Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Arking, Dan E; Pulit, Sara L; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B; Koopmann, Tamara T; Sotoodehnia, Nona; Rossin, Elizabeth J; Morley, Michael; Wang, Xinchen; Johnson, Andrew D; Lundby, Alicia; Gudbjartsson, Daníel F; Noseworthy, Peter A; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M; ... (2014). Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature genetics, 46(8), pp. 826-836. Nature America 10.1038/ng.3014

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The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Medeiros Domingo, Argelia

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1061-4036

Publisher:

Nature America

Language:

English

Submitter:

Argelia Medeiros Domingo

Date Deposited:

03 Mar 2015 09:40

Last Modified:

29 Oct 2015 10:26

Publisher DOI:

10.1038/ng.3014

PubMed ID:

24952745

BORIS DOI:

10.7892/boris.63883

URI:

https://boris.unibe.ch/id/eprint/63883

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