Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction
Sotoodehnia N., Isaacs A., De Bakker PIW., DÖrr M., Newton-Cheh C., Nolte IM., Van Der Harst P., Müller M., Eijgelsheim M., Alonso A., Hicks AA., Padmanabhan S., Hayward C., Smith AV., Polasek O., Giovannone S., Fu J., Magnani JW., Marciante KD., Pfeufer A., Gharib SA., Teumer A., Li M., Bis JC., Rivadeneira F., Aspelund T., KÖttgen A., Johnson T., Rice K., Sie MPS., Wang YA., Klopp N., Fuchsberger C., Wild SH., Leach IM., Estrada K., VÖlker U., Wright AF., Asselbergs FW., Qu J., Chakravarti A., Sinner MF., Kors JA., Petersmann A., Harris TB., Soliman EZ., Munroe PB., Psaty BM., Oostra BA., Cupples LA., Perz S., De Boer RA., Uitterlinden AG., VÖlzke H., Spector TD., Liu FY., Boerwinkle E., Dominiczak AF., Rotter JI., Van Herpen G., Levy D., Wichmann HE., Van Gilst WH., Witteman JCM., Kroemer HK., Kao WHL., Heckbert SR.
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. © 2010 Nature America, Inc. All rights reserved.