire (PSQ) for lifetime psychotic symptoms (SELCoH, N = 322). All samples had genome-wide genotyping and PRS was estimated using PGC2 schizophrenia summary results as the reference panel. Results: We observed a gradient of PRS for schizophrenia in the different groups we analyzed with the lowest PRS in controls, followed by general population individuals who reported psychotic symptoms, followed by people with at risk mental state who did not convert to psychosis and the highest PRS was observed in cases with first episode psychosis (overall regression p = 9.3E-10). To ensure that our results were not driven by the two extremes (cases and controls)


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we repeated the analysis excluding the controls (p = 0.009) and excluding the GAP case-control sample (p = 0.002). Discussion: Our results show that genetic liability for schizophrenia, as measured by the PRS, is associated with a gradient of psychosis phenotypes, supporting the psychosis continuum model. It is noteworthy that people from the general population with non-clinical psychotic symptoms and, more remarkably, individuals with at risk mental state who do not convert to psychosis have an intermediate genetic risk to schizophrenia, higher than controls and lower than cases.


doi: 10.1016/j.euroneuro.2018.08.470

SU107

MULTIPLE ENVIRONMENTAL HITS BEFORE ADULTHOOD

PREDICT VIOLENT AGGRESSION

Marina Mitjans 1 , Jan Seidel 1 , Martin Begemann 1 , Fabian Bockhop 1 , Anna Seelbach 1 , Vikas Bansal 1 , Janina Wesolowski 1 , Jorge Moya-Higueras 2 , Manuel Ignacio Ibáñez 3 , Generós Ortet 3 , Lourdes Fañanás 4 , Luise Poustka 5 , Jürgen L. Müller 6 , Bárbara Arias 4 , Hannelore Ehrenreich 7

1 Max Planck Institute of Experimental Medicine, Göttingen

2 University of Lleida, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBER- SAM) 3 Universitat Jaume I, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBER- SAM) 4 Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Men- tal (CIBERSAM) 5 University of Göttingen

6 University of Göttingen, Asklepios Hospital for Forensic Psychiatry & Psychotherapy 7 Max Planck Institute of Experimental Medicine, Göttingen, DFG Research Center for Nanoscale Microscopy and Molec- ular Physiology of the Brain (CNMPB)

Background: Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Following matched extreme group individuals ( ≤1 vs. ≥3 risk factors), we unexpectedly observed that high-risk subjects had > 5 times greater probability of forensic hospitalization than low-risk individuals. This intriguing discovery led us hypothesize that accumulation of risks before adulthood predisposes to violent aggression and criminal conduct, independent of mental illness. Moreover, we hypothesized that these environmental hits have lasting epigenetic alteration effects. Methods: We determined in 4 independent schizophrenia samples from the Göttingen Research Association for Schizophrenia (GRAS; discovery: n = 134 males; replication

I: n = 606 males, II: n = 320 males, III: n = 503 females) and in 2 general population samples from Spain (replication IV: n = 336; V: n = 229; both genders) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. As proxies of violent aggression, highly intercorre- lated measures were applied as available: (1) violent aggression severity score (VASS) based on questionnaires, interviews and charts; (2) conviction for bodily injury, sexual assault, murder, or forensic history; (3) psychopathy and aggression-hostility scores. To check for differential methylation patterns of 134 extreme group individuals regarding environmental hits ( ≤1 vs. ≥3 risk factors), whole blood-derived DNA was analyzed by Infinium HumanMethy- lation450K. Moreover, histone deacetylase 1 (HDAC1) mRNA levels in peripheral blood mononuclear cells (PBMCs) available from 142 male extreme group subjects ( ≤1 vs. ≥3 risk factors) were determined. Results: All environmental hits were by themselves marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). This accumulation effect was documented premorbid for schizophrenic individuals and likewise seen in healthy samples. An epigenome- wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in PBMCs of HDAC1 mRNA as ‘umbrella mediator’ of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Discussion: Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention. Acknowledgements: Max Planck Society, DFG (CNMPB), EX- TRABRAIN EU-FP7, N-RENNT, EU-AIMS, CIBERSAM; Instituto de Salud Carlos III (PI16/00998), Comissionat per a Universi- tats i Recerca del DIUE (2017SGR1577).


Reference

Mitjans et al. Molecular Psychiatry 2018.

doi: 10.1016/j.euroneuro.2018.08.471

SU108

INFLUENCE OF GENETIC VARIATIONS ASSOCIATED

WITH SCHIZOPHRENIA ON VERBAL FLUENCY

Tobias Wustmann, Tobias Ludwig, Bettina Konte, Annette Hartmann , Ina Giegling, Dan Rujescu

Martin-Luther-University Halle-Wittenberg

Background: Schizophrenia is one of the most devastating psychiatric disorders and presents with an unclear etiology. Multiple environmental and genetic factors have been identified as potentially contributing to the development of the disease. To shed more light on the genetic contributions,



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the PGC carried out the currently largest GWAS in 2014. Significant associations between schizophrenia and 128 linkage-disequilibrium-independent single-nucleotide polymorphisms (SNP) were found in 108 conservatively defined loci (Ripke et al. 2014). Patients suffering from schizophrenia usually experience additional neuropsychiatric deficits of which the disturbance of verbal fluency has been extensively described in the literature. The aim of this study was to examine schizophrenia-associated SNPs for their association with verbal fluency. Methods: The PAGES sample includes 1000 schizophrenia patients who were diagnosed according to DSM IV, and 3000 randomly selected psychiatrically healthy controls that performed a multi-stage selection procedure. Verbal fluency was assessed by the Regensburg word fluency test (RWT) in a subset of 361 cases and 559 controls. Genotype data was obtained using chip technology and imputation. After stringent quality controls, 107 loci were analyzed applying linear regression using an additive model. Results: Of the 127 SNPs tested, rs11191419 showed a significant association (P = 0.00025) with the word switch domain after multiple testing. Further evaluation in cases (P = 0.002257) and controls (P = 0.02287) separately also showed an association. The SNP is located 2 kb upstream

of the BLOC-1 Related Complex Subunit 7 (BORCS7) gene. In addition, rs3849046 localized in the Eukaryotic Transla- tion termination Factor 1 (ETF1) showed a suggestive association (P = 0.00071) with the same cognitive domain in the combined group. Discussion: The BLOC-1 Related Complex (BORC) is thought to be involved in lysosome localization and movement in peripheral regions of the cell. BORCS7, one of the 8 subunits of BORC, in particular is expressed in adult human neurons and astrocytes and shows upregulation in stem cells while they differentiate toward neuronal cell types. In addition, BORC

and Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1) share three proteins and thus may be functionally related. BLOC-1 has been suggested to play a role in neu- rite outgrowth and deficiencies in this complex may contribute to the neurodevelopmental etiology of schizophrenia. The results indicate an influence of the schizophrenia risk variant rs11191419 on verbal fluency performance in healthy subjects, thereby implicating an underlying mechanism which might be involved in such deficits in schizophrenia. Functional relevance of the associated SNP as well as replication in independent samples remains to be determined.


doi: 10.1016/j.euroneuro.2018.08.472

SU109

IS THE ERA OF CANDIDATE GENES X CANNABIS USE

REALLY DEAD?

Diego Quattrone 1 , Cathryn Lewis 2 , Alexander Richards 3 , Evangelos Vassos 2 , Charlotte Gayer-Anderson 4 , Laura Ferraro 5 , Giada Tripoli 2 , Bart Rutten 6 , Michael O’Donovan 3 , Craig Morgan 2 , Jim Van Os 7 ,

Pak Sham

8 , Ulrich Reininghaus 6 , Robin Murray 4 , Marta Di Forti 4

1 MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London


3 Cardiff University 4 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

5 University of Palermo 6 School for Mental Health and Neuroscience, Maastricht University 7 Maastricht University Medical Centre 8 The University of Hong Kong

Background: Historically, gene X environment examinations in psychotic disorders have employed candidate gene methods and environmental determinants impacting on similar biological mechanisms. However, genome wide association studies (GWAS) show that many variants associated with schizophrenia have a modest effect size on risk. In this respect, it is unclear whether the effect of cannabis on psychosis phenotypes is modified by a few genes, e.g. those involved in dopamine signalling, or by the overall genetic susceptibility to schizophrenia. Indeed, candidate gene approaches might be complementary to GWAS to test gene X cannabis interaction. We aimed to investigate the interactive effects of cannabis use on variants in DRD2 gene on: 1) the risk of developing first episode psychosis (FEP); and 2) the frequency of positive symptoms at FEP.

We undertook a replication study of previous Gene X Cannabis interactions for DRD2 (rs1076560); further, we tested interactions between cannabis use and any SNP associated with schizophrenia within DRD2 gene in the last Psychiatric Genomics Consortium (PGC) GWAS. Methods: We genotyped ∼830 FEP patients and ∼1200 controls recruited across six countries as part of the large EUGEI study. OPerational CRITeria system and Cannabis Experience Questionnaire were used for evaluating psychopathology and patterns of cannabis use. Dimensions of psychopathology, which included a specific dimension of positive symptoms, were estimated using multidimensional item response modelling in Mplus.

We tested for an interaction between risk allele count and daily cannabis use on: 1) the risk of psychotic disorder in the case-control study; 2) the positive symptom dimension in the case-only sample. Only one SNP in DRD2 was significantly associated with schizophrenia in the PGC study, so we tested for interaction with rs2514218, in addition to rs1076560.

These regression models, conducted in STATA 14, were adjusted for age, gender, ethnicity, 10 principal components (PC) for population stratification and SNP-environment and SNP-PC interaction terms. Results were corrected for multiple testing of four SNPs (p < 0.0125 as significance threshold). Results: We found a significant interaction between cannabis use and the rs2514218 in DRD2: daily cannabis users with one risk allele showed a 2.5-fold increased probability to suffer a psychotic disorder (OR = 2.43; 95%


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confidence interval [CI]: 1.52–3.89). We did not replicate previous findings of an interaction between cannabis use and rs1076560 in DRD2 for increasing psychosis risk (p = 0.092). Higher levels of positive symptoms were seen in FEP who were daily cannabis users with either rs2514218 (B = 0.34; 95% CI: 0.04–0.64; p = 0.024) or rs1076560 risk alleles (B = 0.54; 95% CI: 0.15–0.93; p = 0.006). Discussion: Our results suggest that dopamine signaling is implicated in cannabis associated psychosis, and, more specifically, that variation within the DRD2 gene may modulate the effect of cannabis use on psychosis phenotypes. Such findings require a replication for rs2514218.


doi: 10.1016/j.euroneuro.2018.08.473

SU110

ASSOCIATION STUDY OF SCHIZOPHRENIA WITH POLY- MORPHISMS AT FOUR CANDIDATE GENES

Anna Li 1 , Jiaxin Yuan 2 , John Ni 2 , Lili Zhang 2 , Steven Dubovsky 1 , Junzhe Xu 1

1 SUNY at Buffalo 2 VHAWNY Healthcare System

Background: Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptors, serotonin receptor and opiate receptor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the dopamine receptor 2 (DRD2), the serotonin 2A receptor (5HTR2A), the δ opioid receptor (OPRD), and the μ opioid receptor (OPRM) in 100 schizophrenic patients and 100 control individuals in an attempt to determine whether they have an association with the disease. Methods: Subjects:

The study sample consisted of 100 schizophrenia or schizoaffective disorder and 100 healthy individuals.

Extraction of genomic DNA: Blood samples were collected in anonymously identified

10-ml Vacutainer tubes (Becton Dickinson). DNA was prepared by a modified SDS/Proteinase K procedure.

PCR-RFLP The genotypes of polymorphism of the DRD2, 5HTR2A,

OPRD, and OPRM1 polymorphisms were assessed by the PCR- RFLP methods.

