Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes Elijah R. Behr 1 , Marylyn D. Ritchie 2,3 , Toshihiro Tanaka 4,17 , Stefan Ka ¨a ¨b 5,18 , Dana C. Crawford 2 , Paola Nicoletti 6 , Aris Floratos 6 , Moritz F. Sinner 5 , Prince J. Kannankeril 2 , Arthur A. M. Wilde 7 , Connie R. Bezzina 7 , Eric Schulze-Bahr 8,19 , Sven Zumhagen 8,19 , Pascale Guicheney 9 , Nanette H. Bishopric 10,21 , Vanessa Marshall 11 , Saad Shakir 11 , Chrysoula Dalageorgou 1 , Steve Bevan 1 , Yalda Jamshidi 1 , Rachel Bastiaenen 1 , Robert J. Myerburg 10,20 , Jean-Jacques Schott 12 , A. John Camm 1 , Gerhard Steinbeck 13 , Kris Norris 2 , Russ B. Altman 14 , Nicholas P. Tatonetti 15 , Steve Jeffery 1 , Michiaki Kubo 4,17 , Yusuke Nakamura 4,16 , Yufeng Shen 6 , Alfred L. George, Jr. 2 , Dan M. Roden 2 * 1 Cardiovascular Sciences and Genetics Research Centers, St George’s University of London, London, United Kingdom, 2 Departments of Medicine, Molecular Physiology and Biophysics, Pediatrics, and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America, 3 Pennsylvania State University, Eberly College of Science, The Huck Institutes of the Life Sciences, University Park, Pennsylvania, United States of America, 4 Tokyo Medical and Dental University, Bunkyo- ku, Tokyo, Japan, 5 Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany, 6 Department of Biomedical Informatics, Columbia University, New York, New York, United States of America, 7 Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 8 Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Mu ¨ nster, 9 Institut National de la Sante ´ et de la Recherche Me ´dicale, UMRS 956, University Pierre et Marie Curie, Univ Paris 06, Paris, France, 10 Department of Medicine (Cardiology), University of Miami Miller School of Medicine, Miami, Florida, United States of America, 11 Drug Safety Research Unit, Southampton, United Kingdom, 12 Institut National de la Sante ´ et de la Recherche Me ´ dicale, UMR1087, CNRS UMR 6291, Universite ´ de Nantes and CHU Nantes, Nantes, France, 13 Center of Cardiology at Hospital of Starnberg, Starnberg, Germany, 14 Department of Bioengineering, Stanford University, Palo Alto, California, United States of America, 15 Department of Biomedical Informatics, Columbia University, New York, New York, United States of America, 16 University of Chicago, Chicago, Illinois, United States of America, 17 RIKEN Center for Genomic Medicine, Yokohama, Japan, 18 Deutsches Zentrum fu ¨ r Herz-Kreislauf-Forschung e.V., partner site Munich Heart Alliance, Munich, Germany, 19 IZKF of the University of Mu ¨ nster, Mu ¨ nster, Germany, 20 Department of Physiology, University of Miami Miller School of Medicine, Miami, Florida, United States of America, 21 Department of Molecular and Cellular Pharmacology and Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America Abstract Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of $2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3 6 10 27 , odds ratio = 2, 95% confidence intervals: 1.5–2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p =3 6 10 29 ). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs. Citation: Behr ER, Ritchie MD, Tanaka T, Ka ¨a ¨ b S, Crawford DC, et al. (2013) Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes. PLoS ONE 8(11): e78511. doi:10.1371/journal.pone.0078511 Editor: Balraj Mittal, Sanjay Gandhi Medical Institute, India Received February 14, 2013; Accepted September 14, 2013; Published November 6, 2013 Copyright: ß 2013 Behr et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by U01HL65962, the Pharmacogenomics of Arrhythmia Therapy site of the Pharmacogenetics Research Network, and by a grant from the Fondation Leducq (Trans-Atlantic Network of Excellence ‘‘Alliance Against Sudden Cardiac Death’’, 05 CVD 01). Genotyping the Leducq samples described in the text was performed by the RIKEN Center for Genomic Medicine, Yokohama, Japan, which is supported in part by the BioBank Japan Project funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology. The DARE study was funded by the British Heart Foundation under special project grant SP/02/001. The DARE samples were genotyped at Gene Expression Ltd. Further support was provided by a collaboration with the International Serious Adverse Events Consortium, whose membership currently includes Abbott, Amgen, Astra-Zeneca, Cerner, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and the Welcome Trust. Portions of the Leducq dataset have been deposited at dbGaP at http://www.ncbi.nlm.nih.gov/projects/ gap/cgi-bin/study.cgi?study_id = phs000331.v1.p1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PLOS ONE | www.plosone.org 1 November 2013 | Volume 8 | Issue 11 | e78511