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Abstract
Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
Highlights
Increased resting heart rate (HR) is a known risk factor for cardiovascular morbidity and mortality (1–3), including stroke (4) and sudden cardiac death (5,6)
We evaluated regions containing the five unreported novel HR loci and five independent secondary variants at previously reported HR loci (12) together with all 67 published HR-associated SNVs [21 loci reported from the original genome-wide association studies (GWASs) (12) plus 46 loci recently published from UK Biobank (17)]
We considered all 67 published HR loci [21 previously reported GWAS loci (12) plus 46 recently published loci from UK Biobank (17)] and extracted all SNVs in high linkage disequilibrium (LD) with the lead variants (r2 ! 0.8), tagging the same association signal, restricted to variants covered on the Exome Chip
Summary
Increased resting heart rate (HR) is a known risk factor for cardiovascular morbidity and mortality (1–3), including stroke (4) and sudden cardiac death (5,6). High HR increases myocardial oxygen consumption yet lessens oxygen delivery to myocardial tissue. It increases arterial stiffness and risk of plaque rupture (8). HR can be influenced by many non-genetic factors (e.g. exercise, smoking and cardiovascular drugs), the heritability of resting HR is estimated to be 26–32% from family studies (9,10), and 55–63% from twin studies (11). There were 21 HR loci previously reported at the time of our study by den Hoed et al (12) in a GWAS analysis of 180 000 individuals, predominantly of European ancestry. Together the previous loci from GWAS at the time of our study only explain a small percentage [0.9% of the variability in HR (12,17)]
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