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.

Figure 1

Manhattan plot of SNPs after meta-analysis of stage 1. The plot shows the significance of associations between all SNPs and heart rate in stage 1. The 7 loci that were previously identified are highlighted in light blue; the 14 newly associated loci are highlighted in dark blue. Loci that reached P < 3 × 10⁻⁵ after stage 1 but did not reach P < 5 × 10⁻⁸ after meta-analysis of stages 1 and 2 combined are highlighted in red.

Figure 2

Effect size as a function of effect allele frequency. The plot shows the effect sizes of the 21 heart rate–associated SNPs after joint meta-analysis of stage 1 and stage 2 results as a function of their effect allele frequencies. Light-blue circles represent the 7 previously identified heart rate loci; dark blue circles represent the 14 newly identified heart rate loci.

Figure 3

Combined effect of heart rate–increasing alleles on heart rate. (a) Combined effect of the 19 available heart rate loci in adults of European descent (LifeLines2, n = 5,053). (b) Combined effect of the 21 heart rate loci in 12-year-old children of European descent (ALSPAC, n = 4,000). In each plot, the number of heart rate–increasing alleles was summed across the heart rate–associated SNPs. The number of heart rate–increasing alleles is shown (x axis), grouped at the extremes, and mean heart rate ± s.e.m. is plotted (right y axis). The lines represent the regression of the mean heart rate values across the GPS distribution. The histogram shows the number of individuals in each GPS window (left y axis).

Figure 4

Effects on heart rate of reduced or ablated expression of orthologs of positional candidate genes from GWAS in D. melanogaster and D. rerio. Bars show the heart rate (± s.e.m.) of (i) D. melanogaster pupae with orthologs of positional candidate genes located within 500 kb of GWAS associations downregulated using RNAi compared with control pupae (blue bars) and (ii) D. rerio (zebrafish) embryos with expression of orthologs of positional candidate genes reduced by injecting morpholino oligonucleotides versus PBS (red bars). Darker coloring indicates that heart rate is significantly different in targeted animals compared with controls after Bonferroni correction for 23 tests in D. melanogaster (P < 2 × 10⁻³) and 12 tests in D. rerio (P < 4 × 10⁻³); lighter coloring indicates that differences do not reach significance. Results are ordered by availability (D. melanogaster and D. rerio, D. melanogaster only, D. rerio only) and by effect size.