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

Gasparini Paolo

doi:10.1038/s41467-020-15706-x

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

Gasparini Paolo

IRCCS pediatrico Burlo Garofolo

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	2542
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15706-x
Publication status	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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@article{af3179933fec428b8061e99d2e7a6f7c,

title = "Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction",

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.",

author = "{Gasparini Paolo} and Ioanna Ntalla and Weng, {Lu Chen} and Cartwright, {James H.} and Hall, {Amelia Weber} and Gardar Sveinbjornsson and Tucker, {Nathan R.} and Choi, {Seung Hoan} and Chaffin, {Mark D.} and Carolina Roselli and Barnes, {Michael R.} and Borbala Mifsud and Warren, {Helen R.} and Caroline Hayward and Jonathan Marten and Cranley, {James J.} and Concas, {Maria Pina} and Paolo Gasparini and Thibaud Boutin and Ivana Kolcic and Ozren Polasek and Igor Rudan and Araujo, {Nathalia M.} and Lima-Costa, {Maria Fernanda} and Ribeiro, {Antonio Luiz P.} and Souza, {Renan P.} and Eduardo Tarazona-Santos and Vilmantas Giedraitis and Erik Ingelsson and Anubha Mahajan and Morris, {Andrew P.} and {Del Greco M}, Fabiola and Luisa Foco and Martin G{\"o}gele and Hicks, {Andrew A.} and Cook, {James P.} and Lars Lind and Lindgren, {Cecilia M.} and Johan Sundstr{\"o}m and Nelson, {Christopher P.} and Riaz, {Muhammad B.} and Samani, {Nilesh J.} and Gianfranco Sinagra and Sheila Ulivi and Mika K{\"a}h{\"o}nen and Mishra, {Pashupati P.} and Nina Mononen and Kjell Nikus and Caulfield, {Mark J.} and Anna Dominiczak and Sandosh Padmanabhan",

note = "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: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-15706-x",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "NLM (Medline)",

number = "1",

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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

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VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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