Statistical Analysis: Comparisons between sets of two populations used the

fisher exact test (FET). Significance was accepted at P <

0.05. Results: Our results suggest that the polymorphisms at the DRD2, 5HTR2A, OPRD gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in Al18G allele frequencies between schizophrenic and control groups for OPRM in the whole sample. The frequency of the Asn40 allele of OPRM was significantly increased in all schizophre-

nia patients (Fisher’s Exact Test P = 0.0000001418) as well as in schizophrenia patients with no history of substance use (Fisher’s Exact Test P = 0.0014). There were no associations of the Asn40Asp polymorphism of OPRM with substance dependence among schizophrenia patients and normal control. This allelic association suggests that the functional Asn40 variant of OPRM may play a role in susceptibility to schizophrenia. Discussion: Various investigations have evaluated the OPRM

polymorphism with regard to drug abuse vulnerability. Com- paring to other studies, our results did not reveal any associations of the Asn40Asp polymorphism of the OPRM with substance dependence among schizophrenia patients and normal control. However, contrary to other studies, we found high Asp40 allele among normal controls and high Asn40 allele among the schizophrenia patients. The frequency of the Asn40 allele was significantly increased in all schizophrenia patients (Fisher’s Exact Test P = 0.0000001418) as well as in schizophrenia patients with no history of substance use (Fisher’s Exact Test P = 0.0014) (tab.4). Although the sample size is small, we observed highly significant differences of the distribution of Asn40Asp polymorphism of OPRM among schizophrenia patients and normal control. To our knowledge this is the first study to show that a functional polymorphism in schizophrenia patients. Our association results provide evidence that the functional Asn40 variant of the OPRM receptor confers susceptibility to schizophrenia, further replication studies are necessary to confirm the present tentative allelic association.


doi: 10.1016/j.euroneuro.2018.08.474

SU111

GENOME-WIDE ANALYSIS OF COPY NUMBER VARI- ATION IN A SOUTH AFRICAN XHOSA POPULATION

AFFECTED BY SCHIZOPHRENIA

Lerato Majara , Celia Van Der Merwe, Mary-Anne Mufford, Emile Chimusa, Dan Stein, Raj Ramesar

University of Cape Town

Background: Schizophrenia (SCZ) is a mental disorder whose genetic etiology is largely unknown. It is well- established that both genome-wide common single nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs) increase risk of developing schizophrenia – with CNVs having a larger effect size. The Psychiatric Genetics Consortium (PGC) recently identified 17 CNVs significantly associating with SCZ in over 41 000 subjects, largely of Eu- ropean descent. With drug development as a goal in mind, it is necessary to determine if risk variants found in one population have the same association in other populations to minimize disparities in global mental healthcare that may arise. Thus, we aim to investigate genome-wide copy number variation in a cohort of 200 schizophrenia cases and 200 controls from South Africa. Methods: DNA was extracted from whole blood using the salting out method. All DNA samples were genotyped on



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the Affymetrix CytoscanHDÒ chip with over 2million CNV probes. Cel files were analyzed using the Chromosome Anal- ysis Suite (ChAS) where CNVs were defined as any genomic aberration of a size larger than 20kb covered by at least 10 probes. Samples that did meet the QC requirements (MAPD

score > 0.25, snpQ < 15 and waviness SD > 0.12) were excluded. CNVs that occurred within 100kb of the telomere on either end of the chromosome were also excluded. Results: In contrast to the PGC analysis, ours did not reveal the pattern of a higher frequency of risk CNVs in cases; and protective CNVs in controls. Of the 17 loci analyzed, no CNVs were found in seven loci in the South African sample. This could be that these CNVs are so rare, that a larger sample size is required to for better resolution or could mean that the CNVs in the South African population are smaller than expected given the shorter blocks of linkage disequilibrium. Discussion: Our results suggest that there might common risk CNVs between the PGC and the South Africa samples, in agreement with the argument for common risk variants between populations. However, they do also suggest that there might in fact be population-specific variation that cannot be ignored. Together with data from whole exome sequencing, the data obtained from this analysis will be used in the design of a Xhosa-specific copy number dense chip. This data may contribute towards identifying genetic variation in an African population and provide insight into additional CNVs that may be associated with SCZ.


doi: 10.1016/j.euroneuro.2018.08.475

SU112

DOES POLYGENIC RISK SCORE FOR SCHIZOPHRENIA

IMPACT ON JUMPING TO CONCLUSIONS? PRELIMINARY

FINDINGS FROM THE EU-GEI CASE-CONTROL STUDY

Giada Tripoli 1 , Diego Quattrone 2 , Charlotte Gayer-Anderson 2 , Victoria Rodríguez 2 , Natasha Benzian-Olsson 2 , Laura Ferraro 3 , Caterina La Cascia 3 , Crocettarachele Sartorio 3 , Lucia Sideli 3 , Fabio Seminerio 3 , Daniele La Barbera 3 , Craig Morgan 2 , Pak Sham

4 , Marta Di Forti 2 , Robin Murray 2


2 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

3 University of Palermo 4 The University of Hong Kong

Background: Jumping to conclusions (JTC) is a reasoning and data gathering bias that results in the tendency to require less evidence and make hasty decisions. Preliminary work on reasoning bias focused primarily on the association with delusions, although jumping to conclusions has also been found in non-deluded schizophrenia (SZ) patients. Lit- erature to date has shown JTC as a well-established bias in psychosis even at First Episode Psychosis (FEP), after remission, and in individuals with at risk mental state. Further- more, JTC has been found to be associated with proneness to psychotic-like experiences in the general population. In-

teresting findings showed also an association with lower cognitive functioning in psychotic patients, and some degree of stability of JTC over the course of illness. Overall, findings to date could suggest a shared genetic liability between the occurrence of JTC and psychosis.

The present study aims to investigate in a sample of FEP and healthy controls: 1) environment, cognitive, and clinical factors associated with JTC bias 2) whether the addition of SZ Polygenic Risk Score (PRS) explains any further variance in the model. Methods: We analyzed data on JTC (Beads task 60:40) in a sample of 503 FEP and 959 population controls for which genetic information was available, recruited as part as the EU-GEI study across UK, Netherlands, France, Spain, Italy and Brazil. In the first step, logistic regressions have been performed to predict JTC respectively in cases and controls considering as covariates: age, gender, level of education, IQ, country, frequency of cannabis use, population density, positive symptoms, and 20 principal components (PCs) for population stratification. In the second step, we estimated a model adding SZ PRS to the aforementioned terms. Results: Individuals coming from Brazil were about 6 times more likely to jump to conclusions in case group (OR = 6.69; CI 95% = 2.23-20.06; p = 0.001) and around 5 times among controls (OR = 4.76; CI 95% = 2.28-9.93; p < 0.001). Likewise, age and low IQ were found to be associated with JTC in both cases (age: OR = 1.04; CI 95% = 1.02-1.06; p < 0.001. IQ: OR = 0.98; CI 95% = 0.94-0.98; p < 0.001) and controls (age: OR = 1.04; CI 95% = 1.02-1.05; p < 0.001. IQ: OR = 0.96; CI 95% = 0.95-0.97; p < 0.001), although a small effect size was observed. A similar trend was detected regarding the association with increased positive symptoms in cases (OR = 1.27; CI 95% = 1.02-1.57; p = 0.02), whereas controls presenting higher level of psychotic-like experiences showed about a 3-fold risk to jump to conclusions (OR = 2.6; CI 95% = 1.12- 6.02; p = 0.02). In addition, being female resulted as significant predictor in cases only (OR = 1.87; CI 95% = 1.16-3.01; p = 0.009).

Finally, PRS for schizophrenia seemed not to be associated with jumping to conclusions in both groups, therefore it does not add any variance explained in the abovemen- tioned model (Cases: R2 = 0.27; Controls: R2 = 0.22). Discussion: This study suggests that the occurrence of jumping to conclusions cannot be explained by schizophrenia genetic underpinnings using polygenic risk score strategy. However, these preliminary results identified interesting environment, cognitive, and clinical factors associated with JTC bias.


doi: 10.1016/j.euroneuro.2018.08.476

SU113

NRG1 GENETIC RISK SCORE PREDICTS ANTISAC- CADE AND MEMORY-GUIDED SACCADE LATENCY IN

SCHIZOPHRENIA

Elizabeth Thomas 1 , Susan Rossell 2 , Jessica Myles 1 , Eric Tan 3 , Erica Neill 4 , Sean Carruthers 3 , Philip Sumner 3 , Kiymet Bozaoglu 5 , Caroline Gurvich 1



60 Abstracts

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1 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash Univer- sity, Melbourne 2 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash Uni- versity, Brain and Psychological Sciences Research Centre (BPsyC), School of Health Sciences, Swinburne University, St Vincent’s Mental Health

3 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash Uni- versity, Brain and Psychological Sciences Research Centre (BPsyC), School of Health Sciences, Swinburne University 4 Brain and Psychological Sciences Research Centre (BPsyC), School of Health Sciences, Swinburne University 5 Bruce Lefroy Centre for Genetic Health Research, Mur- doch Children’s Research Institute, University of Melbourne

Background: Neuregulin-1 (NRG1), involved in neuronal development, migration, myelination and synaptic plasticity, has been identified in numerous linkage association studies as a promising candidate gene for schizophrenia risk. Sev- eral single nucleotide polymorphisms (SNPs) in the NRG1 gene have been associated with schizophrenia and cognitive deficits. In particular, saccadic (eye movement) deficits are one of the most replicated findings in schizophrenia. Previous research investigating NRG1 and saccadic performance has looked at single SNPs. However, genetic liability for schizophrenia is multifactorial, with contributions of multiple risk variants. Therefore, analysis of genetic risk scores may better capture the genetic contribution to cognitive performance in schizophrenia compared to single SNP analysis which have small effect sizes. This study aims to investigate whether the genetic risk score for NRG1 predicts saccadic performance in patients and controls. Methods: One-hundred and sixty-six Caucasian participants (44 patients with schizophrenia/schizoaffective disorder and 122 healthy controls) completed the antisaccade and memory-guided saccade tasks, which engage spatial working memory and inhibition processes. The variables analyzed for both saccade paradigms were error rate, latency (i.e. reaction time) and gain (i.e. spatial accuracy). Partici- pants were also genotyped for five NRG1 SNPs; rs10503929, rs3924999, rs2466058, rs35753505 and rs6994992. Genetic risk scores were then created by assigning one point to the score for each risk allele that a participant had at each of the five polymorphic results, resulting in a genetic risk score ranging from zero to ten. Independent T-tests were conducted to demonstrate significant differences in saccadic performance between patients and controls. Correlations were then conducted separately for patients and controls to observe relationships between risk score and saccade performance and significant variables were subsequently included in standard multiple regressions. Results: Antisaccade and memory-guided saccade latency and error rate were significantly different between patients and controls (p < 0.001). Both antisaccade and memory- guided saccade gain did not significantly differ between the two groups. In patients, the NRG1 risk score significantly correlated with antisaccade latency (p = 0.037, r = 0.389) and explained 15.1% of the total variance of the model. The NRG1 risk score also significantly correlated with memory-

guided saccade latency (p = 0.018, r = 0.435) and explained 18.9% of the total variance of the model. There was no relationship between NRG1 risk score with antisaccade or memory-guided saccade error rate or gain in patients. There was no relationship between NRG1 risk score with antisaccade or memory-guided saccade latency, error rate or gain in controls. Discussion: This is the first study to use risk scores to observe the relationship between NRG1 and eye movement performance. Preliminary findings indicate that a risk score derived from NRG1 SNPs significantly predicts antisaccade and memory-guided saccade latency in schizophrenia. This identifies NRG1 as a potential candidate gene for cognitive impairment in schizophrenia. This finding also supports the use of aggregate genetic risk scores to investigate multifactorial disorders. Future research should investigate other genes associated with saccadic performance in schizophrenia.


doi: 10.1016/j.euroneuro.2018.08.477

SU114

ASSOCIATE STUDY OF SCHIZOPHRENIA WITH THE

POLYMORPHISMS OF GLUR6 KAINATE RECEPTOR GENE

GRIK2

Junzhe Xu 1 , Jianxin Yuan 2 , Anna Li 3 , Lili Zhang 3 , John Ni 3 , Stiven Dubovsky 1

1 School of Medicine, SUNY at Buffalo 2 SUNY at Buffalo 3 VHAWNY Healthcare System

Background: The dysfunction of glutamatergic neurotrans- mission is one of the plausible hypotheses for the pathogenesis of schizophrenia. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21, a schizophrenia susceptibility region, as suggested by multiple linkage studies. The aim of this study is to clarify the contribution of four polymorphisms of the glu -tamate receptor ionotropic kainate 2 gene with schizophrenia Methods: After informed consent was obtained, 100 schizophrenia patients and 100 control subjects were enrolled in this study. All subjects were administered the Di- agnostic Interview for Genetic Studies by a research assis- tant with extensive training in this interview. Blood samples were collected in anonymously identified 10-ml Vacutainer tubes (Becton Dickinson). DNA was prepared by a modified SDS/Proteinase K procedure (Gusells et al., 1979). We genotyped polymorphism rs1338165, rs728024, rs1408768, rs1335042 of the glu -tamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6) with the PCR-RFLP methods. The PCR products were digested by restricted enzyme. Results: We observed no significant associations with the schizophrenia and polymophism rs728024 (Chi-Square Test p-value 0.628135), rs1408768 (Chi-Square Test p-value 0.465334) and rs1335042 (Chi-Square Test p-value 0.448). However, there is a significant association between the poly-


