Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

• Type of Material: Article
• Authors: Honghuang Lin, Boston University; Jessica van Setten, Utrecht University; Albert V Smith, Icelandic Heart Association; Nathan A Bihlmeyer, Johns Hopkins University; Helen R Warren, Queen Mary University London; Jennifer A Brody, University of Washington; Farid Radmanesh, Massachusetts General Hospital; Leanne Hall, University of Leicester; Niels Grarup, University of Copenhagen; Martina Mueller-Nurasyid, Ludwig Maximilians University; Thibaud Boutin, University of Edinburgh; Niek Verweij, University of Groningen; Henry J Lin, UCLA Medical Center; Ruifang Li-Gao, Leiden University; Marten E van den Berg, University Medical Center Rotterdam; Jonathan Marten, University of Edinburgh; Stefan Weiss, Ernst-Moritz-Arndt University; Bram Prins, St George's University; Jeffrey Haessler, Fred Hutchinson Cancer Research Center; Alvaro Alonso, Emory University
• Language: English
• Date: 2018-05-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCGEN.117.002037
• Title of Journal or Parent Work: Circulation: Genomic and Precision Medicine
• ISSN: 2574-8300
• Volume: 11
• Issue: 5
• Start Page: e002037
• End Page: e002037
• Grant/Funding Information: Niek Verweij is supported by ICIN-NHI and Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395).; Dr. Sotoodehnia is supported by NIH grants HL116747 and HL111089.; This work was partly supported by grants from the National Institutes of Health to Drs. Ellinor, Benjamin, and Lunetta (2RO1HL092577); Ellinor and Benjamin (R01HL128914); Ellinor (K24HL105780); and Arking and Sotoodehnia (R01HL116747).; Dr. Lin was partly supported by Boston University Digital Health Initiative;and the National Center for Advancing Translational Sciences; National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430.; Dr. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013); and by the Fondation Leducq (14CVD01).; Dr. Lubitz is supported by NIH grants K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105.
• Keywords: LOCI; MUTATIONS; SUSCEPTIBILITY; Cardiovascular System & Cardiology; LONG QT SYNDROME; SCN10A; atrioventricular node; CONDUCTION; HERITABILITY; GENOME-WIDE ASSOCIATION; VARIANTS; Life Sciences & Biomedicine; genetic loci; Genetics & Heredity; Science & Technology; SCN5A GENE; genome-wide association study; Cardiac & Cardiovascular Systems
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Medicine and Surgery

Abstract

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.