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Nature Research, Nature Genetics, 8(46), p. 826-836

DOI: 10.1038/ng.3014

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

Journal article published in 2014 by Henriette Meyer zu Schwabedissen, Pim van der Harst, Johan Ärnl, Pieter A. van der Vleuten, Johan Ärnlöv, Dan E. Arking, Sara L. Pulit, M. F. del Greco, Lia Crotti, Hm Zu Schwabedissen, Patricia B. Munroe, Tamara Tt Koopmann, Nona Sotoodehnia, Piw De Bakker, Martina Müller-Nurasyid and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

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. © 2014 Nature America, Inc.