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

N Sotoodehnia, Aaron Isaacs, PIW de Bakker, M Dorr, C Newton-Cheh, IM (Ilja) Nolte, P van der Harst, M (Majon) Muller, Mark Eijgelsheim, A Alonso, AA Hicks, S Padmanabhan, C Hayward, AV Smith, O Polasek, S Giovannone, JY Fu, JW Magnani, KD Marciante, A PfeuferSA Gharib, A Teumer, M Li, JC Bis, Fernando Rivadeneira, T Aspelund, A Kottgen, T Johnson, K Rice, MPS Sie, YA Wang, N Klopp, C Fuchsberger, SH Wild, IM Leach, Karol Estrada Gil, U Volker, AF Wright, FW Asselbergs, JX Qu, A Chakravarti, MF Sinner, Jan Kors, A Petersmann, TB Harris, EZ Soliman, PB Munroe, BM Psaty, Ben Oostra, LA Cupples, S Perz, RA de Boer, André Uitterlinden, H Volzke, TD Spector, FY Liu, E Boerwinkle, AF Dominiczak, JI Rotter, Herpen, D Levy, HE Wichmann, WH van Gilst, JCM Witteman, HK Kroemer, WHL Kao, SR Heckbert, T Meitinger, Bert Hofman, H Campbell, AR Folsom, DJ Veldhuisen, C Schwienbacher, CJ O'Donnell, CB Volpato, MJ Caulfield, JM Connell, L Launer, XW Lu, L Franke, RSN Fehrmann, GT Meerman, HJM Groen, RK Weersma, LH van den Berg, C Wijmenga, RA Ophoff, G Navis, I Rudan, H Snieder, JF Wilson, PP Pramstaller, DS Siscovick, TJ Wang, V Gudnason, Cornelia Duijn, SB Felix, GI Fishman, Y Jamshidi

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250 Citations (Scopus)

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 genomewide 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 x 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.
Original languageUndefined/Unknown
Pages (from-to)1068-1076
Number of pages9
JournalNature Genetics
Volume42
Issue number12
DOIs
Publication statusPublished - 2010

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