Discovery of novel heart rate-associated loci using the Exome Chip

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.

Figure 1

Schematic flow diagram of the study design. N, sample size; SKAT, SNV-set Kernel Association Test; P, P-value; LD, linkage disequilibrium; SNV, single nucleotide variant; GCTA, Genome-wide Complex Traits Analysis software; 1958BC, 1958 Birth Cohort; UKB, UK Biobank.

Figure 2

Manhattan plot for the RR-interval discovery meta-analysis in European individuals. The Manhattan plot displays the results from the discovery meta-analysis of RR-intervals from N = 104,452 individuals of European ancestry (from 30 cohorts). On the X axis, P-values are expressed as −log₁₀(P) are plotted according to physical genomic locations by chromosome. The Y-axis is truncated to −log₁₀(P) = 20 with any variants with P < 1 × 10⁻²⁰ displayed on the −log₁₀(P) = 20 line. The nine novel variants validated from the combined meta-analysis with UK Biobank data are represented by squares. Variants in linkage disequilibrium (LD; r² > 0.8) with published GWAS variants are highlighted with black circles (12). New secondary variants validated in our analysis are indicated as triangles. Locus names of the novel loci correspond to the nearest annotated gene, with 5p13.3 denoting an intergenic variant. The dashed line indicates a P-value threshold of 1 × 10⁻⁵, corresponding to the lookup significance threshold and the continuous line indicates a P-value threshold of 2 × 10⁻⁷, corresponding to exome-wide significance.

Figure 3

Enrichment of HR-SNVs in DNase I hypersensitive sites of 299 tissue samples. The right panel shows the enrichment of the combined known and novel (all) HR-SNVs in DNase I hypersensitivity sites of 212 Roadmap Epigenome tissue samples (those with positive Z-scores). Enrichment is expressed as a Z-score compared with the distribution of 1000 matched background SNV sets. Significant enrichments are shown in red (Z-score ≥ 2.58, false discovery rate (FDR) <1.5%), enrichments below this threshold are shown in blue. The left panel shows the enrichment difference (ΔZscore= Zscore_all − Zscore_known) for those tissue samples in which we found significant enrichment using all SNPs and that further show a positive change using all SNVs compared with only known SNVs, with increased enrichment hence due to the novel loci identified.