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

The Pharmacogenomics Journal volume 17, pages 146–154 (2017)Cite this article

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Abstract

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.

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Acknowledgements

Funding for this study was partially provided by Project No. 153 of the Health Authority of Regione Lombardia. The CATIE-derived confirmatory analysis was possible thanks to the National Institute of Mental Health (NIMH), which provided access to the clinical and genetic data of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study to Massimo Gennarelli. The principal investigators of the CATIE trial were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the NIMH (N01 MH900001) along with MH074027 (principal investigator PF Sullivan). Genotyping was funded by Eli Lilly and Company.

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  1. E Sacchetti and C Magri: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Clinical and Experimental Sciences, Neuroscience Section, University of Brescia, Brescia, Italy

    E Sacchetti, P Valsecchi & A Vita

  2. Department of Mental Health, Spedali Civili Hospital, Brescia, Italy

    E Sacchetti, P Valsecchi & A Vita

  3. Department of Mental Health, Psychiatric Service, Brescia University and Brescia Spedali Civili, Brescia, Italy

    E Sacchetti, P Valsecchi & A Vita

  4. Department of Mental Health, Psychiatric Unit 22, Brescia University and Brescia Spedali Civili, Brescia, Italy

    E Sacchetti & P Valsecchi

  5. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    C Magri, A Minelli, M Traversa, S Calza & M Gennarelli

  6. Department of Mental Health, Psychiatric Unit 20, Brescia University and Brescia Spedali Civili, Brescia, Italy

    A Vita

  7. Genetic Unit, IRCCS Centro S. Giovanni di Dio Fatebenefratelli Brescia, Brescia, Italy

    M Gennarelli

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Competing interests

In the past 3 years, ES has received funding for research, advisory board membership and sponsored lectures from the following private companies: Angelini, Chiesi, Content Rd Net srl, EDRA LSWR, Eli Lilly, Health and Publishing Services srl, Janssen-Cilag, Lundbeck, McCann, Otsuka, Pfizer, Roche, Servier, Stroder, Sunovion, Takeda and Valeas. He is not a shareholder in any of these corporations. In the past 3 years, AV has received funding for research, advisory board membership and sponsored lectures from Astra Zeneca Pharmaceuticals, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Otsuka, Sanofi and Stroder. He is not a shareholder in any of these corporations. PV has received funding for research and sponsored lectures from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Innova Pharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer and Wyeth Lederle. He is not a shareholder in any of these corporations. The authors declare no conflicts of interest.

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Sacchetti, E., Magri, C., Minelli, A. et al. The GRM7 gene, early response to risperidone, and schizophrenia: a genome-wide association study and a confirmatory pharmacogenetic analysis. Pharmacogenomics J 17, 146–154 (2017). https://doi.org/10.1038/tpj.2015.90

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