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morphism rs1338165 and the schizophrenia (Chi-Square Test P = 0.0449). Discussion: Schizophrenia is characterized by thought disorders, hallucinations and delusions. Many hypotheses have been made to explain the pathophysiology of schizophrenia and several studies suggest that dysfunctions in metabolism

of neurotransmitters, such as dopamine, serotonin and glutamate, are directly implicated in the pathogenesis of this severe illness. A growing number of studies focused the attention on dysfunctions in glutamatergic pathway as a major susceptibility factor for schizophrenia [12]. An increase in the basic metabolic activity along the glutamatergic ax- ons has been demonstrated by PET scan studies in the cingulate cortex and hippocampal region of schizophrenic patients. [13, 14]. Genetic studies have shown a high linkage at chro -mosome 6q16-21. Among the genes located in this region is the glu -tamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia [2]. A significant decrease of GRIK2 mRNA expression level has been reported in schizophrenic brains [2]. These lines of evidence suggest that GRIK2 is a strong candidate for the susceptibility locus for schizophrenia. Furthermore, abnormal synaptogenesis involving glutamatergic synapses, was recently shown to be associated with schizophrenia [15]. Several studies report decreased kainate receptor expression (including GRIK2) in the brain of schizophrenic patients [2, 16]. In this study we tested for an association of schizophrenia with the glu -tamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6) using 4 common SNAPs rs1338165, rs728024, rs1408768 and rs1335042. We found there is not association with rs728024, rs1408768 and rs1335042. However, the frequency of the polymorphism

of rs1338165 was significantly increased in schizophrenia patients. This allelic association suggests that the functional polymorphism rs1338165 of the glu -tamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6) may play a role in susceptibility to schizophrenia. Further study with larger sample sizes is required.


doi: 10.1016/j.euroneuro.2018.08.478

SU115

INTERACTION EFFECTS OF CHILDHOOD ADVERSITY

AND GLUTAMATERGIC POLYGENIC RISK SCORE ON

BRAIN STRUCTURE AND COGNITION IN SCHIZOPHRENIA

Suriati Mohamed Saini 1 , Sam Mancuso 2 , Chenxing Liu 2 , Md Shaki Mostaid 2 , Vanessa Cropley 3 , Tamsyn Van Rheenen 4 , Ian Paul Everall 5 , Chad Bousman 6 , Christos Pantellis 3

1 University Kebangsaan Malaysia Medical Centre 2 University of Melbourne 3 Melbourne Neuropsychiatry Centre, University of Mel- bourne 4 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash Uni- versity, Brain and Psychological Sciences Research Cen- tre (BPsyC), School of Health Sciences, Swinburne Univer-

sity, Melbourne Neuropsychiatry Centre, University of Mel- bourne 5 Institute of Psychiatry, Psychology and Neuroscience, King’s College London

6 University of Calgary

Background: Childhood adversity increases the risk of cognitive deficits and schizophrenia. Gene and environment factors synergistically contribute to possible aetiology, but evidence also points to variable effects of adversity on brain development. Glutamate regulates synaptic plasticity during brain development. However, the study of its link with childhood adversity is limited. The present study aimed to examine from a brain developmental perspective the extent to which i) structural brain volume mediates the association between childhood adversity and cognition in schizophrenia, and ii) glutamatergic genetic variation moderates the association between childhood adversity and cognition via brain structure as mediator. Methods: Participants were 176 cases and 118 healthy controls from the Australian Schizophrenia Research Bank. Childhood adversity was measured using the Childhood Ad- versity Questionnaire. Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsy- chological Status, Controlled Oral Word Association Test, Letter-Number Sequencing test, and the Wechsler Test of Adult Reading. We assessed intracranial volume, subcortical volume, and brain lobe volume as regions of interest, adjusting for total brain volume. PLINK was used to calculate a weighted polygenic risk score (PRS) as the sum of the schizophrenia risk alleles carried by an individual. Mediation and moderated mediation analyses were tested using the PROCESS macro for SPSS with 5000 bootstrap iterations. The goodness of fit test was determined using structural equation modelling. Results: Schizophrenia participants performed worse on cognitive measures in all domains and were 1.2 times more likely to experience childhood adversity. Mediation modelling revealed that reduced intracranial volume mediated the effects of childhood adversity on the poor performance of delayed memory in schizophrenia, independent of the effect of IQ. Meanwhile, subcortical brain volume mediated poor performance of working memory in schizophrenia with childhood adversity. Schizophrenia participants with high glutamatergic PRS and a history of childhood adversity showed increased frontal lobe volume. These effects were not observed in schizophrenia with low PRS and healthy controls. Discussion: We found mediating effects of global and subcortical brain volume on the memory of schizophrenia participants who had experienced childhood adversity. The present findings also suggest possible resilience effects of glutamatergic variation on frontal lobe in schizophrenia with a history of childhood adversity.


doi: 10.1016/j.euroneuro.2018.08.479



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SU116

PEPTIDE SHARING BETWEEN SCHIZOPHRENIA-RELATED

PROTEINS AND THE INFLUENZA A VIRUS MAY OFFER A

LINK BETWEEN IMMUNITY AND PSYCHOTIC DISORDERS

Adrianna Kepinska , Thomas Pollak, Robin Murray, Conrad Osamede Iyegbe

Institute of Psychiatry, Psychology & Neuroscience, King’s College London

Background: Immunity and influenza infection are implicated in schizophrenia by historical epidemiological evidence and recent genome-wide association study (GWAS) findings. One potential mechanism underlying the association is molecular mimicry; a model whereby specific sub- regions of brain proteins become targets of a misdirected immune response due to sequence sharing with the influenza virus. This study evaluates the profile of sequence sharing between influenza and the translated protein products of schizophrenia GWAS hits. The 1918 influenza virus is used, given that it was associated with an increased number of psychosis cases observed following the 1918 pandemic. The study aims to provide insights into links between influenza and schizophrenia. Methods: All sequences used were downloaded from the UniProt database ( http://www.uniprot.org/ ) and included: 110 coding proteins identified based on 110 out of 145 reported GWAS significant associations for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; GWAS proteins) and the 1918 influenza virus proteome. 14 themed reference sets were created for comparison from the following genes: null GWAS genes (with GWAS p-value > .75); central nervous system (CNS)- expressed genes, e.g. in the brain; non-CNS genes expressed in various tissues, e.g. in lung; and foetal genes expressed in the first trimester, a key neurodevelopmental period (BrainSpan Atlas; http://www.brainspan.org/ ). Risk protein alignments of 5 amino acids were evaluated systematically with a combination of Python scripts and the Batch Pep- tide Match software (downloadable from https://research. bioinformatics.udel.edu/peptidematch/index.jsp ). In each reference set, the 100 subgroups served as independent replicates against which the rates of sequence sharing in the single GWAS group were compared statistically. Results: Differences between GWAS proteins and reference sets were non-significant when mean frequencies of sequence sharing between the influenza virus proteome and GWAS proteins were compared to mean frequencies of sequence sharing between the influenza virus proteome and reference sets proteins (z range = 0.000666-0.384720755, p > .05). However, when frequencies of sequence sharing were compared per each influenza virus protein, the frequency of sequence sharing between GWAS proteins and the influenza virus proteins were significantly higher than the frequency of peptide sharing between reference sets and the influenza virus proteins ( χ2 (1) = 131.984, p < .001, two-tailed), in particular when frequencies of sequence sharing between GWAS proteins and the influenza virus hemagglutinin and matrix protein 1 were compared to

frequencies of sequence sharing between the influenza virus proteins and reference sets. Discussion: This evidence suggests that peptide sharing oc- curs between schizophrenia-related proteins and specific proteins integral to the influenza virus rather across the entire virus proteome. Future research should establish the biological relevance of this finding and assess whether an immune reaction against particular schizophrenia-related proteins is a plausible mechanism contributing to psychotic disorders. Also, exploring peptide sharing in different influenza strains could offer insights into links between influenza pan- demics, maternal infection, and psychosis. Elucidating peptide sharing might have implications for schizophrenia risk management and safe influenza prevention.


doi: 10.1016/j.euroneuro.2018.08.480

SU117

POLYGENIC RISK SCORE AND CNV BURDEN INFLUENCES ON BROADLY AND NARROWLY DEFINED PSYCHOSIS

Eirini Zartaloudi 1 , Johan Hilge Thygesen 1 , Aritz Irizar 1 , Stella Calafato 1 , Andrew McQuillin 1 , Jasmine Harju-Seppanen 1 , Isabelle Austin-Zimmerman 1 , Anjali Bhat 1 , Robin Murray 2 , Elvira Bramon 1

1 University College London


Background: Over 100 genetic loci have been associated with psychosis and their combination into a polygenic risk score (PRS) is a strong disease predictor. Several copy number genetic variants (CNVs) have also been associated with psychosis. Aims: (i) To examine whether schizophrenia and bipolar PRS and CNV burden can distinguish between people with psychosis, their unaffected first-degree relatives and unrelated healthy controls, (ii) to investigate whether there is a relationship between CNV burden and PRS. Methods: The effects of the burden of large and rare CNVs and the PRS are investigated in a multi-center family based genetic association study with 11521 individuals. Results: Preliminary results show that CNV burden, as measured by the number of genes affected, and PRS for both schizophrenia and bipolar disorder are associated with broadly defined psychosis. The schizophrenia PRS explained a higher proportion of the variance in the diagnosis status compared to the bipolar PRS. Discussion: A better understanding of PRS and CNVs influences on the risk of developing psychosis could be useful towards early detection and treatment of psychosis, which leads to better outcomes and prognosis.


doi: 10.1016/j.euroneuro.2018.08.481

http://www.uniprot.org/

http://www.brainspan.org/

https://research.bioinformatics.udel.edu/peptidematch/index.jsp



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SU118

NETRIN ISOFORM VARIATION AS A FACTOR IN

SCHIZOPHRENIA

James Wilcox 1 , David Briones 2

1 University of Arizona 2 Texas Tech University

Background: Introduction Netrin variation in the neocortex has been postulated as

an etiology for schizophrenia (1, 2, 3, 4, 5). Such isoform

changes in NTNG have been associated with subtle neurological changes including variation of NMDA receptor-mediated postsynaptic responses, associated with psychosis (5, 6,7, 8). Netrins have multiple isoforms and allelic subtypes (2, 3, 4). NTNG1 is located on chromosome 1p13.3, a linkage zone associated with psychosis in studies of schizophrenia (4, 5). This study examines isoforms of NTNG1 in an attempt to examine allelic variation contributes to risk for psychosis. Permission for this study was obtained from the appropriate university ethics board. NTNG1 isoforms were selected as the analysis of interest based upon the positive findings of previous studies. Methods: 400 subjects with schizophrenia and 400 controls were evaluated. Three SNPs (rs4132604-SNP1, rs2218404- SNP2 and rs1373336-SNP3 were genotyped in this study. All samples were run blind to diagnosis. (reverse). A case- control design was used for statistical comparison with the SPSS. Deviation from the Hardy-Weinberg equilibrium was examined using the Chi Square test and pairwise linkage disequilibrium. Results: Strong pairwise linkage disequilibrium was found between the three SNPs; rs4132604, rs2218404 and rs1373336 (all [D‘] > 0.60). Significant differences of haplotype containing rs4132604 alleles were found between cases and controls with GG (p = .001) and TG (P = .0001) between rs4132604 and rs2218404, GGT (P = .0001), TGT (P = .01) among the three SNPs. The allele frequencies of rs4132604 in psychotic cases was much different than among healthy controls (p = .0001). Discussion: Our study demonstrated positive association between rs4132604 and schizophrenia on the basis of the alleles (chi square = 7.912, p = .005) and genotype (chi square = 7.772, p = .021) frequency distribution differences between cases and controls. The occurrence of allele G was much higher than T alleles in rs4132604. This suggested that the chromosome that contained allele G (odds ratio = 1.423, 95% CI = 1.102-1.731) had a possible contribution to the susceptibility to schizophrenia.

