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Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

Molecular Psychiatry volume 16, pages 321–332 (2011)Cite this article

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Abstract

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

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Acknowledgements

The CATIE project was supported by NIMH contract N01 MH90001. Dr Sullivan was supported by R01s MH074027 and MH077139 and Dr van den Oord was supported by R01s MH078069 and HG004240.

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Authors and Affiliations

  1. Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA, USA

    D E Adkins, K Åberg, J L McClay, J Bukszár & E J C G van den Oord

  2. Department of Biomedical Informatics, Psychiatry, and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    Z Zhao & P Jia

  3. Department of Psychiatry, University of North Carolina at Chapel Hill, NC, USA

    T S Stroup & D Perkins

  4. Department of Psychiatry, Duke University, Durham, NC, USA

    J P McEvoy

  5. Department of Psychiatry, Columbia University, New York, NY, USA

    J A Lieberman

  6. Department of Genetics, Psychiatry, & Epidemiology, University of North Carolina at Chapel Hill, NC, USA

    P F Sullivan

  7. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden

    P F Sullivan

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  1. D E Adkins
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  2. K Åberg
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  3. J L McClay
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Correspondence to D E Adkins.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Adkins, D., Åberg, K., McClay, J. et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry 16, 321–332 (2011). https://doi.org/10.1038/mp.2010.14

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