The GRM7 gene, early response to risperidone, and schizophrenia: a genome-wide association study and a confirmatory pharmacogenetic analysis

The search for biomarkers of response to antipsychotic medications is hindered by difficulties inherent in the topic or related to persistent methodological difficulties, such as high rates of anticipated discontinuation and consequent distortions in the imputation of missing data. Because early response to antipsychotics represents a sufficiently reliable index of the subsequent treatment response in patients with schizophrenia, we undertook a real-world, genome-wide association study (GWAS) with the aim of identifying genetic predictors of response to risperidone after 2 weeks in 86 patients with schizophrenia. Limited to the associations reaching significance in the GWAS, confirmatory analysis relative to risperidone response over 9 months was also designed involving 97 patients (European only) enroled in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genetic substudy. The GWAS revealed a significant association (false discovery rate 0.02) of the single-nucleotide polymorphism rs2133450 inside the GRM7 gene with Emsley’s positive domain derived from the positive and negative syndrome scale (PANSS). Patients with the rs2133450 CC genotype presented poorer improvement in the positive domain over 2 weeks, with odds ratios of 12.68 (95% CI, 3.51–45.76) and 6.95 (95% confidence interval (CI), 2.37–20.37) compared with patients with the AA and AC genotypes, respectively. Compared with A homozygotes, rs2133450 C homozygotes enroled in the CATIE-derived confirmatory analysis showed less improvement in Emsley’s positive, excited and depression domains, positive and general PANSS subtypes, and total PANSS after 9 months of treatment with risperidone. The original GWAS and the CATIE-derived confirmatory analysis support the proposal that the rs2133450 may have translational relevance as a predictor of response to risperidone.