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 PolasekIgor 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 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, Kenneth 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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number2542
Number of pages12
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 21 May 2020

Keywords

  • cardiovascular diseases
  • cardiovascular genetics
  • genome-wide association studies
  • CARDIOMYOPATHY
  • DECREASE
  • RISK
  • BRADYCARDIA
  • ATRIAL-FIBRILLATION
  • ELEMENTS
  • CALCINEURIN
  • MUTATIONS
  • DURATION
  • GENOME-WIDE ASSOCIATION

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