Dataset Information

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.

SUBMITTER: Sotoodehnia N

PROVIDER: S-EPMC3338195 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Sotoodehnia Nona N Isaacs Aaron A de Bakker Paul I W PI Dörr Marcus M Newton-Cheh Christopher C Nolte Ilja M IM van der Harst Pim P Müller Martina M Eijgelsheim Mark M Alonso Alvaro A Hicks Andrew A AA Padmanabhan Sandosh S Hayward Caroline C Smith Albert Vernon AV Polasek Ozren O Giovannone Steven S Fu Jingyuan J Magnani Jared W JW Marciante Kristin D KD Pfeufer Arne A Gharib Sina A SA Teumer Alexander A Li Man M Bis Joshua C JC Rivadeneira Fernando F Aspelund Thor T Köttgen Anna A Johnson Toby T Rice Kenneth K Sie Mark P S MP Wang Ying A YA Klopp Norman N Fuchsberger Christian C Wild Sarah H SH Mateo Leach Irene I Estrada Karol K Völker Uwe U Wright Alan F AF Asselbergs Folkert W FW Qu Jiaxiang J Chakravarti Aravinda A Sinner Moritz F MF Kors Jan A JA Petersmann Astrid A Harris Tamara B TB Soliman Elsayed Z EZ Munroe Patricia B PB Psaty Bruce M BM Oostra Ben A BA Cupples L Adrienne LA Perz Siegfried S de Boer Rudolf A RA Uitterlinden André G AG Völzke Henry H Spector Timothy D TD Liu Fang-Yu FY Boerwinkle Eric E Dominiczak Anna F AF Rotter Jerome I JI van Herpen Gé G Levy Daniel D Wichmann H-Erich HE van Gilst Wiek H WH Witteman Jacqueline C M JC Kroemer Heyo K HK Kao W H Linda WH Heckbert Susan R SR Meitinger Thomas T Hofman Albert A Campbell Harry H Folsom Aaron R AR van Veldhuisen Dirk J DJ Schwienbacher Christine C O'Donnell Christopher J CJ Volpato Claudia Beu CB Caulfield Mark J MJ Connell John M JM Launer Lenore L Lu Xiaowen X Franke Lude L Fehrmann Rudolf S N RS te Meerman Gerard G Groen Harry J M HJ Weersma Rinse K RK van den Berg Leonard H LH Wijmenga Cisca C Ophoff Roel A RA Navis Gerjan G Rudan Igor I Snieder Harold H Wilson James F JF Pramstaller Peter P PP Siscovick David S DS Wang Thomas J TJ Gudnason Vilmundur V van Duijn Cornelia M CM Felix Stephan B SB Fishman Glenn I GI Jamshidi Yalda Y Stricker Bruno H Ch BH Samani Nilesh J NJ Kääb Stefan S Arking Dan E DE

Nature genetics 20101114 12

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 ...[more]

PMID: 21076409

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Project description:RationaleThe heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood.ObjectiveTo study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning.Methods and resultsUsing mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS.ConclusionsThe CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.

Dataset Information

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

Publications

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

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