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Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders

journal contribution
submitted on 2024-04-30, 07:12 and posted on 2024-04-30, 07:12 authored by Stefan van Duijvenboden, Julia Ramírez, William J Young, Michele Orini, Borbala Mifsud, Andrew Tinker, Pier D Lambiase, Patricia B Munroe

The resting QT interval, an electrocardiographic (ECG) measure of ventricular myocardial repolarization, is a heritable risk marker of cardiovascular mortality, but the mechanisms remain incompletely understood. Previously reported candidate genes have provided insights into the regulatory mechanisms of the QT interval. However, there are still important knowledge gaps. We aimed to gain new insights by (i) providing new candidate genes, (ii) identifying pleiotropic associations with other cardiovascular traits, and (iii) scanning for sexually dimorphic genetic effects. We conducted a genome-wide association analysis for resting QT interval with ~9.8 million variants in 52 107 individuals of European ancestry without known cardiovascular disease from the UK Biobank. We identified 40 loci, 13 of which were novel, including 2 potential sex-specific loci, explaining ~11% of the trait variance. Candidate genes at novel loci were involved in myocardial structure and arrhythmogenic cardiomyopathy. Investigation of pleiotropic effects of QT interval variants using phenome-wide association analyses in 302 000 unrelated individuals from the UK Biobank and pairwise genome-wide comparisons with other ECG and cardiac imaging traits revealed genetic overlap with atrial electrical pathology. These findings provide novel insights into how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.

Other Information

Published in: Human Molecular Genetics
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1093/hmg/ddab197

History

Language

  • English

Publisher

Oxford University Press

Publication Year

  • 2021

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU

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