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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.

Original publication

DOI

10.1038/ng.2610

Type

Journal article

Journal

Nature genetics

Publication Date

06/2013

Volume

45

Pages

621 - 631

Addresses

Medical Research Council MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

Keywords

Global BPgen Consortium, CARDIoGRAM Consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, CHARGE-AF Consortium, Heart Conduction System, Animals, Humans, Heart Rate, Gene Frequency, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Metabolic Networks and Pathways, Arrhythmias, Cardiac, Genome-Wide Association Study, Genetic Loci