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

Ntalla, I.; Weng, L.C.; Cartwright, J.H.; Hall, A.W.; Sveinbjornsson, G.; Tucker, N.R.; ... ; Munroe, P.B. (2020)

Article / Letter to editor

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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

• All authors: Ntalla, I.; Weng, L.C.; Cartwright, J.H.; Hall, A.W.; Sveinbjornsson, G.; Tucker, N.R.; Choi, S.H.; Chaffin, M.D.; Roselli, C.; Barnes, M.R.; Mifsud, B.; Warren, H.R.; Hayward, C.; Marten, J.; Cranley, J.J.; Concas, M.P.; Gasparini, P.; Boutin, T.; Kolcic, I.; Polasek, O.; Rudan, I.; Araujo, N.M.; Lima-Costa, M.F.; Ribeiro, A.L.P.; Souza, R.P.; Tarazona-Santos, E.; Giedraitis, V.; Ingelsson, E.; Mahajan, A.; Morris, A.P.; Greco, M.F. del; Foco, L.; Gogele, M.; Hicks, A.A.; Cook, J.P.; Lind, L.; Lindgren, C.M.; Sundstrom, J.; Nelson, C.P.; Riaz, M.B.; Samani, N.J.; Sinagra, G.; Ulivi, S.; Kahonen, M.; Mishra, P.P.; Mononen, N.; Nikus, K.; Caulfield, M.J.; Dominiczak, A.; Padmanabhan, S.; Montasser, M.E.; O'Connell, J.R.; Ryan, K.; Shuldiner, A.R.; Aeschbacher, S.; Conen, D.; Risch, L.; Theriault, S.; Hutri-Kahonen, N.; Lehtimaki, T.; Lyytikainen, L.P.; Raitakari, O.T.; Barnes, C.L.K.; Campbell, H.; Joshi, P.K.; Wilson, J.F.; Isaacs, A.; Kors, J.A.; Duijn, C.M. van; Huang, P.L.; Gudnason, V.; Harris, T.B.; Launer, L.J.; Smith, A.V.; Bottinger, E.P.; Loos, R.J.F.; Nadkarni, G.N.; Preuss, M.H.; Correa, A.; Mei, H.; Wilson, J.; Meitinger, T.; Muller-Nurasyid, M.; Peters, A.; Waldenberger, M.; Mangino, M.; Spector, T.D.; Rienstra, M.; Vegte, Y.J. van de; Harst, P. van der; Verweij, N.; Kaab, S.; Schramm, K.; Sinner, M.F.; Strauch, K.; Cutler, M.J.; Fatkin, D.; London, B.; Olesen, M.; Roden, D.M.; Shoemaker, M.B.; Smith, J.G.; Biggs, M.L.; Bis, J.C.; Brody, J.A.; Psaty, B.M.; Rice, K.; Sotoodehnia, N.; Grandi, A. de; Fuchsberger, C.; Pattaro, C.; Pramstaller, P.P.; Ford, I.; Jukema, J.W.; Macfarlane, P.W.; Trompet, S.; Dorr, M.; Felix, S.B.; Volker, U.; Weiss, S.; Havulinna, A.S.; Jula, A.; Saaksjarvi, K.; Salomaa, V.; Guo, X.Q.; Heckbert, S.R.; Lin, H.J.; Rotter, J.I.; Taylor, K.D.; Yao, J.; Mutsert, R. de; Maan, A.C.; Mook-Kanamori, D.O.; Noordam, R.; Cucca, F.; Ding, J.; Lakatta, E.G.; Qian, Y.; Tarasov, K.V.; Levy, D.; Lin, H.H.; Newton-Cheh, C.H.; Lunetta, K.L.; Murray, A.D.; Porteous, D.J.; Smith, B.H.; Stricker, B.H.; Uitterlinden, A.; Berg, M.E. van den; Haessler, J.; Jackson, R.D.; Kooperberg, C.; Peters, U.; Reiner, A.P.; Whitsel, E.A.; Alonso, A.; Arking, D.E.; Boerwinkle, E.; Ehret, G.B.; Soliman, E.Z.; Avery, C.L.; Gogarten, S.M.; Kerr, K.F.; Laurie, C.C.; Seyerle, A.A.; Stilp, A.; Assa, S.; Said, M.A.; Ende, M.Y. van der; Lambiase, P.D.; Orini, M.; Ramirez, J.; Duijvenboden, S. van; Arnar, D.O.; Gudbjartsson, D.F.; Holm, H.; Sulem, P.; Thorleifsson, G.; Thorolfsdottir, R.B.; Thorsteinsdottir, U.; Benjamin, E.J.; Tinker, A.; Stefansson, K.; Ellinor, P.T.; Jamshidi, Y.; Lubitz, S.A.; Munroe, P.B.
• Date: 2020-05-21
• Journal: Nature Communications
• Volume: 11
• Issue: 1
• DOI: doi:10.1038/s41467-020-15706-x
• Link: https://www.nature.com/articles/s41467-020-15706-x