A genome-wide pharmacogenomic study of patients with schizophrenia suggests that GRM7 mediates the effects of risperidone on positive symptoms

Antipsychotic response is often variable, therefore, identification of genetic markers helping in predicting the treatment response is extremely interesting. The Positive and Negative Syndrome Scale (PANSS) is widely used in clinical and research settings and its factor structure analysis could better identify symptoms clusters for the treatment response assessment. We performed a genome wide association study on a group of schizophrenia patients in monotherapy with risperidone, whose symptoms improvement was measured after two weeks using the five and seven factors models. No SNPs achieved a genome wide significant association p-value (p<5x10-8) with the PANSS total score, or with the five and seven factors models. However, an association p-value (p=6.88x10-8) very close to the threshold for declaring significance was observed for a SNP inside the metabotropic glutamate receptor 7 (GRM7) gene and Emsley scale’s positive symptoms. Seven factors model showed that risperidone gave a worst amelioration of positive symptoms after two weeks treatment in recessive homozygous subjects compared to others. The same trend was observed for the Marder scale’s positive symptoms. Glutamatergic system is a promising target for novel antipsychotic compounds and its dysfunction is one of the major hypotheses to explain the pathogenesis of schizophrenia. Based on these considerations our preliminary data appear very promising and require further investigation in other data sets. In conclusion, this study suggests that a better characterization of endophenotypes using factor model analysis of PANSS could be useful in pharmacogenomics of antipsychotic drugs response.