Nature Genetics 38, 644 - 651 (2006)
Published online: 30 April 2006; | doi:10.1038/ng1790
A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarizationDan E Arking1, 2, 16, Arne Pfeufer3, 4, 16, Wendy Post2, 5, W H Linda Kao5, Christopher Newton-Cheh6, 7, 8, Morna Ikeda1, Kristen West1, Carl Kashuk1, Mahmut Akyol3, 4, Siegfried Perz9, Shapour Jalilzadeh3, 4, Thomas Illig10, Christian Gieger10, Chao-Yu Guo6, 11, Martin G Larson6, 11, H Erich Wichmann10, 12, Eduardo Marbán2, Christopher J O'Donnell6, 7, 8, Joel N Hirschhorn7, 13, 14, Stefan Kääb15, Peter M Spooner2, Thomas Meitinger3, 4
& Aravinda Chakravarti11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 2
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 3
Institute of Human Genetics, Technical University Munich, D-81675 Munich, Germany. 4
Institute of Human Genetics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Germany. 5
Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. 6
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702, USA. 7
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02139, USA. 8
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 9
Institute of Medical Informatics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Germany. 10
Institute of Epidemiology, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Germany. 11
Department of Mathematics and Statistics, Boston University, Boston 02215, Massachusetts, USA. 12
Institute of Information Management, Biometry and Epidemiology, Ludwig-Maximilians-Universität, D-81377 Munich, Germany. 13
Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston 02115, Massachusetts, USA. 14
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. 15
Department of Medicine I, Ludwig-Maximilians-Universität, D-81377 Munich, Germany. 16
These authors contributed equally to this work.
Correspondence should be addressed to Aravinda Chakravarti aravinda@jhmi.edu Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.
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