Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction
Authors: Ntalla Ioanna , Weng Lu-Chen , Cartwright James H. , Hall Amelia Weber , Sveinbjornsson Gardar , Tucker Nathan R. , Choi Seung Hoan , Chaffin Mark D. , Roselli Carolina , Barnes Michael R. , Mifsud Borbala , Warren Helen R. , Hayward Caroline , Marten Jonathan , Cranley James J. , Concas Maria Pina , Gasparini Paolo , Boutin Thibaud , Kolcic Ivana , Polasek Ozren , Rudan Igor , Araujo Nathalia M. , Lima-Costa Maria Fernanda , Ribeiro Antonio Luiz P. , Souza Renan P. , Tarazona-Santos Eduardo , Giedraitis Vilmantas , Ingelsson Erik , Mahajan Anubha , Morris Andrew P. , Fabiola Del Greco M. , Foco Luisa , Gögele Martin , Hicks Andrew A. , Cook James P. , Lind Lars , Lindgren Cecilia M. , Sundström Johan , Nelson Christopher P. , Riaz Muhammad B. , Samani Nilesh J. , Sinagra Gianfranco , Ulivi Sheila , Kähönen Mika , Mishra Pashupati P. , Mononen Nina , Nikus Kjell , Caulfield Mark J. , Dominiczak Anna , Padmanabhan Sandosh , Montasser May E. , O’Connell Jeff R. , Ryan Kathleen , Shuldiner Alan R. , Aeschbacher Stefanie , Conen David , Risch Lorenz , Thériault Sébastien , Hutri-Kähönen Nina , Lehtimäki Terho , Lyytikäinen Leo-Pekka , Raitakari Olli T. , Barnes Catriona L. K. , Campbell Harry , Joshi Peter K. , Wilson James F. , Isaacs Aaron , Kors Jan A. , van Duijn Cornelia M. , Huang Paul L. , Gudnason Vilmundur , Harris Tamara B. , Launer Lenore J. , Smith Albert V. , Bottinger Erwin P. , Loos Ruth J. F. , Nadkarni Girish N. , Preuss Michael H. , Correa Adolfo , Mei Hao , Wilson James , Meitinger Thomas , Müller-Nurasyid Martina , Peters Annette , Waldenberger Melanie , Mangino Massimo , Spector Timothy D. , Rienstra Michiel , van de Vegte Yordi J. , van der Harst Pim , Verweij Niek , Kääb Stefan , Schramm Katharina , Sinner Moritz F. , Strauch Konstantin , Cutler Michael J. , Fatkin Diane , London Barry , Olesen Morten , Roden Dan M. , Shoemaker M. Benjamin , Smith J. Gustav , Biggs Mary L. , Bis Joshua C. , Brody Jennifer A. , Psaty Bruce M. , Rice Ken , Sotoodehnia Nona , De Grandi Alessandro , Fuchsberger Christian , Pattaro Cristian , Pramstaller Peter P. , Ford Ian , Jukema J. Wouter , Macfarlane Peter W. , Trompet Stella , Dörr Marcus , Felix Stephan B. , Völker Uwe , Weiss Stefan , Havulinna Aki S. , Jula Antti , Sääksjärvi Katri , Salomaa Veikko , Guo Xiuqing , Heckbert Susan R. , Lin Henry J. , Rotter Jerome I. , Taylor Kent D. , Yao Jie , de Mutsert Renée , Maan Arie C. , Mook-Kanamori Dennis O. , Noordam Raymond , Cucca Francesco , Ding Jun , Lakatta Edward G. , Qian Yong , Tarasov Kirill V. , Levy Daniel , Lin Honghuang , Newton-Cheh Christopher H. , Lunetta Kathryn L. , Murray Alison D. , Porteous David J. , Smith Blair H. , Stricker Bruno H. , Uitterlinden André , van den Berg Marten E. , Haessler Jeffrey , Jackson Rebecca D. , Kooperberg Charles , Peters Ulrike , Reiner Alexander P. , Whitsel Eric A. , Alonso Alvaro , Arking Dan E. , Boerwinkle Eric , Ehret Georg B. , Soliman Elsayed Z. , Avery Christy L. , Gogarten Stephanie M. , Kerr Kathleen F. , Laurie Cathy C. , Seyerle Amanda A. , Stilp Adrienne , Assa Solmaz , Said M. Abdullah , van der Ende M. Yldau , Lambiase Pier D. , Orini Michele , Ramirez Julia , Van Duijvenboden Stefan , Arnar David O. , Gudbjartsson Daniel F. , Holm Hilma , Sulem Patrick , Thorleifsson Gudmar , Thorolfsdottir Rosa B. , Thorsteinsdottir Unnur , Benjamin Emelia J. , Tinker Andrew , Stefansson Kari , Ellinor Patrick T. , Jamshidi Yalda , Lubitz Steven A. , Munroe Patricia B. 
Published: July 2019

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. 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.