Our findings replicate early work on Netrin variations in psychosis Our study was among the first to document this association in Caucasian population and suggests that previous Asian work may be generalizable to other populations.


doi: 10.1016/j.euroneuro.2018.08.482

SU119

GENETIC OVERLAP AND CAUSALITY AMONG

SCHIZOPHRENIA AND SUBSTANCE USE: FINDINGS FROM THE GENOMIC PSYCHIATRY COHORT

Roseann Peterson 1 , Tim Bigdeli 2 , Jacquelyn Meyers 2 , Giulio Genovese 3 , Michele Pato 2 , Steven McCarroll 4 , Carlos Pato 2 , Genomic Psychiatry Cohort Consortium, Ayman Fanous 2

1 Virginia Commonwealth University 2 SUNY Downstate Medical Center 3 Broad Institute 4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard

Background: Despite epidemiological and genetic reports on the association between schizophrenia and substance use, there has been limited research on the nature of causality with respect to these psychiatric disorders, particularly in cohorts of diverse ancestry. Methods: We used the latest results from the Genomic Psychiatry Cohort (GPC) to dissect genetic overlap and causality between schizophrenia and tobacco and cannabis use. The GPC has undertaken the largest collection effort among persons of African ancestry to date, with 6,152 cases with a diagnosis of schizophrenia and 3,918 screened controls among 12,548 admixed African individuals with genotype data and includes participants of Latino (1,234 cases and 3,090 controls) and European ancestry (6,046 cases and 4,534 controls). Using data from the GPC, we estimated genetic correlations between schizophrenia and substance use traits including cross-ancestry associations. We also tested whether polygenic risk scores constructed from

the results of the Tobacco and Genetics Consortium (TAG) meta-analyses of smoking behaviors and the International Cannabis Consortium (ICC) were associated with schizophrenia risk or substance use behaviors among schizophrenia cases. Results: Results indicated significant genetic correlations of schizophrenia with smoking initiation, cigarettes-smoked- per-day, and age-of-onset of smoking, as well as lifetime cannabis use. Comparing substance use behaviors among schizophrenia cases to the general population (TAG, ICC), we observe positive genetic correlations for smoking initiation and cannabis use. Similarly, TAG and ICC based polygenic risk scores were significantly associated with smoking behaviors and cannabis use among schizophrenia cases. Additionally, we report on the first cross-ancestry genome- wide association studies of smoking and cannabis use behaviors among schizophrenia cases. We will also explore whether these traits show genetic correlation because of shared genetic effects independently on each trait (i.e., pleiotropy) or because of causal processes as indexed by genetic instruments through Mendelian randomization. Discussion: Results provide additional support for a partially shared genetic basis for schizophrenia and substance use and for substance use among schizophrenia patients and the


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general population and suggest possible population differences in patterns of genome-wide pleiotropic effects.


doi: 10.1016/j.euroneuro.2018.08.483

SU120

COMPLEMENT COMPONENT (C4) STRUCTURAL VARI- ANTS IN THE RISK AND CLINICAL CHARACTERISTICS OF

SCHIZOPHRENIA

Cheng Chen , Julia Woo, Jennie Pouget, Clement Zai, James L. Kennedy

Centre for Addiction and Mental Health

Background: Schizophrenia (SCZ) is a heritable psychiatric disorder which affects approximate 0.7% of the population. The disease is characterized by both positive and negative symptoms, as well as decline in cognitive functioning. SCZ often becomes clinically apparent from late adolescence to early adulthood and severely impacts the quality of life. Al- though treatments exist, the development of preventive or curative interventions is hindered by the lack of mechanistic understanding of the pathophysiology of SCZ. The complement component 4 (C4) gene has been identified as one of the largest effect size markers for SCZ risk (Sekar et al., 2016). Sekar et al. have shown the longer version of C4A (C4AL) is linked with higher neural C4A expression which is associated with higher SCZ risk. The C4 gene discovery opened a new direction in SCZ research. In this study, we aim to replicate the findings from Sekar et al. and further explore the relationship between C4 genetics variants and SCZ, as well as treatment response in SCZ. Methods: 537 subjects with SCZ or schizoaffective disorder were recruited from our CAMH hospital. Clinical and demographic information was gathered through structured clinical interviews (SCID) and chart review. The copy numbers of the C4A, C4B, C4L, and C4S in each sample were determined using ABI TaqMan copy number variation (CNV) protocol. In addition, C4 CNV data on healthy controls were obtained on a small preliminary sample (n = 93) from the Sekar et al. paper. All statistical analyses were conducted using IBM SPSS software. Results: Following Bonferroni correction, our SCZ subjects had significantly lower copy numbers of C4A compared to control group (p = 0.03), whereas there was no difference in C4L CNV between groups. Among patients, there was no significant relationship between C4 CNV and any of the following: age of onset; symptom severity; Global Assessment of Function; and presence of symptoms such as delusions, hallucinations, disorganized speech or behavior, catatonia, alogia, avolition, inappropriate affect, and affective flat- tening. Discussion: In the brain, C4 plays a crucial role in synaptic pruning. The process of synaptic pruning reaches a peak in late adolescence which is the same time when SCZ becomes clinically apparent. Synaptic pruning also explains the deficit of synaptic connections, as well as the cognitive decline that is commonly seen in SCZ. Sekar et al. previously

identified the combination of C4A and the retroviral inser- tion creating long version (C4AL) as a risk haplotype for SCZ. We found mixed preliminary evidence for a link between the C4 haplotype component and SCZ risk. Further, we found no evidence to support the relationship between the C4 CNV variation and SCZ phenotypes. More detailed analyses involving the C4 haplotype (as opposed to CNV) and neural C4A expression are needed to further clarify the role of C4 in SCZ risk and phenotypes.


doi: 10.1016/j.euroneuro.2018.08.484

SU121

GENETIC VARIATION RELATED TO IMMUNE FUNCTION

AND SCHIZOPHRENIA RISK: EVIDENCE FOR EFFECTS ON

COGNITION

Gary Donohoe 1 , Jessica Holland 1 , David Mothersill 1 , Aiden Corvin 2 , Michael Gill 2 , Donna Cosgrove 1 , Derek Morris 3

1 National University of Ireland Galway 2 Trinity College Dublin

3 Neuroimaging and Cognitive Genomics (NICOG) Centre, School of Psychology, National University of Ireland Galway

Background: Altered immune response is associated with many psychiatric disorders, but whether and how

these changes confer increased risk remains unclear. In schizophrenia, robust association between illness risk and the MHC region general, and complement component 4 (C4) specifically, has been demonstrated, along with evidence from both gene enrichment and other genetic analysis highlighting the broader role of genetic variation in additional immune related networks to schizophrenia risk. Methods: In a series of recent studies from our group, we examined the effects of immune-related genetic variation, implicated in neural function both behaviorally in samples of ∼1200 cases and controls, and cortically in samples of ∼150 cases and controls for whom GWAS data was available. We further investigated immune gene-set enrichment analysis in three datasets (PGC, ENIGMA, and UK Biobank). Results: We found that (1) increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected) and a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected); (2) variation in a geneset associated with both increased Schizophre- nia risk and immune function (CSMD1, DPP4, SRPK2, TRIM8, STAT6, FES, EP300, TNFRSF13c) were associated with both variation in both episodic memory and general cognitive ability; and (3) in an enrichment analysis of immune gene- sets using MAGMA, a gene set related to complement function emerged as showing significant enrichment for cognition. Discussion: Based on these findings we conclude that schizophrenia risk associated with variation within immune related genes is likely to be conferred at least partly via



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effects on cognition, and that genetic variation within the complement system may have a particularly important role.


doi: 10.1016/j.euroneuro.2018.08.485

SU122

SCHIZOPHRENIA AND ITS SEVERE COGNITIVE SYMP- TOMS ARE ASSOCIATED WITH POLYGENIC ALTERATION

OF RETINOID SIGNALING

William Reay 1 , Joshua Atkins 1 , Yann Quide 2 , Vaughan Carr 2 , Melissa Green 2 , Murray Cairns 1

1 University of Newcastle 2 University of New South Wales

Background: The biologically active retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. This is supported by preliminary trials of a retinoid receptor agonist, Bexarotene, as an adjuvant and the association of five common variants in proximity to members of this pathway at genome wide significance. We suspect that the polygenic burden of common variation, along with high impact rare variants, in retinoid loci may be clinically significant, particularly for the cognitive symptoms of the disorder. Methods: Schizophrenia cases and controls from the Aus- tralian Schizophrenia Research Bank were genotyped via SNP microarray (N = 676). Cases were clustered by a battery of cognitive measures to derive a severe cognitive deficit (CD) subtype, along with a cognitively spared (CS) subpopulation. Summary statistics from the 2014 schizophrenia GWAS were obtained and the effect of common variants aggregated in a panel of 107 retinoid genes using MAGMA. Genes with nominal significance (PMAGMA < 0.05) were selected to construct a retinoid polygenic risk score (PRS), and its enrichment tested in schizophrenia along with CD

cases only. Rare variant (Frequency < 0.01%) association from a subset who underwent whole genome sequencing (N = 469) was calculated in these prioritized genes with the sequence kernel association test (SKAT-O). The impact of rare variant burden in significant genes after correction on neuroanatomy was investigated for patients with MRI imaging available (N = 210). Voxel-based morphometry (VBM) and multivariate source-based morphometry (SBM) tested the effect of rare variant burden on grey matter concentration. Non-coding rare variation was also mapped to genome wide predicted retinoic acid response elements (DR5-RARE), to which retinoid receptors bind. Results: We revealed evidence of a polygenic variant signal in retinoid genes from the schizophrenia GWAS with 22 retinoid genes nominally significant. Retinoid PRS in these genes was associated with schizophrenia in the ASRB cohort covaried for genome wide PRS (P = 1.78 × 10-4, χ^ 2 test of residual deviance). However, it did not differentiate CD and CS patients. In contrast, in cases with marked cognitive deficit (CD) rare variants were enriched in the retinoic acid receptor gene RARB compared to the CS subpopulation

after Bonferroni correction (PCorr = 0.029). RARB rare variant burden was also associated with reduced posterior cerebellar volume in the CD group (PCorr = 0.023), and with covariation in grey matter (R2 = 0.638, P = 0.049), particularly in the cerebellum and parietal regions. Further, we demonstrated preliminary evidence that rare variation impacting DR5-RARE, and potentially retinoid receptor binding, is enriched in schizophrenia (P = 0.0226). Discussion: Our findings suggest that retinoid signaling is disrupted by common variation in schizophrenia, while patients with poor cognitive performance are affected dis- proportionately by high impact rare variants. RARB variant burden was associated with reduced cerebellar volume in a region with both known implications for cognition and vulnerability to retinoid pathologies. Downstream dysregulation of retinoid signaling may also be conferred by rare variation altering DR5-RARE binding motifs. Future work will examine whether patients with high genomic risk of retinoid disruption would benefit from targeted pharmacological intervention.


doi: 10.1016/j.euroneuro.2018.08.486

SU123

PREDICTION OF MORTALITY USING DNA METHYLA- TION AGE IN SCHIZOPHRENIA

Kaarina Kowalec 1 , Eilis Hannon 2 , Georgina Mansell 3 , Joe Burrage 3 , Jonathan Mill 3 , Patrick Sullivan 4

1 Karolinska Institutet 2 University of Exeter Medical School 3 University of Exeter 4 University of North Carolina at Chapel Hill, Karolinska In- stitutet

Background: DNA methylation levels vary over the course of life. Surprisingly, pre-selected combinations of methylation array probes can be used to estimate “methylation age” (mAge), which usually correlates highly with chronological age. Occasionally, mAge is greater than chronological age, and this difference is a replicated predictor of all- cause mortality. Schizophrenia (SCZ) is associated with significantly higher mortality and decreased life expectancy. We tested the association between mAge and mortality in individuals with SCZ and controls, hypothesizing that mAge predicts subsequent death in SCZ. Methods: We selected 190 SCZ cases and 190 controls sam- pled between 2004-2010 from the Sweden Schizophrenia Study. SCZ cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts, and ≥5 antipsychotic prescriptions. Controls are those with no lifetime psychotic disorder or antipsychotic prescriptions. Subjects were selected if deceased ( ≥1 year after sampling) or alive ( ≥3 years after sampling) as determined using the Swedish Cause of Death Register (4-10 years of follow-up). We excluded those who died by suicide, acci- dent, or violence. Cases and controls were matched 2:1 on sex and 5-year age band. DNA from whole blood was as-



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sayed on the Illumina MethylationEPIC array. mAge was calculated using the Hannum, Horvath, and Levine clocks. We regressed mAge on chronological age to obtain a measure of age acceleration for each clock. Using Cox proportional hazards regression, the association between age acceleration and mortality was tested: SCZ deceased vs. SCZ alive, SCZ deceased vs. controls alive, and SCZ deceased vs. controls deceased. Results: Among individuals with SCZ, 126 died and 63 were alive, whereas for the controls, 127 died and 62 were alive, following quality control of the methylation data. We did not find a significant association between any of the three age acceleration clocks and mortality in SCZ (adjusted P = 0.16-0.62). We had 88% power to detect the effect size for mAge and mortality. Discussion: We did not confirm our hypothesis that age acceleration would predict subsequent mortality in people with SCZ. Further analyses of these data will be presented at the conference.

