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

Duijvenboden, S; Ramírez, J; Young, WJ; Orini, M; Mifsud, B; Tinker, A; Lambiase, PD; (2021) Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders. Human Molecular Genetics 10.1093/hmg/ddab197. (In press). Green open access

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Abstract

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 (1) providing new candidate genes, (2) identifying pleiotropic associations with other cardiovascular traits, and (3) 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 on how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.

Type: Article
Title: Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddab197
Publisher version: http://dx.doi.org/10.1093/hmg/ddab197
Language: English
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 Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10132038
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