Our analyses of coding variants at all known HR loci indicated that the majority of HR-associated SNVs and the variants in high LD with them are non-coding. We thus investigated which variants could have a causal effect through regulatory chromatin interactions, such as promoter–enhancer contacts. We considered all 67 published HR loci [21 previously reported GWAS loci (12) plus 46 recently published loci from UK Biobank (17)], and the five novel loci reported here. We found variants that potentially affect enhancer function using RegulomeDB (21) and found genes whose promoter regions form significant chromatin interaction with them from right ventricle Hi-C data (22). We found 64 potential target genes in 49 HR loci (4 new loci, 18 loci from the GWAS and 27 loci from the UK Biobank study; Supplementary Material, Table S10). Including these long-range interactors in the candidate causal genes list increased the significance of enrichment for many HR-related terms, such as arrhythmia and cardiac fibrillation in our Ingenuity® Pathway Analysis (IPA®; Supplementary Material, Table S11).
