Nathan A Bihlmeyer1, Jennifer A Brody1, Albert Vernon Smith1, Helen R Warren1, Honghuang Lin1, Aaron Isaacs1, Ching-Ti Liu1, Jonathan Marten1, Farid Radmanesh1, Leanne M Hall1, Niels Grarup1, Hao Mei1, Martina Müller-Nurasyid1, Jennifer E Huffman1, Niek Verweij1, Xiuqing Guo1, Jie Yao1, Ruifang Li-Gao1, Marten van den Berg1, Stefan Weiss1, Bram P Prins1, Jessica van Setten1, Jeffrey Haessler1, Leo-Pekka Lyytikäinen1, Man Li1, Alvaro Alonso1, Elsayed Z Soliman1, Joshua C Bis1, Tom Austin1, Yii-Der Ida Chen1, Bruce M Psaty1, Tamara B Harrris1, Lenore J Launer1, Sandosh Padmanabhan1, Anna Dominiczak1, Paul L Huang1, Zhijun Xie1, Patrick T Ellinor1, Jan A Kors1, Archie Campbell1, Alison D Murray1, Christopher P Nelson1, Martin D Tobin1, Jette Bork-Jensen1, Torben Hansen1, Oluf Pedersen1, Allan Linneberg1, Moritz F Sinner1, Annette Peters1, Melanie Waldenberger1, Thomas Meitinger1, Siegfried Perz1, Ivana Kolcic1, Igor Rudan1, Rudolf A de Boer1, Peter van der Meer1, Henry J Lin1, Kent D Taylor1, Renée de Mutsert1, Stella Trompet1, J Wouter Jukema1, Arie C Maan1, Bruno H C Stricker1, Fernando Rivadeneira1, André Uitterlinden1, Uwe Völker1, Georg Homuth1, Henry Völzke1, Stephan B Felix1, Massimo Mangino1, Timothy D Spector1, Michiel L Bots1, Marco Perez1, Olli T Raitakari1, Mika Kähönen1, Nina Mononen1, Vilmundur Gudnason1, Patricia B Munroe1, Steven A Lubitz1, Cornelia M van Duijn1, Christopher H Newton-Cheh1, Caroline Hayward1, Jonathan Rosand1, Nilesh J Samani1, Jørgen K Kanters1, James G Wilson1, Stefan Kääb1, Ozren Polasek1, Pim van der Harst1, Susan R Heckbert1, Jerome I Rotter1, Dennis O Mook-Kanamori1, Mark Eijgelsheim1, Marcus Dörr1, Yalda Jamshidi1, Folkert W Asselbergs1, Charles Kooperberg1, Terho Lehtimäki1, Dan E Arking1, Nona Sotoodehnia1. 1. From the Predoctoral Training Program in Human Genetics (N.A.B.) and McKusick-Nathans Institute of Genetic Medicine (N.A.B., D.E.A.), Johns Hopkins School of Medicine, Baltimore, MD; Cardiovascular Health Research Unit, Department of Medicine (J.A.B., J.C.B., T.A., N.S.), Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), and Cardiovascular Health Research Unit, Department of Epidemiology (S.R.H.), University of Washington, Seattle; Icelandic Heart Association, Kopavogur (A.V.S., V.G.); Faculty of Medicine, University of Iceland, Reykavik (A.V.S., V.G.); Clinical Pharmacology Department, William Harvey Research Institute, Barts and London School of Medicine and Dentistry (H.R.W., P.B.M.) and NIHR Barts Cardiovascular Biomedical Research Unit (H.R.W., P.B.M.), Queen Mary University of London, United Kingdom; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, MA (H.L., Z.X.); School for Cardiovascular Diseases, Maastricht Center for Systems Biology and Department of Biochemistry, Maastricht University, The Netherlands (A.I.); Genetic Epidemiology Unit, Department of Epidemiology (A.I., C.M.v.D.) and Department of Medical Informatics (J.A.K.), Erasmus University Medical Center, Rotterdam, The Netherlands; Biostatistics Department, Boston University School of Public Health, MA (C.-T.L.); Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (J.M., C.H.), Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine (A.C.), and Usher Institute for Population Health Sciences and Informatics (I.R.), University of Edinburgh, United Kingdom; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (F.R., P.T.E., S.A.L., J.R.); Center for Human Genetic Research (F.R., J.R.), Cardiovascular Research Center (P.L.H., P.T.E., S.A.L.), and Center for Human Genetic Research and Cardiovascular Research Center (C.H.N.-C.), Harvard Medical School, Massachusetts General Hospital, Boston; Department of Cardiovascular Sciences (L.M.H., C.P.N., N.J.S.) and Genetic Epidemiology Group, Department of Health Sciences (M.D.T.), University of Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit (L.M.H., C.P.N.) and NIHR Leicester Respiratory Biomedical Research Unit (M.D.T.), Glenfield Hospital, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences (N.G., J.B.