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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.

Original publication

DOI

10.1038/ng.3014

Type

Journal article

Journal

Nature genetics

Publication Date

08/2014

Volume

46

Pages

826 - 836

Addresses

1] Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2].

Keywords

CARe Consortium, COGENT Consortium, DCCT/EDIC, eMERGE Consortium, HRGEN Consortium, Myocardium, Heart Ventricles, Humans, Long QT Syndrome, Death, Sudden, Cardiac, Genetic Predisposition to Disease, Electrocardiography, Calcium Signaling, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Arrhythmias, Cardiac, Genome-Wide Association Study