Disclosures: Emerald Lake Safety - Consultant, Self. Fraser Health Multiple Sclerosis Clinic - Honoraria, Self.

doi: 10.1016/j.euroneuro.2018.08.487

SU124

DE NOVO VARIANTS IN CHILDHOOD-ONSET-PSYCHOSIS

Mitra Sato 1 , Marinos Kyriakopoulos 2 , Anthony James 3 , Niran Okewole 4 , Anna Need 1

1 Imperial College London

2 Bethlem Royal Hospital 3 Warneford Hospital 4 Neuropsychiatric Hospital, Ogun State

Background: Childhood-Onset Psychosis (COP) is a very rare (prevalence 0.2 in 100,000 in the UK) and debilitating disorder characterised by the onset of psychotic symptoms before age 14. COP has been shown to be neurobiologically continuous with the adult-onset form of the disease, schizophrenia. Copy number variant (CNV) examination has previously revealed a higher frequency of pathogenic CNVs in the childhood-onset form, in comparison to adult-onset schizophrenia. Methods: In order to elucidate the de novo variant spectrum

in this rare group of patients we performed exome sequencing on 17 trios with COP. Results: We identified 13 de novo variants in 9/17 probands, across 13 genes. We found a coding de novo mutation rate of 0.76 per exome in this cohort, which is lower than the previously reported rate of 1.17 per exome in the de novo study of COP and adult-onset schizophrenia (1.03 per exome). This decrease in de novo rate is most likely due to the enrichment of positive family history for psychiatric illness in the studied cohort. In addition, we found that the ratio of non-synonymous (n = 10) to synonymous (n = 3) de novo variants in COP probands were consistent with the previous de novo study of COP.

A total of 10 de novo damaging (CADD > 15) missense and protein truncating variants were identified. We found 3 de novo protein truncating variants (2 frameshifts and 1

splice acceptor) in loss of function intolerant genes; KDM5C, PIK3CD and PIAS4. These genes have previously been shown to harbour truncating and missense mutations in previous sequencing studies of adult-onset schizophrenia, as well as autism and the deciphering developmental disorders (DDD) cohort. KDM5C is a particularly interesting candidate as it is also a Mendelian disease gene responsible for a range of X-linked intellectual disability phenotypes.

In addition to the loss of function variants, we identified 7 damaging (CADD > 15) missense variants, majority (6/7) of which have been shown to harbour truncating and missense mutations in previous sequencing studies of adult- onset schizophrenia and other neurodevelopmental disorders. Four of these de novo variants were in genes intolerant to missense variation (RVIS < 35) and very deleterious to protein function (CADD > 20 and polyphen > 0.9). These were GPR107, RANBP1, LEMD3 and NEDD9. Interestingly the previous de novo study of COP reported GPR153 as a novel COP candidate, which is in the same gene family as GPR107. The majority of these genes are involved in neuronal and synaptic function and are therefore interesting candidates for follow up functional studies. Discussion: This work suggests that de novo variants could make up an important aspect of the genetic architecture that underlies the development of childhood onset psychosis.


doi: 10.1016/j.euroneuro.2018.08.488

SU125

MODELLING THE IMPACT OF SCHIZOPHRENIA GWAS LOCI DURING HUMAN BRAIN DEVELOPMENT USING

SPATIO-TEMPORAL GENE EXPRESSION DATA

Sathish Periyasamy 1 , Bryan Mowry 2

1 Queensland Brain Institute 2 Queensland Brain Institute, The University of Queensland

Background: Epidemiological data and the recent brain- specific molecular and genetic discoveries have revealed that early neurodevelopmental activities have been implicated in pathogenesis. Mapping the genetic, epigenetic and environmental factors affecting the human brain development will be fundamental to identifying disease mechanisms in schizophrenia. Remarkably many collaborative GWAS studies have recently identified discrete risk loci associated with schizophrenia. The vast majority of these are situated in non-coding regions such as enhancers and promoters that affect gene regulation. Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Moreover, heritability tends to be enriched in transcriptionally- active regions in relevant tissues. Numerous -omics data sources have emerged to aid the development of spatio-temporal gene expression models. We adopted a molecular systems approach to reconstruct the regulatory activities in the developing human brain using time-series gene expression and gene regulatory data. Methods: Brain eQTL datasets were used to identify the regulatory regions in PGC2-SCZ significant loci. Various reg-



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ulatory databases such as RegNetwork were used to identify transcription factors (TF), transcription cofactors (TcoF) and miRNAs present in all PGC2-SCZ loci. We reconstructed the dynamic TF/miRNA regulated interaction network using dynamic regulatory event minor (DREM) that incorpo- rates developmental transcriptome data obtained from post conception to adulthood (i.e. prenatal and postnatal) in 16 brain regions. Integrated analysis of time-series gene expression data and static regulatory interaction data reconstructed dynamic developmental activities regulated by TFs and miRNAs. Significant regulators in every brain region were identified and mapped to the disease-associated TFs/miRNAs obtained from the genome-wide significant loci. ReMap was used to identify statistical enrichment of TF bindings present within PGC2-SCZ associated regulatory regions compare to random expectations. This permitted to prioritise TFs based on over-represented bindings at the disease-associated loci. Results: More than 600 genome-wide significant variants and 49 TFs associated with gene regulation were identified from PGC2-SCZ GWAS loci. Of these, one TF was identified as a significant regulator impacting the prenatal developmental activities across all brain regions; another seven TFs were significant in some of the brain regions. Most regulatory activities were observed during prenatal stages of brain development. The target genes of these TFs are involved in cell differentiation, proliferation and mitogenesis. ReMap analysis revealed that some TF bindings were over-represented at the disease-associated loci. Discussion: The purpose of this analysis was to associate crucial TFs identified in schizophrenia GWAS loci with TFs involved in neurodevelopment. Some of the over-represented TFs could be the core genes having the most direct effect on schizophrenia pathogenesis. To re-analyze future GWAS studies with the latest versions of -omics databases, we developed an adaptable bioinformatic pipeline integrating significant regulators identified from DREM analysis with TFs/miRNAs obtained from GWAS loci.


doi: 10.1016/j.euroneuro.2018.08.489

SU126

TARGET SEQUENCING OF GENES INVOLVED IN NEU- RODEVELOPMENT FROM WHOLE GENOME COPY NUM- BER VARIATION ANALYSIS OF JAPANESE SCHIZOPHRE- NIA

Hiroki Kimura 1 , Branko Aleksic 1 , Kanako Ishizuka 2 , Chenyao Wang 1 , Itaru Kushima 1 , Norio Ozaki 1

1 Nagoya University 2 Nagoya University Hospital

Background: Recent large-scale whole genome sequencing and copy-number variant (CNV) analysis with Schizophre- nia (SCZ) and Autism Spectrum disorder (ASD) samples have revealed that rare single-nucleotide variants (SNVs) and CNV exert significantly larger effects than common single- nucleotide polymorphisms (SNPs). Despite large effect size of the CNV, the pathological roles of CNV remains largely un-

known, partially because it remains unclear how the functional change of the genes within the regions of the CNVs lead to the pathogenesis of neuropsychiatric disorders. On the other hand, there is growing evidence that rare SNVs, discovered from deep sequencing of SCZ candidate genes, may have large effect sizes, as well as contribute to understanding of the pathogenesis of neuropsychiatric disease through in vitro and in silico functional analysis. Thus, sequencing the candidate genes from CNV analyses of neuropsychiatric disorders may be a promising method for elucidating the pathophysiology of neuropsychiatric disorders such as SCZ and ASD. Methods: To discover rare variants with large effect size and to evaluate their role in the pathophysiology of SCZ and ASD, we sequenced the genes involved in neurodevelopment in the several regions of CNV associated with Japanese SCZ by Sanger or Next Generation sequencing method (Thermo Fisher Scientific Ion PGM) with 370 SCZ. Nonsense mutations, missense mutations, small insertions/deletions and canonical splicing site variations with an allele frequency of < 1% were selected from the sequencing data. Then, we performed genetic association analysis using a large number of unrelated individuals, and in silico structural analysis and in vitro functional assays of the variants that could have large effects. Results: Through the mutation screening, prioritizing the discovered variants and genetic association analysis, we found that rare SNVs in genes (NDE1 in chr16p13.11, RTN4R in chr22q11.2) related to neurodevelopment have statistically significant association with SCZ. Based on in silico 3D

protein structure analysis of RTN4R-R292H and NDE1-S214F, we predicted that the variants could be located at the site of protein-protein interactions. We discovered a reduced interaction by the GST-binding assay as our in silico structural analysis predicted. Furthermore, in vitro functional assays showed that the rare mutations affected the neurodevelopment. Discussion: This study strengthens the evidence for association between rare variants in the regions of CNV associated with SCZ and ASD and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.


doi: 10.1016/j.euroneuro.2018.08.490

SU127

INVESTIGATION OF MATERNAL EFFECTS, MATERNAL- FETAL INTERACTIONS AND PARENT-OF-ORIGIN EFFECTS (IMPRINTING) FOR CANDIDATE GENES POSITIONALLY

ON CHROMOSOME 18Q21, USING MOTHERS AND THEIR

OFFSPRING WITH SCHIZOPHRENIA

Byung Dae Lee , Kang Yoon Lee, Je Min Park, Young Min Lee, Eunsoo Moon, Hee Jeong Jeong, Soo Yeon Kim, Hwagyu Suh, Young In Chung, Dae Wook Kim, Chan Hum Park

Pusan National University Hospital

Background: A popular design for the investigation of such effects, including effects of parent-of-origin (imprinting), maternal genotype, and maternal-fetal genotype interac-



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tions, is to collect DNA from affected offspring and their mothers (case/mother duos) and to compare with an appropriate control sample. We investigate the effects of estimation of maternal, imprinting and interaction effects using multimodal modeling using parents and their offspring with schizophrenia in Korean population. Methods: We have recruited 27 probands (with schizophrenia) with their parents and siblings whenever possible. We analyzed 20 SNPs of 7 neuronal genes in chromosome 18 for DNA samples that was checked for the data quality and genotype error. We used EMIM analysis program for the estimation of maternal, imprinting and interaction effects using multimodal modeling. Results: Of analyzed 20 SNPs, significant SNP (rs 2276186) was suggested in EMIM analysis for child genetics effects (p = 0.0225438044) (and child genetic effects allowing for maternal genetic effects: p = 0.0209453210) with very stringent multiple comparison Bonferroni correction. Addi- tionally, analysis results for maternal genetic effects (and maternal genetic effects allowing for child genetic effects) was presented. Discussion: Alternative methodologies in genetic research are required with many methodological limitations in approaches evaluating the correlations between genotyping and phenotyping. Epigenetics and gene-environment interactions are represented underlying statistical genetics. Our results are the pilot study for epigenetic study in mental disorder and help to understanding and use of EMIM (Estimation of Maternal, Imprinting and interaction effects using Multi- nomial modelling) statistical genetics analysis program with many limitations including small pedigree numbers.


doi: 10.1016/j.euroneuro.2018.08.491

SU128

OPEN BOARD

SU129

TYPE 2 DIABETES MELLITUS IN PATIENTS WITH

SCHIZOPHRENIA: THE EFFECT OF (POLY)GENETIC

RISK SCORE OF SCHIZOPHRENIA AND TYPE 2 DIABETES AND ANTIPSYCHOTIC MEDICATION USE

Tesfa Habtewold 1 , Richard Bruggeman 2 , Edith J. Liemburg 1 , Md. Atiqul Islam

3 , Behrooz Z. Alizadeh 1

1 University of Groningen, University Medical Center Groningen

2 University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Re- search Center 3 Shahjalal University of Science and Technology

Background: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underlying pathophysiologic mechanisms are yet to be found, although it can be argued that antipsychotic usage and genetic susceptibility are involved in the emergence of T2D.