-J., T.H., O.P.), Department of Clinical Medicine, Faculty of Health and Medical Sciences (A.L.), and Laboratory of Experimental Cardiology (J.K.K.), University of Copenhagen, Denmark; Department of Data Science, School of Population Health (H.M.) and Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center, Jackson; Institute of Genetic Epidemiology (M.M.-N.), Institute of Epidemiology II (A.P., M.W., S.P.), Research Unit of Molecular Epidemiology (M.W.), and Institute of Human Genetics (T.M.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Germany (M.M.-N., M.F.S., S.K.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance (M.M.-N., M.F.S., A.P., T.M., S.K.); MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Scotland (J.E.H.); Department of Cardiology (N.V., R.A.d.B., P.v.d.M., P.v.d.H.) and Department of Internal Medicine (M.E.), University Medical Center Groningen, University of Groningen, The Netherlands; Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., J.Y., Y.-D.I.C.); Department of Clinical Epidemiology (R.L.-G., R.d.M.) and University of Split School of Medicine (I.K., O.P.), University of Split, Croatia; Departments of Cardiology (S.T., J.W.J., A.C.M.), Gerontology and Geriatrics (S.T.), and Public Health and Primary Care (D.O.M.-K.), Leiden University Medical Center, The Netherlands; Departments of Medical Informatics (M.v.d.B.), Epidemiology (B.H.C.S.), and Epidemiology (M.E.), Erasmus MC - University Medical Center Rotterdam, The Netherlands; Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University, Greifswald, Germany (S.W., U.V., G.H.); DZHK (German Centre for Cardiovascular Research), partner site Greifswald (S.W., U.V., H.V., S.B.F., M.D.); Cardiogenetics Lab, Genetics and Molecular Cell Sciences Research Centre, Cardiovascular and Cell Sciences Institute, St George's, University of London, United Kingdom (B.P.P., Y.J.); Division Heart and Lungs, Department of Cardiology, (J.v.S., F.W.A.) and Julius Center for Health Sciences and Primary Care (M.L.B.), University Medical Center Utrecht, The Netherlands; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K.); Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., N.M., T.L.); Department of Clinical Physiology, Tampere University Hospital, University of Tampere School of Medicine, Finland (M.K.); Division of Nephrology and Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City (M.L.); Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.); Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC (E.Z.S.); Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD (T.B.H., L.J.L.); Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.D.); Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, United Kingdom (A.D.M.); Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen (A.L.); Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark (A.L.); German Center for Diabetes Research, Neuherberg (A.P.); Institute of Human Genetics, Technische Universität München, Germany (T.M.); Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands (J.W.J.); Interuniversity Cardiology Institute of Netherlands, Utrecht (J.W.J.); Inspectorate of Health Care, Utrecht, The Netherlands (B.H.C.S.); Human Genomics Facility (F.R.) and Human Genotyping Facility (A.U.), Erasmus MC - University Medical Center Rotterdam, The Netherlands; Institute for Community Medicine (H.V.) and Department of Internal Medicine B (S.B.F., M.D.), University Medicine Greifswald, Germany; Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom (M.M., T.D.S.); Stanford School of Medicine, CA (M.P.); Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland (O.T.R.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge (C.H.N.-C.); NIHR Leicester Biomedical Research Unit in Cardiovascular Disease, United Kingdom (N.J.S.); Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
Abstract
BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
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