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

  • Author(s): Sotoodehnia, Nona
  • Isaacs, Aaron
  • de Bakker, Paul IW
  • Dörr, Marcus
  • Newton-Cheh, Christopher
  • Nolte, Ilja M
  • van der Harst, Pim
  • Müller, Martina
  • Eijgelsheim, Mark
  • Alonso, Alvaro
  • Hicks, Andrew A
  • Padmanabhan, Sandosh
  • Hayward, Caroline
  • Smith, Albert Vernon
  • Polasek, Ozren
  • Giovannone, Steven
  • Fu, Jingyuan
  • Magnani, Jared W
  • Marciante, Kristin D
  • Pfeufer, Arne
  • Gharib, Sina A
  • Teumer, Alexander
  • Li, Man
  • Bis, Joshua C
  • Rivadeneira, Fernando
  • Aspelund, Thor
  • Köttgen, Anna
  • Johnson, Toby
  • Rice, Kenneth
  • Sie, Mark PS
  • Wang, Ying A
  • Klopp, Norman
  • Fuchsberger, Christian
  • Wild, Sarah H
  • Mateo Leach, Irene
  • Estrada, Karol
  • Völker, Uwe
  • Wright, Alan F
  • Asselbergs, Folkert W
  • Qu, Jiaxiang
  • Chakravarti, Aravinda
  • Sinner, Moritz F
  • Kors, Jan A
  • Petersmann, Astrid
  • Harris, Tamara B
  • Soliman, Elsayed Z
  • Munroe, Patricia B
  • Psaty, Bruce M
  • Oostra, Ben A
  • Cupples, L Adrienne
  • Perz, Siegfried
  • de Boer, Rudolf A
  • Uitterlinden, André G
  • Völzke, Henry
  • Spector, Timothy D
  • Liu, Fang-Yu
  • Boerwinkle, Eric
  • Dominiczak, Anna F
  • Rotter, Jerome I
  • van Herpen, Gé
  • Levy, Daniel
  • Wichmann, H-Erich
  • van Gilst, Wiek H
  • Witteman, Jacqueline CM
  • Kroemer, Heyo K
  • Kao, WH Linda
  • Heckbert, Susan R
  • Meitinger, Thomas
  • Hofman, Albert
  • Campbell, Harry
  • Folsom, Aaron R
  • van Veldhuisen, Dirk J
  • Schwienbacher, Christine
  • O'Donnell, Christopher J
  • Volpato, Claudia Beu
  • Caulfield, Mark J
  • Connell, John M
  • Launer, Lenore
  • Lu, Xiaowen
  • Franke, Lude
  • Fehrmann, Rudolf SN
  • te Meerman, Gerard
  • Groen, Harry JM
  • Weersma, Rinse K
  • van den Berg, Leonard H
  • Wijmenga, Cisca
  • Ophoff, Roel A
  • Navis, Gerjan
  • Rudan, Igor
  • Snieder, Harold
  • Wilson, James F
  • Pramstaller, Peter P
  • Siscovick, David S
  • Wang, Thomas J
  • Gudnason, Vilmundur
  • van Duijn, Cornelia M
  • Felix, Stephan B
  • Fishman, Glenn I
  • Jamshidi, Yalda
  • Stricker, Bruno H Ch
  • Samani, Nilesh J
  • Kääb, Stefan
  • Arking, Dan E
  • et al.

Published Web Location

https://doi.org/10.1038/ng.716
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.

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