Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

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, Fabiola Del Greco M, 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. 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. Vegte, Pim 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, Kenneth Rice, Nona Sotoodehnia, Alessandro 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 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. 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 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 () and Patricia B. Munroe ()
Additional contact information
Ioanna Ntalla: Queen Mary University of London
Lu-Chen Weng: Massachusetts General Hospital
James H. Cartwright: Queen Mary University of London
Amelia Weber Hall: Massachusetts General Hospital
Gardar Sveinbjornsson: deCODE genetics/Amgen, Inc.
Nathan R. Tucker: Massachusetts General Hospital
Seung Hoan Choi: The Broad Institute of MIT and Harvard
Mark D. Chaffin: The Broad Institute of MIT and Harvard
Carolina Roselli: The Broad Institute of MIT and Harvard
Michael R. Barnes: Queen Mary University of London
Borbala Mifsud: Queen Mary University of London
Helen R. Warren: Queen Mary University of London
Caroline Hayward: Institute of Genetics and Molecular Medicine, University of Edinburgh
Jonathan Marten: Institute of Genetics and Molecular Medicine, University of Edinburgh
James J. Cranley: Queen Mary University of London
Maria Pina Concas: Institute for Maternal and Child Health-IRCCS ‘Burlo Garofolo’
Paolo Gasparini: Institute for Maternal and Child Health-IRCCS ‘Burlo Garofolo’
Thibaud Boutin: Institute of Genetics and Molecular Medicine, University of Edinburgh
Ivana Kolcic: University of Split School of Medicine
Ozren Polasek: University of Split School of Medicine
Igor Rudan: University of Edinburgh
Nathalia M. Araujo: Universidade Federal de Minas Gerais, Belo Horizonte
Maria Fernanda Lima-Costa: Oswaldo Cruz Foundation, Belo Horizonte
Antonio Luiz P. Ribeiro: Hospital das Clínicas e Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte
Renan P. Souza: Universidade Federal de Minas Gerais, Belo Horizonte
Eduardo Tarazona-Santos: Universidade Federal de Minas Gerais, Belo Horizonte
Vilmantas Giedraitis: Geriatrics, Uppsala University
Erik Ingelsson: Stanford University School of Medicine
Anubha Mahajan: University of Oxford
Andrew P. Morris: University of Oxford
Fabiola Del Greco M: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Luisa Foco: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Martin Gögele: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Andrew A. Hicks: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
James P. Cook: University of Liverpool
Lars Lind: Uppsala University Hospital
Cecilia M. Lindgren: Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, University of Oxford
Johan Sundström: Uppsala University
Christopher P. Nelson: Cardiovascular Research Centre, Glenfield Hospital, University of Leicester
Muhammad B. Riaz: Cardiovascular Research Centre, Glenfield Hospital, University of Leicester
Nilesh J. Samani: Cardiovascular Research Centre, Glenfield Hospital, University of Leicester
Gianfranco Sinagra: Azienda Ospedaliera Universitaria Integrata of Trieste
Sheila Ulivi: Institute for Maternal and Child Health-IRCCS ‘Burlo Garofolo’
Mika Kähönen: Tampere University Hospital
Pashupati P. Mishra: Fimlab Laboratories
Nina Mononen: Fimlab Laboratories
Kjell Nikus: Heart Center, Tampere University Hospital
Mark J. Caulfield: Queen Mary University of London
Anna Dominiczak: University of Glasgow
Sandosh Padmanabhan: University of Glasgow
May E. Montasser: University of Maryland School of Medicine
Jeff R. O’Connell: University of Maryland School of Medicine
Kathleen Ryan: University of Maryland School of Medicine
Alan R. Shuldiner: University of Maryland School of Medicine
Stefanie Aeschbacher: University Hospital
David Conen: University Hospital
Lorenz Risch: Inselspital Bern, University Hospital, University of Bern
Sébastien Thériault: McMaster University
Nina Hutri-Kähönen: Tampere University Hospital
Terho Lehtimäki: Fimlab Laboratories
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Olli T. Raitakari: Turku University Hospital
Catriona L. K. Barnes: University of Edinburgh
Harry Campbell: University of Edinburgh
Peter K. Joshi: University of Edinburgh
James F. Wilson: Institute of Genetics and Molecular Medicine, University of Edinburgh
Aaron Isaacs: CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), Department of Biochemistry, and Department of Physiology, Maastricht University
Jan A. Kors: University Medical Center Rotterdam
Cornelia M. Duijn: Erasmus University Medical Center
Paul L. Huang: Massachusetts General Hospital
Vilmundur Gudnason: Icelandic Heart Association
Tamara B. Harris: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH
Lenore J. Launer: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH
Albert V. Smith: Icelandic Heart Association
Erwin P. Bottinger: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Ruth J. F. Loos: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Girish N. Nadkarni: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Michael H. Preuss: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Adolfo Correa: Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center
Hao Mei: University of Mississippi Medical Center
James Wilson: University of Mississippi Medical Center
Thomas Meitinger: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Martina Müller-Nurasyid: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Annette Peters: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Melanie Waldenberger: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Massimo Mangino: Kings College London
Timothy D. Spector: Kings College London
Michiel Rienstra: University of Groningen, University Medical Center Groningen
Yordi J. Vegte: University of Groningen, University Medical Center Groningen
Pim Harst: University of Groningen, University Medical Center Groningen
Niek Verweij: University of Groningen, University Medical Center Groningen
Stefan Kääb: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Katharina Schramm: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Moritz F. Sinner: DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance
