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

• Type of Material: Article
• Authors: Ionna Ntalla, Queen Mary University London; Lu-Chen Weng, Massachusetts General Hospital; James H. Cartwright, Queen Mary University London; Amelia Weber Hall, Massachusetts General Hospital; Gardar Sveinbjornsson, Amgen Inc; Nathan R. Tucker, Massachusetts General Hospital; Seung Hoan Choi, Broad Institute MIT & Harvard; Adolfo Correa, Emory University; Alvaro Alonso, Emory University; Steven A. Lubitz, Massachusetts General Hospital
• Language: English
• Date: 2020-05-21
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-15706-x
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 2542
• End Page: 2542
• Keywords: Risk; Cardiomyopathy; Science & Technology; Atrial fillibration; Calcineurin; Decrease; Elements; Duration; Mutations; Genome-wide association; Bradycardia; Multidisciplinary Sciences; Science & Technology - Other Topics
• Research Categories: Health Sciences, Oncology; Health Sciences, Public Health; Health Sciences, Epidemiology; Biology, Genetics

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.