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

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

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    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 languageEnglish
    Pages (from-to)1068-1076
    Number of pages11
    JournalNature Genetics
    Volume42
    Issue number12
    DOIs
    Publication statusPublished - Dec 2010

    Keywords

    • GENOME-WIDE ASSOCIATION
    • QT INTERVAL DURATION
    • RICH REPEAT PROTEIN
    • HEART-RATE
    • TRANSCRIPTION FACTOR
    • GENE-EXPRESSION
    • PR INTERVAL
    • SYSTEM
    • DISEASE
    • ELECTROCARDIOGRAM

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