SU84 - THE GLUTAMATE RECEPTOR - GRM3 GENE AND ANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA

Abstract

Background Schizophrenia (SCZ) is a chronic, debilitating mental disorder characterized by positive, negative and cognitive symptoms. Currently, Antipsychotics (AP) are the best treatment for SCZ, but the clinical responses are highly variable across individuals. Many hypotheses have been proposed to explain the inter-individual difference in AP response. The glutamate system is a target for studying the pharmacogenetics of AP based on the research drug pomaglumetad (GRM2/3) that showed similar efficacy to olanzapine in clinical trials, as well as some evidence of genetic association from previous studies. Also, Bitopertin, a glycine reuptake inhibitor also showed promise in alleviating negative symptoms in SCZ. Glycine acts as co-agonist for the NMDA receptor thus influencing glutamate signaling in the brain. The glutamate genes that have been investigated for their roles in predicting AP response in SCZ include GRIN2A, GRM3 and GRIA1. We conducted an association study between variants in the GRM3 gene and AP using the CATIE sample (n=306). 23 SNPs were extracted from the sample. Methods We investigated 23 SNPs across the GRM3 gene using the CATIE sample. We selected 306 European ancestry patients that have been treated with one of 4 AP (olanzapine, risperidone, quetiapine, and ziprasidone). Treatment response was evaluated using the Positive and Negative Syndrome scale (PANSS). All SNPs with the GRM3 gene were selected from the UCSC genome browser (GRCh36/hg19) and extracted from the CATIE sample using PLINK 1.9. CATIE investigators arranged the genotyping at Perlegen Science using the Affymetrix 500 K two chip genotyping platform plus a custom 164 K fill-in chip. Linkage disequilibrium and Hardy-Weinberg equilibrium calculations were conducted using HaploView 4.2, and all statistical analyses were performed using IBM SPSS v24. Results Among the 23 SNPs obtained from the CATIE dataset, only rs274621 was significantly associated with AP response (p=0.02) under a recessive model. However, the results did not remain significant after correction for independent tests. Discussion Several association studies have investigated GRM3 polymorphisms versus clinical response to AP and yielded promising results in the past. We found a trend for rs274621 to be associated with AP response. The rs274621 marker is an upstream variant which may be located in the promoter region of GRM3 and may affect the transcription of the gene. Interestingly, rs274621 was also significantly associated with bipolar disorder in the University College London 1 (UCL1) subsample GWAS. Overall, the analyses of the European ancestry subsample of CATIE did not provide significant evidence for a role of GRM3 in AP responses. However, further studies of the glutamate system in AP response are required.