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Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics

Abstract

Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.

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Acknowledgements

The CATIE project was supported by NIMH contract N01 MH90001. Dr Sullivan was supported by R01 s MH074027 and MH077139 and Dr Van den Oord was supported by R01 s MH078069 and HG004240. We are indebted to AnnCatherine Downing and Mark W Farmen for their helpful comments on an earlier draft of the paper. We thank Jonathan Sebat for providing copy-number variant calls for the CATIE sample.

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Correspondence to J L McClay.

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Eli Lilly funded the GWAS genotyping conducted at Perlegen Sciences. Dr Sullivan reports receiving research funding from Eli Lilly in connection with this project. Dr Stroup reports receiving research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline and Bristol-Myers Squibb. Dr Lieberman reports receiving research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica and Pfizer, and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer and Solvay.

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McClay, J., Adkins, D., Åberg, K. et al. Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Mol Psychiatry 16, 76–85 (2011). https://doi.org/10.1038/mp.2009.89

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