title: Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.
abstract: The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA. nsotoo@u.washington.edu
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mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002877:Chromosomes, Human / Q000235:genetics; D019295:Computational Biology; D004562:Electrocardiography; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels