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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-15706-x

2041-1723

Ιωάννα Ντάλλα, Lu‐Chen Weng, James Cartwright, Amelia Weber Hall, Garðar Sveinbjörnsson, Nathan R. Tucker, Seung Hoan Choi, Mark Chaffin, Carolina Roselli, Michael R. Barnes, Borbála Mifsud, Helen Warren, Caroline Hayward, Jonathan Marten, James Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolčić, Ozren Polašek, Igor Rudan, Nathalia Matta Araujo, Maria Fernanda Lima‐Costa, Antônio Luiz Pinho 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 Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna F. Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff O’Connell, Kathleen A. 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 Guðnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Böttinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael Preuß, Adolfo Correa, Hao Mei, James G. Wilson, Thomas Meitinger, Martina Müller‐Nurasyid, Annette Peters, Mélanie 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 S. Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. G. 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 Newton‐Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André G. Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Álvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne M. Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramírez, Stefan van Duijvenboden, Davíð O. Arnar, Daníel F. Guðbjartsson, Hilma Hólm, Patrick Sulem, Guðmar Þorleifsson, Rósa B. Þórólfsdóttir, Unnur Þorsteinsdóttir, Emelia J. Benjamin, Andrew Tinker, Kāri Stefánsson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, Patricia B. Munroe,

Cardiac electrophysiology and arrhythmias

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.