TY - JOUR
T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
AU - Gasparini Paolo
AU - Ntalla, Ioanna
AU - Weng, Lu Chen
AU - Cartwright, James H.
AU - Hall, Amelia Weber
AU - Sveinbjornsson, Gardar
AU - Tucker, Nathan R.
AU - Choi, Seung Hoan
AU - Chaffin, Mark D.
AU - Roselli, Carolina
AU - Barnes, Michael R.
AU - Mifsud, Borbala
AU - Warren, Helen R.
AU - Hayward, Caroline
AU - Marten, Jonathan
AU - Cranley, James J.
AU - Concas, Maria Pina
AU - Gasparini, Paolo
AU - Boutin, Thibaud
AU - Kolcic, Ivana
AU - Polasek, Ozren
AU - Rudan, Igor
AU - Araujo, Nathalia M.
AU - Lima-Costa, Maria Fernanda
AU - Ribeiro, Antonio Luiz P.
AU - Souza, Renan P.
AU - Tarazona-Santos, Eduardo
AU - Giedraitis, Vilmantas
AU - Ingelsson, Erik
AU - Mahajan, Anubha
AU - Morris, Andrew P.
AU - Del Greco M, Fabiola
AU - Foco, Luisa
AU - Gögele, Martin
AU - Hicks, Andrew A.
AU - Cook, James P.
AU - Lind, Lars
AU - Lindgren, Cecilia M.
AU - Sundström, Johan
AU - Nelson, Christopher P.
AU - Riaz, Muhammad B.
AU - Samani, Nilesh J.
AU - Sinagra, Gianfranco
AU - Ulivi, Sheila
AU - Kähönen, Mika
AU - Mishra, Pashupati P.
AU - Mononen, Nina
AU - Nikus, Kjell
AU - Caulfield, Mark J.
AU - Dominiczak, Anna
AU - Padmanabhan, Sandosh
N1 - Funding Information:
I.N. became a full-time employee of Gilead Sciences Ltd following submission of the manuscript. S.A.L. receives sponsored research support from Bristol Myers Squibb/ Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P. T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. M.J.C. is Chief Scientist for Genomics England, a UK Government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a modest honorarium for participating in an advisory board meeting. K.S., H.H., P.S., G.S., G.T., R.B.T., U.T., D.O.A., D.F.G. are employed by deCODE genetics/ Amgen Inc. E.I. is employed by GlaxoSmithKline. A.M. is employed by Genentech Inc.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15706-x
DO - 10.1038/s41467-020-15706-x
M3 - Article
C2 - 32439900
AN - SCOPUS:85085157192
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2542
ER -