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

Abstract

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.

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

“…These include early onset, 100% penetrant postnatal lethality, cardiomyopathy, bradycardia, and cardiac dysfunction, together with defects in cellular metabolism and mitochondrial structure and function. Intriguingly, the Mfn1 locus was recently found to impact heart rate in humans through genome-wide association studies (GWAS), and its knockdown reduced heart rate in both fruit fly and zebrafish (64). These findings raise the possibility that these cardiac phenotypes are controlled by a common cellular pathway involving ERR, Representative ECG of 16-day-old mice.…”

Fibrosis, Electrics and Genetics

“…In addition to Mendelian inheritance described below, there is polygenetic susceptibility to SND; a genome-wide association study identified polymorphisms at 21 loci, including HCN4 and Nkx-2.5 that determine the HR in healthy individuals. 67 These were found to associate with the risk of SND and pacemaker implantation.…”

The formation and function of the cardiac conduction system

“…Several genome-wide association studies (GWAS) have been conducted in the last decade, uncovering common variants within the human population that are associated with traits affecting CCS function, including perturbed PR interval, QRS duration and QT interval. The loci identified in these studies harbour genes encoding well-known cardiac transcription factors such as TBX3, TBX5, TBX20, NKX2-5, MEIS1 and HEY2, and genes encoding ion channels such as SCN5A, SCN10A, KCNQ1, KCNH2 and HCN4 (Holm et al, 2010;Pfeufer et al, 2010;Sotoodehnia et al, 2010;Bezzina et al, 2013;den Hoed et al, 2013;Verweij et al, 2014; Table 1). Interestingly, as discussed above, many of these genes are implicated in the CCS gene regulatory network.…”