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.
Conflict of interest statement
COMPETING FINANCIAL INTERESTS
The authors declare competing financial interests: details are available in the online version of the paper.
Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk.Circulation. 2013 Apr 2;127(13):1377-85. doi: 10.1161/CIRCULATIONAHA.112.000604. Epub 2013 Mar 5. Circulation. 2013. PMID: 23463857 Free PMC article. Clinical Trial.
Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac conduction.PLoS Genet. 2012;8(12):e1003113. doi: 10.1371/journal.pgen.1003113. Epub 2012 Dec 6. PLoS Genet. 2012. PMID: 23236294 Free PMC article.
Quantitative trait loci for electrocardiographic parameters and arrhythmia in the mouse.J Mol Cell Cardiol. 2011 Mar;50(3):380-9. doi: 10.1016/j.yjmcc.2010.09.009. Epub 2010 Sep 18. J Mol Cell Cardiol. 2011. PMID: 20854825
Genetic polymorphisms and arrhythmia susceptibility.Circ J. 2007;71 Suppl A:A54-60. doi: 10.1253/circj.71.a54. Circ J. 2007. PMID: 17587741 Review.
Genome-wide association studies of late-onset cardiovascular disease.J Mol Cell Cardiol. 2015 Jun;83:131-41. doi: 10.1016/j.yjmcc.2015.04.004. Epub 2015 Apr 11. J Mol Cell Cardiol. 2015. PMID: 25870159 Free PMC article. Review.
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