Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Ιωάννα Ντάλλα; Lu-Chen C Weng; James Cartwright; Amelia Weber Hall; Garðar Sveinbjörnsson; Nathan R. Tucker; Seung Hoan Choi; Mark D. Chaffin; Carolina Roselli; Michael R. Barnes; Borbála Mifsud; Helen R. Warren; Caroline Hayward; Jonathan Marten; James J. Cranley; Maria Pina Concas; Paolo Gasparini; Thibaud Boutin; Ivana Kolčić; Ozren Polašek; Igor Rudan; Nathalia M. Araujo; Maria Fernanda Lima‐Costa; Antônio Luiz Pinho Ribeiro; Renan P. Souza; Eduardo Tarazona-Santos; Vilmantas Giedraitis; Erik Ingelsson; Anubha Mahajan; Andrew P. Morris

doi:10.1101/712398

GeneticsbioRxivJul 30, 2019

Preprint

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Ιωάννα Ντάλλα iD, Lu-Chen C Weng iD, James Cartwright iD, Amelia Weber Hall iD, Garðar Sveinbjörnsson iD, Nathan R. Tucker iD, Seung Hoan Choi iD, Mark D. Chaffin iD, Carolina Roselli iD, Michael R. Barnes iD, Borbála Mifsud iD, Helen R. Warren iD, Caroline Hayward iD, Jonathan Marten iD, James J. Cranley iD, Maria Pina Concas iD, Paolo Gasparini iD, Thibaud Boutin iD, Ivana Kolčić iD, Ozren Polašek iD, Igor Rudan iD, Nathalia M. Araujo, Maria Fernanda Lima‐Costa iD, Antônio Luiz Pinho Ribeiro iD, Renan P. Souza, , Dan M. Roden iD

Abstract

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.

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