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Genome-wide association study of antipsychotic-induced QTc interval prolongation

The Pharmacogenomics Journal volume 12, pages 165–172 (2012)Cite this article

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Abstract

QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10−05 and 2.66 × 10−13, respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10−7, Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.

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Acknowledgements

This work was supported by the National Institute of Mental Health (grant number N01 MH90001). Eli Lilly funded the GWAS genotyping done at Perlegen Sciences.

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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

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

  2. Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Y Liu & P F Sullivan

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

    P Jia & Z Zhao

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

    D Perkins

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

    T S Stroup & J A Lieberman

  6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    P F Sullivan

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  1. K Åberg
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Correspondence to K Åberg.

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Competing interests

Dr PF Sullivan reports receiving research funding from Eli Lilly in connection with this project. Dr TS Stroup reports receiving consulting funds from Janssen and Lilly. Dr D Perkins reports having received research funding from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Otsuka Pharmaceutical, Eli Lilly, Janssen Pharmaceutica Products and Pfizer; and consulting and educational fees from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, GlaxoSmithKline, Forest Labs, Pfizer Inc and Shire. Dr JA Lieberman reports having received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, Wyeth, Merck, Forest Labs, Allon and Pfizer, has participated in research, consulting, advisory board or DSMB activities from Chephalon, Eli Lilly, Pfizer, Bioline, Lilly, AstraZeneca, Forest Labs, GlaxoSmithKline, Janssen Pharmaceutica, Otsuka, Wyeth and Solvay, and a patent with Repligen. Drs K Aberg, JL McClay, Y Liu, DE Adkins, J Bukszár, P Jia, Z Zhao and EJCG van den Oord report no financial relationships with commercial interests and have nothing to disclose.

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Åberg, K., Adkins, D., Liu, Y. et al. Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J 12, 165–172 (2012). https://doi.org/10.1038/tpj.2010.76

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