Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

Abstract

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K SNPs, from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study. Outcomes included twelve indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. Twenty-one SNPs satisfied this criterion. The top finding indicated a SNP in MEIS2 mediated the effects of risperidone on hip circumference ( q =.004). The same SNP was also found to mediate risperidone's effect on waist circumference ( q =.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.