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

Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daníel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M LahtinenIlja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Åsa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Marcel den Hoed, CARe Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)826-36
Number of pages11
JournalNature Genetics
Volume46
Issue number8
DOIs
Publication statusPublished - Aug 2014
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Arrhythmias, Cardiac/genetics
  • Calcium Signaling/genetics
  • Death, Sudden, Cardiac/etiology
  • Electrocardiography/methods
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study/methods
  • Genotype
  • Heart Ventricles/metabolism
  • Humans
  • Long QT Syndrome/genetics
  • Male
  • Middle Aged
  • Myocardium/metabolism
  • Polymorphism, Single Nucleotide

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