SU86 - VALIDATION STUDY IN TWO GENOME-WIDE SIGNIFICANT RISK VARIANTS FOR ANTIPSYCHOTIC INDUCED WEIGHT GAIN

Abstract

Background Antipsychotic drugs are the primary intervention in the treatment of psychotic disorders, however, the use of antipsychotics is often accompanied by weight gain and metabolic syndrome. A recent Genome-Wide Association Study (GWAS) investigating a Han Chinese sample suggested a possible role of rs1097714 and rs10977154 variants of the protein tyrosine phosphatase, receptor type D (PTPRD) gene in antipsychotic induced weight gain (AIWG). Additionally, two upstream variants (rs1886243 and rs6915627) of T-complex 11 (TCP11) were among the 20 most significant SNPs in the original study. The purpose of this study was to replicate the association of the top 20 variants from the aforementioned GWAS in two independent samples to evaluate whether these associations are also present in patients of European and African American ancestry. Methods The following two independent samples were used: 1) schizophrenia or schizoaffective disorder patients (based on DSM III and DSM IV criteria) primary undergoing first exposure to atypical antipsychotic drugs and 2) patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sample. Samples 1 and 2 were genotyped using Illumina Omni 2.5 Chip, Affymetrix 500 K “A” chipset, and the Perlegen custom 164 K chip, respectively. In the main analyses in two replication samples. Analysis of Covariance (ANCOVA) was used to investigate the percentage of change in weight (Sample 1) or Body Mass Index (BMI) (Sample 2) from baseline to last observation carried forward (LOCF), where genotypes were coded as factors. Models in both samples were corrected for study duration, and additionally for age in Sample 1, and medications used in Sample 2. Results In Sample 1 (122 men (65.9%), mean±SD age; 36±11 years, baseline body weight; 79.72±15.9 kg % of weight change (LOCF); 5.08±7.11, weight gainer (>7%); n=57 (31.0%), medication: clozapine, olanzapine, and risperidone were mainly used), none of 14 genetic variants showed a significant association with % of weight change in the European population. In African Americans, the nominal association was observed (F2,50=4.814; p=0.034) between rs3853114 variant of dynein axonemal heavy chain 5 (DNAH5). In Sample 2 (118 men (78.1%), mean±SD age; 40±12 years, baseline BMI; 28.63±5.43, % of BMI change (LOCF); 2.95±7.79, weight gainer (>7%); n=31 (20.5%), medication: olanzapine, risperidone, and quetiapine were used), nominal associations with two TCP11 variants rs1886243 (F2,148=3.14; p=0.046) and AIWG were observed. None of the variants described above survived correction for multiple testing. Discussion To the best of our knowledge, this is the first genetic association study evaluating PTPRD and TCP11 in European and African American patients. However, the associations between PTPRD variants and AIWG were not replicated; whereas the effects of TCP11 remained nominally significant. More studies across different ancestries are needed to examine if PTPRD and TCP11 can be considered susceptibility genes for AIWG.