Article abstract
Nature Genetics 41, 399 - 406 (2009)
Published online: 22 March 2009 | doi:10.1038/ng.364
Common variants at ten loci influence QT interval duration in the QTGEN Study
Christopher Newton-Cheh1,2,3,22, Mark Eijgelsheim4,22, Kenneth M Rice5,22, Paul I W de Bakker2,6,22, Xiaoyan Yin3,7, Karol Estrada8, Joshua C Bis9,10, Kristin Marciante9,10, Fernando Rivadeneira4,8, Peter A Noseworthy1, Nona Sotoodehnia9,11, Nicholas L Smith9,12,13, Jerome I Rotter14, Jan A Kors15, Jacqueline C M Witteman4,16, Albert Hofman4,16, Susan R Heckbert9,12,17, Christopher J O'Donnell3,18,19, André G Uitterlinden4,8,16, Bruce M Psaty9,10,12,17,20, Thomas Lumley5,23, Martin G Larson3,7,23 & Bruno H Ch Stricker4,8,15,16,21,23
Abstract
QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 
10-8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
- Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
- National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
- Department of Biostatistics, University of Washington, Seattle, Washington, USA.
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
- Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
- Cardiovascular Health Research Unit, University of Washington, Metropolitan Park East Tower, Seattle, Washington, USA.
- Department of Medicine, University of Washington, Seattle, Washington, USA.
- Division of Cardiology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
- Department of Epidemiology, University of Washington, Seattle, Washington, USA.
- Seattle Epidemiologic Research Center, Veterans Administration Office of Research and Development, Seattle, Washington, USA.
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
- Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
- Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
- Center for Health Studies, Group Health, Seattle, Washington, USA.
- National Heart, Lung and Blood Institute, Bethesda, Maryland, USA.
- Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
- Department of Health Services, University of Washington, Seattle, Washington, USA.
- Inspectorate of Health Care, The Hague, The Netherlands.
- These authors contributed equally to this work.
- These authors jointly directed this work.
Correspondence to: Christopher Newton-Cheh1,2,3,22 e-mail: cnewtoncheh@chgr.mgh.harvard.edu
Correspondence to: Bruno H Ch Stricker4,8,15,16,21,23 e-mail: b.stricker@erasmusmc.nl
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