Konstantin Strauch: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
Michael J. Cutler: Intermountain Medical Center
Diane Fatkin: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute
Barry London: University of Iowa
Morten Olesen: University Hospital of Copenhagen
Dan M. Roden: Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center
M. Benjamin Shoemaker: Vanderbilt University Medical Center
J. Gustav Smith: Clinical Sciences, Wallenberg Center for Molecular Medicine, Lund University Diabetes Center, Lund University and Skane University Hospital
Mary L. Biggs: Cardiovascular Health Research Unit, Department of Medicine, University of Washington
Joshua C. Bis: Cardiovascular Health Research Unit, Department of Medicine, University of Washington
Jennifer A. Brody: Cardiovascular Health Research Unit, Department of Medicine, University of Washington
Bruce M. Psaty: Cardiovascular Health Research Unit, Department of Medicine, University of Washington
Kenneth Rice: University of Washington
Nona Sotoodehnia: Cardiovascular Health Research Unit, Department of Medicine, University of Washington
Alessandro Grandi: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Christian Fuchsberger: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Cristian Pattaro: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Peter P. Pramstaller: Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck
Ian Ford: Robertson Center for Biostatistics, University of Glasgow
J. Wouter Jukema: Leiden University Medical Center
Peter W. Macfarlane: Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow
Stella Trompet: Leiden University Medical Center
Marcus Dörr: DZHK (German Centre for Cardiovascular Research)
Stephan B. Felix: DZHK (German Centre for Cardiovascular Research)
Uwe Völker: DZHK (German Centre for Cardiovascular Research)
Stefan Weiss: DZHK (German Centre for Cardiovascular Research)
Aki S. Havulinna: Finnish Institute for Health and Welfare
Antti Jula: Finnish Institute for Health and Welfare
Katri Sääksjärvi: Finnish Institute for Health and Welfare
Veikko Salomaa: Finnish Institute for Health and Welfare
Xiuqing Guo: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Susan R. Heckbert: Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington
Henry J. Lin: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Jerome I. Rotter: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Kent D. Taylor: Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Jie Yao: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Renée Mutsert: Leiden University Medical Center
Arie C. Maan: Leiden University Medical Center
Dennis O. Mook-Kanamori: Leiden University Medical Center
Raymond Noordam: Leiden University Medical Center
Francesco Cucca: University of Sassari
Jun Ding: Laboratory of Genetics and Genomics, NIA/NIH
Edward G. Lakatta: Laboratory of Cardiovascular Science, NIA/NIH
Yong Qian: Laboratory of Genetics and Genomics, NIA/NIH
Kirill V. Tarasov: Laboratory of Cardiovascular Science, NIA/NIH
Daniel Levy: Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute
Honghuang Lin: National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Christopher H. Newton-Cheh: The Broad Institute of MIT and Harvard
Kathryn L. Lunetta: National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Alison D. Murray: The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen
David J. Porteous: Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital
Blair H. Smith: Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
Bruno H. Stricker: University Medical Center Rotterdam
André Uitterlinden: Human Genotyping Facility Erasmus MC University Medical Center Rotterdam
Marten E. Berg: University Medical Center Rotterdam
Jeffrey Haessler: Fred Hutchinson Cancer Research Center, Division of Public Health Sciences
Rebecca D. Jackson: Ohio State University
Charles Kooperberg: Fred Hutchinson Cancer Research Center, Division of Public Health Sciences
Ulrike Peters: Fred Hutchinson Cancer Research Center, Division of Public Health Sciences
Alexander P. Reiner: Fred Hutchinson Cancer Research Center, Division of Public Health Sciences
Eric A. Whitsel: University of North Carolina
Alvaro Alonso: Rollins School of Public Health, Emory University
Dan E. Arking: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Eric Boerwinkle: Human Genetics Center, University of Texas Health Science Center at Houston
Georg B. Ehret: Cardiology, Geneva University Hospitals
Elsayed Z. Soliman: Epidemiological Cardiology Research Center, Wake Forest School of Medicine
Christy L. Avery: University of North Carolina
Stephanie M. Gogarten: University of Washington
Kathleen F. Kerr: University of Washington
Cathy C. Laurie: University of Washington
Amanda A. Seyerle: Division of Pharmaceutical Outcomes and Policy, University of North Carolina
Adrienne Stilp: University of Washington
Solmaz Assa: University of Groningen, University Medical Center Groningen
M. Abdullah Said: University of Groningen, University Medical Center Groningen
M. Yldau van der Ende: University of Groningen, University Medical Center Groningen
Pier D. Lambiase: Barts Heart Centre, St Bartholomews Hospital
Michele Orini: Barts Heart Centre, St Bartholomews Hospital
Julia Ramirez: Queen Mary University of London
Stefan Duijvenboden: Queen Mary University of London
David O. Arnar: deCODE genetics/Amgen, Inc.
Daniel F. Gudbjartsson: deCODE genetics/Amgen, Inc.
Hilma Holm: deCODE genetics/Amgen, Inc.
Patrick Sulem: deCODE genetics/Amgen, Inc.
Gudmar Thorleifsson: deCODE genetics/Amgen, Inc.
Rosa B. Thorolfsdottir: deCODE genetics/Amgen, Inc.
Unnur Thorsteinsdottir: deCODE genetics/Amgen, Inc.
Emelia J. Benjamin: National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Andrew Tinker: Queen Mary University of London
Kari Stefansson: deCODE genetics/Amgen, Inc.
Patrick T. Ellinor: Massachusetts General Hospital
Yalda Jamshidi: Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London
Steven A. Lubitz: Massachusetts General Hospital
Patricia B. Munroe: Queen Mary University of London

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Date: 2020
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DOI: 10.1038/s41467-020-15706-x

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