We, therefore, aimed to investigate whether (poly)genetic risk score for T2D and SCZ, and antipsychotic drugs are associated with T2D among patients with SCZ. Methods: Data of 820 patients with non-affective psychosis were extracted from the Genetic Risk and Outcome of Psychosis (GROUP) cohort in the Netherlands and Bel- gium. A weighted (poly)genetic risk score was calculated by summing the phenotype associated risk alleles across genetic loci, which were multiplied by the corresponding effect sizes, estimated from a meta-analysis of genome- wide association studies. Multiple linear regression analysis was applied to identify factors associated with glycated hemoglobin (HbA1C), which is a proxy measure for T2D. Results: The genome-wide significant genetic risk score of T2D (p-value = 0.002) was significantly associated with HbA1C and explained 3.4% of the variance in HbA1C. The polygenic risk score of SCZ and high metabolic risk antipsychotics explained 0.7% and 0.1% of the variance of HbA1C, although the association was not significant (p- value = 0.31 and p-value = 0.89, respectively). In addition, gender, daily cigarette smoking and history of cardiovascu- lar diseases were significantly associated with HbA1C. To examine shared genetic susceptibility, we tested another model using GRS-T2D instead of HbA1C as an outcome variable and only PRS-SCZ as a predictor. Consequently, the genetic overlap was 0.1% and there was no significant association ( β = 0.01, 95% CI = -0.02-0.04, p-value = 0.50). Discussion: The public health burden of the comorbidity between SCZ and T2D is high and leads to poor functioning and quality of life, poor prognosis of both diseases and prema- ture death due to complications. Thus, our study has important implications for clinical practice and evidence-based medicine, as three-fourths of T2D cases in patients with SCZ were undiagnosed. In addition, our study helps to advance understanding the underlying pathogenetic mechanisms of this comorbidity. Since the genetic biomarker of T2D was used, which is believed to be sensitive to alteration due to genetic liability, GRST2D can also be used as a tool for the prediction of T2D among patients with SCZ. Altogether, this may ultimately contribute to improve quality of later life and healthy aging in patients with psychotic disorder.


doi: 10.1016/j.euroneuro.2018.08.493

SU130

ANALYSING SCHIZOPHRENIA RISK VARIANTS IN NRXN1

USING FUNCTIONAL AND MATURE NEURONAL CUL- TURES FROM PATIENT-DERIVED IPS CELLS

Matthias Jung , Annika Majer, Jessica Reinsch, Jovita Schiller, Annette Hartmann, Bettina Konte, Ina Giegling, Dan Rujescu

Martin-Luther-University Halle-Wittenberg

Background: Schizophrenia is a complex psychiatric disorder that affects nearly 1% of the world’s population. We previously described deletions in neurexin 1 (NRXN1) to be associated with schizophrenia. Neurexins are transcribed from



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of three different genes in mammalians (NRXN1, NRXN2, and NRXN3) and are widely expressed in excitatory as well as inhibitory neurons, in particular in presynaptic terminals required for normal synapse function. Neurexins are neuronal adhesion molecules functioning as a receptor for neuroligins. Disruption of the neurexin 1 gene leads to changing properties of synapses and to the disruption of neuronal networks. Deletions in α-neurexin 1 are involved in altered neural connectivity. Methods: For further analysis of neurexin1-related disease mechanisms, we used an in vitro cell culture model based on human induced pluripotent stem cells (iPS cells). iPS cells have been obtained by reprogramming of B-lymphoblastoid cell lines (B-LCLs) that have been obtained from two schizophrenia patients carrying CNVs in NRXN1. In one case the deletion is located in promotor region and exon 1-6 and in the other case in exon 4-6. Patient derived induced pluripotent stem cells and healthy control cells were differentiated into mature and functional cortical neurons by using a four-step culture system. The analysis focused on altered gene expression and function of signaling molecules of NRXN1 related cellular pathways using IF, WB, flow cy- tometry, and metabolic phenotyping. Results: Transcript and immunofluorescence analysis confirmed the successful generation of glial and neuronal cells (TUBB3, STX, GFAP, and CD68). The presence of different neuronal subtypes such as GABAergic and glutamatergic neurons was demonstrated (SLC17A7, GAD1, GABBR1, GRIA2, and GRIN1). Immunofluorescence-microscopy verified the presence of NRXN1 and its interaction partners such as neuroligins. Discussion: In summary, the characterization of iPS cells bearing patient-specific genetic information and their differentiation into schizophrenia-specific neurons has potential to elucidate the impact of specific genetic variations in NRXN1. It also carries major opportunities to enable the identification of potential therapeutic targets in schizophrenia.


doi: 10.1016/j.euroneuro.2018.08.494

SU131

THE ROLE OF BEHAVIOUR IN THE GENETIC AETIOLOGY

OF SCHIZOPHRENIA

Paul O’Reilly , Jessye Maxwell, Adam Socrates, Evangelos Vassos

King’s College London

Background: Exploiting schizophrenia PRS, we performed a survey of shared aetiology between schizophrenia and a range of behavioural traits across the UK Biobank data. A key objective was to investigate the degree of mediation of schizophrenia by behaviour. Methods: Among the top findings was an association between schizophrenia PRS and risk-taking (P = 2 × 10-26), and so we hypothesized that part of the genetics of schizophrenia may be the genetics of risk-taking, leading

to migration, urbanicity of drug-taking. Given the availability of locations of birth and current residence, cross- referencing with population density data from the National Office of Statistics, we were able to investigate migration patterns, and substance abuse from the corresponding ICD

code. We further investigate the complex relationship between migration, urbanicity and schizophrenia. Results: Self-reported risk-taking is associated with UK-based internal migration, in terms of distance- moved (P = 3 × 10-123) and increasing population density (P = 7 × 10-37), and also with substance abuse (P = 8 × 10- 74), and schizophrenia PRS were also associated with each of these. We also report results from Mendelian Randomiza- tion conducted to test the hypothesized pathway from risk- taking genetics, via migration/drug-taking, to schizophrenia. Discussion: Behaviour plays a potentially important role in schizophrenia aetiology, and given the high heritability of many high-risk behaviours, the large portion of the genetics of schizophrenia is the genetics of relevant patterns of behaviour, such as risk-taking, migration and substance abuse.


doi: 10.1016/j.euroneuro.2018.08.495

SU132

CANNABIS USE AND SCHIZOPHRENIA: CAN GENET- ICS TELL IF IS IT “THE CHICKEN OR THE EGG”?

Marta Di Forti 1 , Beatrice Wu 1 , Diego Quattrone 1 , Alexander Richards 2 , Michael O’Donovan 2 , Craig Morgan 1 , Jim van Os 3 , Bart Rutten 4 , Paul O’Reilly 5 , Evangelos Vassos 5 , Giada Tripoli 1 , Pak Chung Sham

6 , Robin Murray 1 , Cathryn Lewis 1

1 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

2 Cardiff University 3 University of Utrecht 4 School for Mental Health and Neuroscience, Maastricht University 5 King’s College London

6 Centre for Genomic Sciences, University of Hong Kong

Background: Cannabis use remains the most widely used recreational drug worldwide. In the USA several states have legalized its used and in some for medicinal use. Never- theless, a significant amount of Epidemiological and experimental studies have reported that cannabis use, especially frequent use of high potency varieties, increases the risk of psychosis.

Therefore, it becomes a research priority to identify those individuals at greatest risk to develop psychosis following cannabis use. Methods: Using the genetic and cannabis use data from a large first episode case-control study (N = 2300), we aim 1) to use Polygenic Risk Scores for Psychosis (PRS) to test if genetic load for psychosis increases the individual vulnerability to the psychotogenic effects of cannabis; 2) to test



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if those with high PRS for psychosis are also more likely to smoke cannabis and with high frequency. Results: Subjects with a PRS for schizophrenia in the highest quartile had a 7-fold increase in the odds to suffer from a psychotic disorder (Adj OR = 7.0; 95% CI 3.46-14.25). Regular, users of high potency cannabis did not differ on PRS profiles from occasional users or never users (Pearson chi2(3) = 5.6001 Pr = 0.133). We did not find a significant interaction between PRS X cannabis use in influencing risk to Psychosis. Discussion: Summary scores, such as PRS for Schizophrenia, do not explain individual susceptibility to the psychotogenic effects of cannabis. More research is needed to investigate the role of genes mapping at biological plausible pathways.


doi: 10.1016/j.euroneuro.2018.08.496

SU133

AKT1 GENE AND CANNABIS USE: ANALYSIS OF MOD- ERATION EFFECTS ON COGNITIVE PERFORMANCE IN

NON-CLINICAL SUBJECTS

Mar Fatjó-Vilas 1 , Jordi Soler 2 , Manuel Ignacio Ibáñez 3 , Jorge Moya 4 , Generós Ortet 3 , Maria Guardiola 5 , Lourdes Fañanás 2 , Bárbara Arias 2

1 FIDMAG Hermanas Hospitalarias Research Foundation

2 University of Barcelona, CIBERSAM

3 Universitat Jaume I, CIBERSAM

4 University of Lleida, CIBERSAM

5 FIDMAG Research Foundation, CIBERSAM, University of Barcelona

Background: Genetic factors may explain the differences in individual sensitivity to the psychosis-inducing effects of cannabis (Di Fort et al. 2012). Investigation of the interaction between cannabis use and genetic variability on relevant intermediate phenotypes for psychosis, such as cognition, may help to clarify the underlying mechanism of such sensitivity.

AKT1 gene has been identified as a candidate for gene × cannabis interaction (van Winkel et al. 2011). It codes for a protein kinase that is a key-signalling molecule downstream of the dopamine receptor and hence has a plausible biological mechanism for interacting with cannabis to confer an increased risk of psychosis.

Our aim was to analyze the effect of lifetime cannabis use, AKT1 variability and their interaction on cognitive performance in non-clinical individuals. Methods: The sample consisted of 389 Spanish non-clinical subjects (43% males, mean age = 21.1(2.19)). Subjects were interviewed on their cannabis frequency of cannabis consumption and then dichotomized as users (29%) or non- users (71%). Attention (d’ shapes/digits of CPT-IP), Verbal Memory (percentile scores of WMS-R) and Working Memory (perseverative errors of WCST) were selected as the cognitive outcome measures based on previously described effect of cannabis use on these tasks (Henquet et al. 2006; van Winkel et al. 2011). The intellectual quotient (IQ) was es-

timated using the Block Design and Information subtests of the WAIS-III. Two SNPs at AKT1 were genotyped (rs2494732 and rs1130233), individual haplotypes were estimated, and each subject was defined as a carrier of zero, one or two copies of the haplotype CA (rs2494732(C)-rs1130233(A)). Multiple linear regressions were used to test the effect of genetic and environmental factors and their interaction on cognitive scores (adjusted for sex, age, IQ and the use of other drugs). Results: Cannabis use was not associated with any cognitive measure. A main effect of AKT1 was found on CPT d’ shapes (rs2494732: β= 0.14 p = 0.003; rs1130233: β= 0.16 p < 0.001; haplotype: β= 0.17 p < 0.001) but not on d’ digits. Individuals with the genotype CC for rs2494732, the AA for rs1130233 and with two copies of the CA haplotype presented better d’ shapes performance. Evidence for AKT1 x cannabis interaction was not found. Discussion: Our findings indicate the AKT1 effect on a measure of sustained attention independently of cannabis use in healthy subjects. This result is in line with: i) several studies that have reported the AKT1 involvement on different cognitive domains (e.g. Tan et al. 2008, Pietiläinen et al. 2009); ii) evidence on the role of AKT1 in normal dopaminergic transmission and expression of dopamine-associated behaviours (Beaulieu et al. 2005, 2007). Therefore, it is plausible that variability in AKT1 may result in changes in responses to dopamine receptors stimulation and dopaminergic deregulations (Arguello and Gogos 2008).

Despite the AKT1 moderation of cannabis-induced cognitive alterations has been previously reported in psychotic disorders (van Winkel et al, 2011); we have not observed such effect in non-clinical subjects. Acknowledgements: i) Plan Nacional Sobre Drogas, Min- isterio de Salud (2008/090), ii) ISCIII through de project PI15/01420 (co-funded by European Regional Development Fund/European Social Fund) "Investing in your future"), iii) 2014SGR1636, iv) APIF-UB JS and CD16/00264 to MF-V.


doi: 10.1016/j.euroneuro.2018.08.497

SU134

A CASE REPORT OF A CAT-EYE SYNDROME PRESENTING

WITH AN AUTISM SPECTRUM DISORDER

Sofia Barbosa 1 , Marta Lages 1 , Nuno Borja-Santos 1 , Patrícia Gonçalves 1 , Ana Barreta 2 , Teresa Maia 1

1 Hospital Prof. Doutor Fernando Fonseca, E.P.E. 2 Joaquim Chaves Saúde

Background: Cat-Eye syndrome (CES) is a genomic disorder associated with a highly variable phenotype. Concerning its psychiatric manifestations, the most described is mental retardation.

