Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J. J. M. Brundel, David S. Peal, David M. Evans, Ilja M. Nolte, Ayellet V. Segre, Hilma Holm, Robert E. Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle BochudGabrielle Boucher, Marilyn C. Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U. Jackson, Zoltan Kutalik, Jian'an Luan, John P. Kemp, Kati Kristiansson, Toshiko Tanaka, Femke Hoogstra-Berends, Bart Kanon, Meena Kumari, Irene Mateo Leach, Albert V. Smith, Cisca Wijmenga, Rudolf A. de Boer, Wiek H. van Gilst, Melanie M. van der Klauw, Gerjan Navis, Lu Qi, Ronald P. Stolk, Dirk J. van Veldhuisen, Lude Franke, Ody C. M. Sibon, Harold Snieder, Global BPGen Consortium, CARDIoGRAM Consortium, PR GWGWAS Consortium, QRS GWGWAS Consortium, QT-IGCGC Consortium, CHARGE-AF Consortium

OnderzoeksoutputAcademicpeer review

194 Citaten (Scopus)
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Samenvatting

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Originele taal-2English
Pagina's (van-tot)621-31
Aantal pagina's11
TijdschriftNature Genetics
Volume45
Nummer van het tijdschrift6
DOI's
StatusPublished - jun-2013

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