Poster 86CLOZAPINE-INDUCED WEIGHT CHANGE ASSOCIATED WITHG-2548A POLYMORPHISM OF THE LEPTIN GENE IN PATIENTSWITH CHRONIC SCHIZOPHRENIA

Shi Hyun Kang, Jong-il Lee, Hye Ree Han, Minah SohSeoul National Hospital Seoul, no, South Korea

Background: Clozapine is known to cause severe weight gain.A variety of genetic polymorphisms have been reported as putativemechanisms for antipsychotics-induced weight gain. Antipsycho-tics-induced weight gain has an inverse correlation with body massindex at baseline. A functional polymorphism in the leptin promoterregion G-2548A is a candidate polymorphism for antipsychotics-induced weight change, but results are inconsistent.Methods: We examined the association between clozapine-inducedweight change and LEPG-2548Apolymorphism in113Koreanpatientswith schizophrenia taking clozapine for at least one year at SeoulNational Hospital. All patients enrolled in this study fulfilled thefollowing criteria: (1) had schizophrenia or schizoaffective disorder,diagnosed by DSM-IV-TR criteria, (2) had been taking clozapine for atleast one year, (3) were more than 18 years and less than 65 years old,and (4) had no physical disease that affected body weight, such asdiabetes or tuberculosis. Body weight and BMI were cross-sectionallymeasured during the study period. Body weight and BMI beforestarting clozapine were abstracted from medical records.Results: All 113 subjects were Koreans. The mean clozapine dosagewas419.0±127.6 mg/day, and themeanduration of clozapine usewas50.4±31.0 months. Body weight increased by 3.9±13.7% aftertreatment with clozapine. Clozapine-induced weight change wasinversely correlated with baseline BMI (r=-0.304, p=0.01), and LEPG-2548A polymorphism was significantly associated with this nega-tive correlation. During clozapine treatment, the A/A group had lowerbaseline BMI and gained weight, whereas the G/G group had higherbaseline BMI and lost weight during clozapine treatment. When thebaseline BMI was adjusted in the regression analysis, the associationbetween clozapine-induced weight change and the polymorphismbecame weaker; thus, baseline BMI may affect the direction of AP-induced weight change due to the polymorphism.Discussion: The LEP G-2548A polymorphism is significantlyassociated with the negative correlation between weight changeand baseline BMI during clozapine treatment. To the best of ourknowledge, this is the first study to show that LEP G-2548Apolymorphism is significantly associated with a negative correlationbetween weight change and baseline BMI during clozapinetreatment. The polymorphism may be associated with homeostaticcontrol of body weight during antipsychotic treatment.

doi:10.1016/j.schres.2010.02.581

Poster 87EVIDENCE THAT PUTATIVE ADHD LOW RISK ALLELES AT SNAP25MAY INCREASE THE RISK OF SCHIZOPHRENIA

Liam S. Carroll, Kimberley M. Kendall, Michael C. O'Donovan,Michael J. Owen, Nigel M. WilliamsDepartment of Psychological Medicine and Neurology, School ofMedicine Cardiff University, Cardiff, United Kingdom

Background: Schizophrenia is a complex disorder affecting ∼1% ofthe population. The estimated heritability is 80%, a significantproportion of which is likely due to polygenic factors. SynaptosomalAssociated Protein 25 kDa (SNAP25) is an important member of theSNARE complex, a structure that mediates synaptic vesicle

exocytosis. Altered SNAP25 levels have been found in schizophreniaand genetic variation at SNAP25 has been reported to be associatedwith Attention-Deficit/Hyperactivity Disorder (ADHD). Expressionof the putative schizophrenia susceptibility gene DTNBP1 has alsobeen shown to influence SNAP25 levels in vitro. We carried outmutation screening of the SNAP25 gene followed by associationanalysis in a UK schizophrenia case control sample.Methods: We performed mutation screening of the SNAP25 gene in14 unrelated schizophrenic individuals (7male, 7 female) selected atrandom from our UK association sample. We examined the sevenSNPs that emerged from the mutation screen and then a further 31informative tag SNPs spanning the SNAP25 locus in a case controlsample collected from theUK. This consisted of 662 cases (448males,214 females) with a consensus diagnosis of schizophrenia accordingto DSM-IV criteria and 716 controls (482 males, 234 females), all ofwhom were unrelated and of white European descent. Associationanalyses were performed using PLINK 1.01 and SNPTEST. Imputationof genotypes was performed using IMPUTE.Results: We screened 3,965 bases at the SNAP25 locus in 14 unrelatedschizophrenics and identified seven SNPs (rs6039769 (intronic),rs362998 (synonymous), rs363006 (intronic), rs3746544 (3'UTR),rs1051312 (3'UTR), rs8636 (3'UTR)). A novel SNP (G/T transversion,ss107056528) was found in the putative promoter region. Genotypingthese seven SNPs in our case control sample revealed significantevidence for allelic association at rs3746544 (P=0.004, OR=1.26)and rs8636 (P=0.003, OR=1.27). These results remained significantafter 10,000 permutations to allow for multiple testing (P=0.02).Intermarker LD analysis revealed rs8636 and rs3746544were stronglycorrelated (D'=1, r2=0.997). 31 additional tag SNPs were combinedwith the original six independent SNPs to capture 79% of the 131 SNPsgenotyped in the HapMap CEU samples at this locus (r2>0.8,MAF>0.01). This revealed nominally significant association at anadditional five SNPs. The strongest of these was at rs3787283(P=0.006, OR=1.25). Taken together with the SNPs identified forprimary association no SNP survived correction for multiple testing(best experiment-wise permuted P-value=0.10 at rs3746544). Im-putation of genotypes for the 131 HapMap SNPs spanning the SNAP25locus failed to identify evidence for allelic association greater than ouroriginal observation at rs3746544 (maximum P=0.003at rs3746544).Discussion: Our results should be considered as hypothesis generatingand require followup in additional samples.We compared our results tostudies reporting evidence for association with (i) antipsychoticresponse in schizophrenia and (ii) ADHD. In schizophrenia, carriers ofthe allele which showed the strongest association in our study (G alleleat rs3746544) show significantly poorer clinical response to antipsycho-tic treatment than non-carriers. Two of the SNPs nominally associatedwith schizophrenia in our study (rs3787283, rs3746544) have beenfound to be associatedwith ADHD but in the reverse allelic direction i.e.risk alleles for schizophrenia are protective in ADHD. Our findingssuggest that SNAP25may influence risk of developing schizophrenia andclinical response to antipsychotic treatment. If this is the case, the samemechanism may reduce the risk of developing ADHD.

doi:10.1016/j.schres.2010.02.582

Poster 88COMPLEXIN2 GENE POLYMORPHISMS MODIFY COGNITIVEPERFORMANCE IN SCHIZOPHRENIA

Sabrina Klaus1,7, Martin Begemann1, Sergi Papiol2, Dörthe Malzahn4,Heidi Friedrichs1,7, Katja Ribbe1,7, Ahmed El-Kordi1,7, KonstantinRadyushkin1, Fritz Benseler3, Kerstin Reim3, Joachim Riggert5, PeterFalkai6, Heike Bickeböller4, Klaus-Armin Nave2, Nils Brose3,Hannelore Ehrenreich1

Abstracts 337