CES results from trisomy or tetrasomy of proximal 22q usually originated by a small supernumerary marker chromosome (sSMC). Methods: We report the case of a male presenting with an autism spectrum disorder (according to DSM-5 criteria) and



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dysmorphic features; with a karyotype identifying a small supernumerary marker chromosome. To ascertain the chro- mosomal origin and segmental composition of the sSMC microarray was performed. Results: The patient presented with an autism spectrum

disorder, with mild mental retardation and behavioural changes; also, mild non-specific facial dysmorphism was noted.

A constitutional karyotype identified a small supernumerary marker chromosome; and the microarray revealed a copy number gain for 22q11.1q11.21 region, compati- ble with a derivative of chromosome 22 [del(22)(q11.21)]. Therefore, patient presents partial trisomy of proximal 22q including the critical regions for CES (CESCRs). Discussion: Our case illustrates the clinical heterogeneity of the Cat-Eye Syndrome as well as the importance to carry out genetic evaluation of patients with autism spectrum disorders, especially if they present atypical or dysmorphic characteristics. This clinical case also reinforces the wide genetic complexity of autism spectrum disorders.


doi: 10.1016/j.euroneuro.2018.08.498

SU135

GENETIC SUBTYPES OF SCHIZOPHRENIA ELUCIDATED

BY MULTISTATE DIAGNOSIS TRAJECTORIES

Gonçalo Espregueira Themudo 1 , Morten Krebs 2 , Michael Benros 3 , iPSYCH-BROAD Working Group, Thomas Werge 2 , Wesley Thompson 2

1 Research Institute of Biological Psychiatry 2 Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services of the Capital Region of Denmark 3 Mental Health Centre Copenhagen, Copenhagen University

Background: Schizophrenia is a disorder with a high degree of heterogeneity. Identifying distinct subgroups that potentially reflect shared common etiology and clinical presentation is much needed. However, no studies have used genetic risk and disease trajectories in the context of an entire population to identify relations between clinical profiles such as temporal patterns of disease and genetic risk. These could advance our insight into etiological mechanisms and more personalized treatments. To investigate if specific subtypes of schizophrenia can be identified in a population- based sample we combined longitudinal register data sum- marized into diagnosis trajectories with genetic data from

the Danish population Methods: Using information from the nationwide Danish registers we conducted a cohort study on a population- based sample born in Denmark between 1981 and 2005, and during follow-up until 2016, we identified 5442 individuals with schizophrenia. We also obtained data on a true population random sample of 30000 people born in Denmark within the same time period, of which 29828 did not have a diagnosis of schizophrenia. Total sample size was thus n = 35270. For all patients we constructed a sequence corresponding

to the trajectory of psychiatric diagnoses, and for all sequence pairs we computed a dissimilarity corresponding to the number of alterations required to turn one sequence into the other.

Our data consist of date of first hospital contact for all psychiatric ICD codes. We also obtained birth related outcomes, as well as date of first hospital contact for any ICD code corresponding to infection diagnosis at discharge. Genotype data were obtained on a subset of 24249 subjects of European ancestry (2350 with schizophrenia). For genotyped subjects, we computed polygenic risk scores (PRS) for psychiatric disorders, personality traits, cognition, and anthropomorphic phenotypes, using as weights summary statistics from consortia not overlapping with the current study sample. We also ascertained copy number variation (CNV) for 12 large CNVs well characterized in the literature as well as genetic load for rare and damaging mutations Results: Individuals with schizophrenia had increased relative risk (RR) estimates ranging from 6 to more than 60 for developing comorbid psychiatric conditions, compared to population controls. Multidimensional scaling (MDS) based on pairwise dissimilarity of sequences followed by multivariate analysis of covariance revealed significant association between 4 stable MDS dimensions and several genetic and phenotypic characteristics, such as PRS for schizophrenia and education years; several types of psychiatric contacts; birth and pregnancy features; birth complications; and rare mutations. For example, Dimension 1 corresponds to higher number of comorbidities and earlier age of first diagnosis. Dimension 3 distinguishes trajectories with comorbid autism and ones with substance abuse. Dimension 3 is also associated with more rare and damaging mutations and older maternal age but negatively associated with the PRS for schizophrenia. Discussion: Our results suggest that diagnosis sequence analysis can be a useful method to subcategorize complex disorders with high comorbidities and rare and common genetic variants may contribute separately to risk of developing schizophrenia.


doi: 10.1016/j.euroneuro.2018.08.499

SU136

INTERACTION BETWEEN ZNF804A GENE AND CANNABIS USE ON THE RISK FOR PSYCHOSIS IN A NON-CLINICAL

SAMPLE

Jordi Soler Garcia 1 , Barbara Arias 2 , Jorge Moya 3 , Manuel Ignacio Ibañez 4 , Generós Ortet 5 , Lourdes Fañanás 6 , Mar Fatjó-Vilas 7

1 Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB) 2 University of Barcelona, CIBERSAM (Biomedical Research

Network in Mental Health; Instituto de Salud Carlos III) 3 University of Lleida, CIBERSAM

4 Centro de Investigaciones Biomédicas en Red de Salud

Mental (CIBERSAM), Universitat Jaume I 5 Universitat Jaume I



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6 University of Barcelona 7 FIDMAG Research Foundation / University of Barcelona

Background: The ZNF804A gene and cannabis use are risk factors for psychosis and both have also been associated with schizotypal traits. This study aimed to investigate: i) the association of life-time cannabis use (and its dose- effect) with schizotypal personality traits, ii) whether the genetic variability at ZNF804A gene modulates such association. Methods: The sample consisted of 389 Spanish non-clinical subjects (43% males, mean age = 21.1(2.19)). Schizotypy was evaluated with the three factors of the Schizotypal Personality Questionnaire-Brief: Cognitive-Perceptual (SPQ- CP), Interpersonal (SPQ-I) and Disorganized (SPQ-D). Sub- jects were classified regarding their cannabis frequency of consumption and then dichotomized as users or non-users. The effect of a genetic variant at ZNF804A (rs1344706) and cannabis use and their interaction on each of the three SPQ- B factors was tested by means of linear models. Sex, SCL anxiety scores and the use of other drugs were included as covariates. P-values were adjusted for false discovery rate (FDR cutoff at p < 0.05). Results: The analyses showed a significant relationship between ZNF804A and SPQ-I: homozygotes AA presented higher scores ( β= 0.884 p = 0.018). An interaction between the genotype AA and the life-time cannabis use was found on SPQ-CP ( β= 1.29 p = 0.029). This interaction showed a dose-effect pattern among AA subjects: schizotypy scores increased with the increment of the cannabis use frequency (sporadically users: β= 0.74 p = 0.20; monthly users: β= 1.68 p = 0.091; intense users: β= 1.62 p = 0.037). Discussion: On the one hand, the detected association between the rs1344706 genotype and schizotypy scores is in line with previous studies reporting the association of the A allele with schizophrenia risk (Purcell et al., 2009; Williams et al., 2011) and with schizotypy (Stefanis et al., 2013; Ya- suda et al., 2011). On the other hand, our interaction analyses report that life-time cannabis seems to act as a modifier of the association between the rs1344706 genotype and Cognitive Perceptual schizotypy. Among cannabis users, individuals AA showed higher scores in SPQ-CP factor. In addition, we have also observed that the interaction effect followed a relation of dose-effect within AA subjects: the SPQ-CP scores increase as cannabis use frequency does.

These results add evidence on that ZNF804A gene is associated with schizotypy and suggest that the interaction between cannabis use and the ZNF804A genotype could modulate psychosis proneness. Acknowledgements: i) Plan Nacional Sobre Drogas, Min- isterio de Salud (2008/090), ii) ISCIII through de project PI15/01420 (co-funded by European Regional Development Fund/European Social Fund) "Investing in your future"), iii) 2014SGR1636, iv) APIF-UB JS and CD16/00264 to MF-V.


doi: 10.1016/j.euroneuro.2018.08.500

SU137

DIFFERENCES DETWEEN AUDIT-C AND AUD PHENO- TYPES REVEALED BY GENOME-WIDE ANALYSIS

Rachel Kember 1 , Hang Zhou 2 , Amy Justice 3 , Rachel Smith 4 , Janet Tate 5 , William Becker 3 , John Concato 6 , David Fiellin 2 , Ke Xu 3 , Hongyu Zhao 7 , Joel Gelernter 2 , Henry Kranzler 8

1 University of Pennsylvania 2 Yale University School of Medicine 3 Yale University School of Medicine, Veterans Affairs Con- necticut Healthcare System; Yale School of Public Health

4 School of Nursing, University of Louisville 5 Veterans Affairs Connecticut Healthcare System

6 Connecticut Epidemiology Research Center 7 Yale University 8 University of Pennsylvania, Crescenz VAMC

Background: Excessive drinking is associated with a variety of adverse medical, psychiatric, and social consequences, including the development of alcohol use disorder (AUD), a chronic, relapsing condition characterized by impaired control over drinking. Patients with AUD often have psychiatric and medical comorbidities that can complicate their clinical presentation and treatment. In contrast, in some studies, moderate alcohol consumption has been associated with potential health benefits, including a decreased risk for heart disease and diabetes. Both AUD and levels of alcohol consumption have a genetic component, and genetic variants have been identified that contribute to one or both phenotypes. Methods: To investigate the genetic similarities and differences between AUD and alcohol consumption, we uti- lized data from the Million Veteran Program, a genomic mega-biobank supported by the U.S. Department of Veter- ans Affairs. Alcohol consumption was measured using longitudinal self-report recorded in the VA electronic health record (EHR) via the Alcohol Use Disorders Identification Test-Consumption questionnaire (AUDIT-C) and AUD was determined by ICD-9/10 diagnostic codes also from the EHR; a blood sample for genetic testing was also obtained. We performed a genome-wide association analysis (GWAS) for both phenotypes in > 350,000 individuals. Results: Despite a high degree of overlap between the most significant SNPs for these traits, further analysis revealed distinguishable genetic architectures. The genetic correlation between AUD and AUDIT-C GWAS was significant, but moderate (rg = 0.52, p = 2.4 × 10-43). Cross-trait linkage disequilibrium (LD) score regression identified significant positive genetic correlations between AUD (but not AUDIT-C) and several psychiatric phenotypes (e.g., major depressive disorder, rg = 0.41; p = 2.2 × 10-20), and significant negative genetic correlations between AUDIT-C (but not AUD) and both anthropometric and cardiometabolic measures (e.g., body mass index, rg = -0.35, p = 3.6 × 10-19; coronary artery disease, rg = -0.21, p = 8.3 × 10-8). Using additional phenotype data from the EHR, we confirmed this dual relationship within the MVP sample. AUD was associated with higher rates of psychiatric, digestive and cardiometabolic phenotypes; AUDIT-C was associated with decreased car-


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diometabolic phenotypes, among others. Phenome-wide association analysis (PheWAS) further identified significant pleiotropic effects for many genome-wide significant (GWS) variants. For example, rs13107325 in SLC39A8 increases risk for AUD and higher AUDIT-C scores (OR = 1.13, Beta = 0.10; respectively), yet decreases risk for obesity, diabetes, and osteoarthrosis in MVP (OR = 0.91, 0.87, 0.91; respectively). Discussion: Collectively, this work demonstrates that AUD

and AUDIT-C phenotypes, despite considerable genetic overlap, are not wholly congruent. In addition, many of the variants associated with one or both traits are highly pleiotropic, which could partly explain the comorbidity of AUD with other psychiatric and medical disorders. Our results are consistent with a model of AUD in which heavy drinking is a necessary, but not sufficient, cause of AUD, and the findings underscore the need to identify variants that contribute uniquely to AUD to fully capture its genetic basis.


doi: 10.1016/j.euroneuro.2018.08.501

SU138

SHARING OF GENETIC RISK FACTORS BETWEEN DIFFER- ENT PROXY MEASURES OF ALCOHOL USE DISORDERS AND RISK OF MENTAL HEALTH DISORDERS

Andries Marees 1 , Dirk Smit 2 , Jue_Sheng Ong 3 , Stuart MacGregor 3 , Jiyuan An 3 , Damiaan Denys 2 , Florence Vorspan 4 , Wim van den Brink 2 , Eske Derks 3

