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Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Lin, H; van Setten, J; Smith, AV; Bihlmeyer, NA; Warren, HR; Brody, JA; Radmanesh, F; ... Isaacs, A; + view all (2018) Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circulation: Genomic and Precision Medicine , 11 (5) , Article e002037. 10.1161/CIRCGEN.117.002037. Green open access

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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.

Type: Article
Title: Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/CIRCGEN.117.002037
Publisher version: https://doi.org/10.1161/CIRCGEN.117.002037
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Electrocardiogram, PR interval, genetics, exome chip, epidemiology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10067463
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