Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
Bibliographical noteFunding Information:
1Department of Epidemiology, 2Department of Internal Medicine, 3Department of Medical Informatics and 4Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands, 5Center for Human Genetic Research, Cardiovascular Research Center and 6Cardiology Division, Massachusetts General Hospital, Boston, MA, USA, 7Program in Medical Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA, 8National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA,9Division of Cardiology, Department of Medicine, School of Medicine, 10Cardiovascular Health Research Unit, Metropolitan Park East Tower, 11Department of Medicine, 12Department of Biostatistics, 13Department of Epidemiology and 14Department of Health Services, University of Washington, Seattle, WA, USA, 15Division of Genetics, Department of Medicine, Brigham’s and Women’s Hospital, Boston, MA, USA, 16Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 17Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and 18Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany, 19Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA, 20Icelandic Heart Association Research Institute, Kopavogur, Iceland, 21Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy, 22Department of Internal Medicine B, 23Interfaculty Institute for Genetics and Functional Genomics and
24Institute for Community Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany, 25MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK, 26Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Germany), 27Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands, 28Department of Biological Psychology, VU University, Amsterdam, The Netherlands, 29Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA, 30National Institute of Aging’s Laboratory for Epidemiology, Demography, and Biometry, Bethesda, MD, USA, 31Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Munich, Germany, 32McKusick-Nathans Institute of Genetic Medicine and 33Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 34Department of Twin Research and Genetic Epidemiology Unit, St Thomas’ Campus, King’s College London, St Thomas’ Hospital, London, UK, 35Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA, 36Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK, 37Institute of Applied Genomics, Udine, Italy, 38Department of Psychiatry, VU Medical Centre, Amsterdam, The Netherlands, 39EPICARE Center, Winston, Salem, NC, USA, 40Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Ageing, Rotterdam, The Netherlands, 41Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 42Cardiology Division, University of Mississippi Medical Center, Jackson, MS, USA, 43Department of Pharmacology, Center for Pharmacology and Experimental Therapeutics, Greifswald, Germany, 44Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA, 45Institute of Human Genetics, Helmholtz Center Munich, Munich, Germany, 46Institute of Human Genetics, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany, 47Group Health Research Institute, Seattle, WA, USA, 48Klinikum Grosshadern, Munich, Germany, 49St George’s University of London, Cranmer Terrace, London, UK, 50Department of Mathematics and Statistics, Boston University, Boston, MA, USA, 51Department of Neurology, General Central Hospital, Bolzano, Italy, 52Department of Neurology, University of Lübeck, Lübeck, Germany, 53University of Iceland, Reykjavik, Iceland, 54Inspectorate of Health Care, The Hague, The Netherlands and 55National Heart, Lung and Blood Institute, Bethesda, MD, USA