1 Academic Medical Center, University of Amsterdam

2 Academic Medical Center 3 QIMR Berghofer 4 AP-HP, Hôpital Fernand Widal

Background: Frequency and quantity of alcohol consumption are metrics commonly used to measure alcohol consumption behaviors. Epidemiological studies indicate that these alcohol consumption measures are differentially associated with (mental) health outcomes and with levels of socio-economic status (SES). The aim of the current study is to elucidate to what extent genetic risk factors are shared between the phenotypes alcohol consumption frequency and alcohol consumption quantity, and how these measures relate to four broad phenotypic categories: (i) SES; (ii) substance use disorders; (iii) other psychiatric disorders; and (iv) psychological/personality traits. Methods: GWA analyses were conducted to test genetic associations with alcohol consumption frequency (N = 438,308) and alcohol consumption quantity (N = 307,098 alcohol drinkers) within UK Biobank. For the other phenotypes, we used GWAS summary statistics. Genetic correlations (rg) between the alcohol measures and the other phenotypes were investigated using LD score regression. Results: We found a substantial genetic correlation between alcohol consumption frequency and alcohol consumption quantity (rg = 0.54). Frequency and quantity of alcohol consumption were consistently correlated in opposite directions with SES traits, and to many substance use,

psychiatric, and psychological/personality traits. Increased alcohol consumption frequency was associated with higher SES and often lower risk of substance use and psychiatric disorders. Discussion: Although frequency and quantity of alcohol consumption show substantial overlap in genetic etiology, they consistently show opposite pattern of rg in the relation with SES-related phenotypes. Future studies should carefully consider the potential influence of SES on the shared genetic etiology between alcohol and adverse (mental) health outcomes.


doi: 10.1016/j.euroneuro.2018.08.502

SU139

GENOME-WIDE ASSOCIATION ANALYSIS OF LIFETIME

CANNABIS USE (N = 184,765) IDENTIFIES NEW RISK

LOCI, GENETIC OVERLAP WITH MENTAL HEALTH, AND A CAUSAL INFLUENCE OF SCHIZOPHRENIA ON

CANNABIS USE

Joelle Pasman 1 , Karin Verweij 2 , Eske Derks 3 , Jacqueline Vink 1

1 Behavioural Science Institute, Radboud University Ni- jmegen

2 Amsterdam Medical Center 3 QIMR Berghofer

Background: Cannabis use is a heritable trait that has been associated with adverse mental health outcomes, including schizophrenia. We conducted the largest (N = 184,765) genome-wide association study (GWAS) for lifetime cannabis use to date to provide insight into the genetic architecture of cannabis use. In addition, we explored the genetic association with other mental health phenotypes and the causal relationship with schizophrenia. Methods: We meta-analyzed GWAS data from 3 general population cohorts (International Cannabis consortium, N = 35,297; UK-Biobank, N = 126,785; 23andMe, N = 22,683), followed up by gene-based tests. S-PrediXcan analysis was used to test whether genes had different expression levels in cannabis users versus non-users. LD score regression analysis was conducted to establish SNP-based heritability and genetic correlations with other phenotypes. Mendelian randomization analysis was applied to test the causal direction of the association with schizophrenia. Results: We identified 8 genome-wide significant independent single nucleotide polymorphisms in 6 regions. All measured genetic variants combined explained 11% of the variance. Results revealed 35 significant genes in 16 regions, and analyses showed that 21 genes (including in 1 additional region) had different expression levels for cannabis users versus non-users. The strongest finding across the different analyses was CADM2. Significant genetic correlations were found with 14 of 25 tested substance use and mental health traits, including smoking, alcohol use, schizophrenia, and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk



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on cannabis use, but no significant evidence for a causal relationship in the other direction. Discussion: In summary, our GWAS of lifetime cannabis use revealed significant SNP and genes associations in 16 regions, 15 of which have not been previously implicated in cannabis use. Our strongest gene finding was CADM2, which has been associated with substance use, personality and risk-taking in previous studies. Genetic correlations also place the cannabis use phenotype within the personality and mental health domain. The association between cannabis use and schizophrenia is well investigated, but evidence for causal relations is still inconclusive. This study provides support for a causal relationship between schizophrenia and cannabis use, which is in line with the self-medication hypothesis. Overall, our study gives novel insights about the etiology of cannabis use and its relation to mental health.


doi: 10.1016/j.euroneuro.2018.08.503

SU140

ILLICIT DRUG USE AND THE GENETIC OVERLAP WITH

SMOKING, ALCOHOL CONSUMPTION AND CANNABIS USE

Jacqueline Vink 1 , Laura Veul 2 , Abdel Abdellaoui 2 , Jouke-Jan Hottenga 3 , Dorret Boomsma 3 , Karin Verweij 2

1 Radboud University Behavioural Science Institute 2 Amsterdam Medical Center 3 VU Amsterdam

Background: Commonly used illegal drugs include cannabis, heroin, cocaine, amphetamine, methamphetamines and club drugs such as ecstasy (MDMA). In the Netherlands, cannabis is the most frequently used illicit drugs, with ecstasy on the second place. Several attempts have been made to investigate determinants of ecstasy use, with mixed results. We know from twin and family studies that licit and illicit substance use, such as cigarette smoking, alcohol use, lifetime cannabis, and ecstasy use are heritable traits. Twin studies have also indicated that there is genetic overlap between the use of different substance. Genome- wide association studies have successfully identified (some of the) genetic variants associated with smoking, alcohol use and cannabis use.

With methodological advances in molecular genetics and increased sample sizes in GWA studies it has become viable to use measured genetic variation among individuals to examine the genetic relationship between substances. Methods: In the present study we will: (1) Compare profiles of ecstasy users with non-users with regard to (ab)use of other licit and illicit substances to explore phenotypic overlap. (2) Explore the association between polygenic risk scores and multiple indices of illicit drug use (e.g. ecstasy use, overall hard drug use).

Data of the Netherlands Twin Register will be used. With regard to aim 1, a cross-sectional sample is available with data on ecstasy use and other licit and illicit substance use consisting of almost 10,000 participants (66,8% female,

18-45 years, prevalence of ecstasy use almost 10%). With regard to aim 2, longitudinal data were available for around 5,000 participants with information on both licit and illicit substance use. We calculated polygenic risk scores for alcohol, tobacco and cannabis use, based on the summary statistics from the largest available genome-wide association meta-analyses to date. Note that for other substance use phenotypes no large GWA data are available. Therefore, we explored the association between these polygenic risk scores and multiple indices of illicit drug use (e.g. ecstasy use, overall hard drug use). Results: Preliminary results indicated ecstasy users were more likely to have used every other substance we investigated, but ecstasy users especially differed from non-users on illicit substance use. Smoking and alcohol use often preceded first use of ecstasy, while first ecstasy use often preceded first use of other illicit substances. Preliminary results indicate that only the polygenic risk score for cannabis (and not for smoking and alcohol) predicted ecstasy use/illicit drug use. Discussion: In conclusion, the phenotypic association between illicit substances (cannabis, ecstasy) is stronger than the association between illicit substances and alcohol and smoking. The genetic analyses showed there is genetic overlap between cannabis (not alcohol or smoking) and other illicit drug use (ecstasy, others), suggesting a general genetic vulnerability for illicit drug use.


doi: 10.1016/j.euroneuro.2018.08.504

SU141

DECREASED CEREBROPLACENTAL RATIO IS ASSOCIATED

WITH BIOLOGICAL AGE DECELERATION: AN EPIGE- NETIC APPROACH BASED ON A CLINICAL POPULATION

EXPOSED TO OBSTETRIC COMPLICATIONS

Helena Palma-Gudiel 1 , Elisenda Eixarch 2 , Fátima Crispi 2 , Sebastián Morán 3 , Anthony Zannas 4 , Lourdes Fañanás 5

1 University of Barcelona, Centre for Biomedical Research

Network on Mental Health (CIBERSAM), Instituto de Salud

Carlos III, Barcelona 2 Fetal i + D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu) - CIBERER

3 Cancer Epigenetics & Biology Program (PEBC), IDIBELL, L’Hospitalet 4 Max Planck Institute of Psychiatry 5 University of Barcelona, CIBERSAM

Background: Exposure to prenatal stress and/or obstetric complications has been reliably associated with a wide range of complex disorders, including those of a psychiatric nature. Placental insufficiency and hypoxia alter the blood flow of the umbilical artery (UA) and middle cerebral artery (MCA), which can be prenatally measured via Doppler ultrasound. Both stressors involve a decreased supply of oxy- gen and nutrients to the fetus thus impairing neurodevel-



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opment. The ratio between both measures, cerebroplacental ratio (CPR), has been widely used as a risk marker for adverse perinatal outcomes such as prematurity, caesarean birth and reduced birthweight and Apgar scores, among others. Exposure to adverse prenatal insults has been suggested to mediate long-term deleterious effects on adulthood via epigenetic programming. In this regard, exposure to environmental threats has been hypothesized to accelerate biological aging, which can be measured by means of the epigenetic clock. Methods: Genomic DNA was extracted from cord blood samples from 30 monochorionic twin pregnancies (n = 60). Genome-wide DNA methylation was analyzed by means of the Infinium MethylationEPIC Kit, which measures DNA methylation at over 850,000 CpG sites across the whole human genome. MCA and UA pulsatility index (PI) were measured by means of Doppler ultrasound before birth (at a mean gestational age of 34 weeks, range: 28 to 36 weeks). CPR was measured as the ratio between MCA PI and UA PI. The gestational age epigenetic clock was calculated following the script published by Knight and colleagues (2016). Chronological gestational age at birth was calculated from

last menstrual period before pregnancy as retrospectively retrieved from clinical databases. Age acceleration was calculated as the epigenetic gestational age minus the chronological gestational age. Results: Chronological and epigenetic gestational ages were significantly correlated (r = 0.76; p < 0.001). There was no maternal contamination in genomic DNA collected from

cord blood according to Morin et al. (2017). Increased CPR was significantly associated with gestational age acceleration (t = 3.19; p = 0.003) after adjusting for sex, chronological gestational age, birthweight, cell types count (CD4 + , CD8 + , B cells, NK cells, monocytes, granulocytes and nu- cleated red blood cells) and the presence of obstetric complications. Discussion: The association of an obstetric predictor of perinatal risk reflecting both placental insufficiency and prenatal hypoxia with the epigenetic clock-based gestational age deceleration suggests the critical role of epigenetic mechanisms in adjusting homeostasis to deal with stress. Further longitudinal prospective research focusing on epigenetic long-term programming of psychiatric phenotypes is required to disentangle which genes and pathways are critically involved in the origin of these disorders and when are they most vulnerable to environmental programming.


doi: 10.1016/j.euroneuro.2018.08.505

SU142

NORDIC – NORDIC OCD AND RELATED DISORDERS CONSORTIUM

Julia Boberg 1 , James Crowley 2 , David Mataix-Cols 1 , Christian Rück 1

1 Karolinska Institutet 2 University of North Carolina

Background: Obsessive compulsive disorder (OCD) is a severe psychiatric condition with a prevalence of about 2%. OCD is often disabling, increases risk for suicide attempt and has a chronic course if not treated. Genetic and environmental factors each explain about 50% of variance of OCD in the general population, nevertheless we know very little about which specific genes or environmental factors.

1: Collect the world’s largest richly phenotyped sample of OCD cases

2: Discover genomic loci for OCD, OC symptom dimensions and response to psychological and pharmacological treatment

3: Identify gene ∗environment interactions using genetic, clinical and epidemiological data Methods: Participants are adults and children that has been diagnosed with a DSM-IV or DSM-5 diagnosis of OCD. Partici- pants are recruited from twelve specialist clinics in Sweden and 28 specialist clinics in Norway.

All participants provide DNA through blood or saliva. Sam- ples are being stored at the KI biobank. In tailored software solutions; Scarab LIMS and ViZu, samples are matched with data for every individual.

In addition to DNA, all participants provide routine clinic data; OCD symptoms are measured pre and post treatment with Y-BOCS/CY-BOCS and OCI-R/OCI-CV. Depression is measured pre and post treatment with MADRS, improvement is measured post treatment with CGI-I, disorder severity is measured pre and post with CGI-S, global functioning is measured pre and post with GAF. Data on psychotropic drugs pre and post treatment, heredity for psychiatric disorder, comorbidity is also available from the clinic.

Data from the Swedish national registers will provide information about environmental factors such as perinatal complications, smoking during pregnancy, maternal infections, etc. Results: (NA, study description only). Discussion: (NA, study description only).


doi: 10.1016/j.euroneuro.2018.08.506



abstracts of the 26th world congress of psychiatric...

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