Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction
Year: 2019
Type: preprint
Study design: Observational Study
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality 1,2 . We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
DOI: 10.1101/712398
Authors: Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Greco M. Fabiola Del, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Ken Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, Patricia B. Munroe
Institutions: Queen Mary University of London, William Harvey Research Institute, Broad Institute, Massachusetts General Hospital, deCODE Genetics (Iceland), University Medical Center Groningen, University of Groningen, National Institute for Health and Care Research, Hamad bin Khalifa University, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, IRCCS Materno Infantile Burlo Garofolo, University of Trieste, University of Split, Psychiatric Hospital Sveti Ivan, Klinički Bolnički Centar Split, Universidade Federal de Minas Gerais, Fundação Oswaldo Cruz, Hospital das Clínicas da Universidade Federal de Minas Gerais, Uppsala University, Science for Life Laboratory, Stanford Medicine, Stanford Diabetes Research Center, Stanford Cardiovascular Institute, Stanford University, Centre for Human Genetics, University of Oxford, University of Liverpool, University of Manchester, Eurac Research, Institute for Biomedicine, Uppsala University Hospital, University of Leicester, Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Azienda Sanitaria Universitaria Integrata di Trieste, Tampere University, Tampere University Hospital, University of Tampere, Fimlab (Finland), University of Glasgow, University of Maryland, Baltimore, University Hospital of Basel, Population Health Research Institute, McMaster University, University of Bern, University Hospital of Bern, Private University in the Principality of Liechtenstein, Université Laval, University of Turku, Turku University Hospital, University of Mississippi Medical Center, Maastricht University, Erasmus MC, Erasmus University Rotterdam, University of Iceland, Icelandic Heart Association, National Institutes of Health, National Institute on Aging, University of Michigan, Icahn School of Medicine at Mount Sinai, TUM Klinikum, Helmholtz Munich, German Centre for Cardiovascular Research, Institut für Humangenetik, Technical University of Munich, LMU Klinikum, Ludwig-Maximilians-Universität München, German Center for Diabetes Research, King's College London, Guy's and St Thomas' NHS Foundation Trust, Genomics (United Kingdom), Intermountain Healthcare, Intermountain Medical Center, Victor Chang Cardiac Research Institute, UNSW Sydney, St Vincent's Hospital Sydney, University of Iowa, University of Iowa Health Care, University of Copenhagen, Copenhagen University Hospital, Rigshospitalet, Vanderbilt University, Vanderbilt University Medical Center, Lund University, Skåne University Hospital, University of Washington, Kaiser Permanente Washington Health Research Institute, Leiden University Medical Center, Universitätsmedizin Greifswald, Universität Greifswald, University of Helsinki, Finnish Institute for Health and Welfare, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, The Lundquist Institute, Harbor–UCLA Medical Center, Boston University, Framingham Heart Study, University of Sassari, National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute Division of Intramural Research, Harvard University, University of Aberdeen, Western General Hospital, University of Dundee, Ninewells Hospital, Fred Hutch Cancer Center, The Ohio State University, University of North Carolina at Chapel Hill, Emory University, Johns Hopkins University, The University of Texas Health Science Center at Houston, University Hospital of Geneva, Wake Forest University Health Sciences, Wake Forest University, St Bartholomew's Hospital, University College London, National University Hospital of Iceland, University of London, St George's, University of London
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7213364261