Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Nat Genet. 2010 Dec;42(12):1068-76. doi: 10.1038/ng.716. Epub 2010 Nov 14.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Chromosomes, Human / genetics
  • Computational Biology
  • Electrocardiography*
  • Genetic Loci / genetics*
  • Genome-Wide Association Study*
  • Heart Conduction System / physiology*
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Myocytes, Cardiac / metabolism
  • NAV1.8 Voltage-Gated Sodium Channel
  • Polymorphism, Single Nucleotide / genetics*
  • Sodium Channels / genetics

Substances

  • NAV1.8 Voltage-Gated Sodium Channel
  • SCN10A protein, human
  • Scn10a protein, mouse
  • Sodium Channels

Grant support