Dissecting regulatory non-coding GWAS loci reveals fibroblast causal genes with pathophysiological relevance to heart failure.

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. Here, we hypothesize that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. To test this, we utilized male primary cardiac fibroblasts to generate high-resolution Hi-C data and integrate it with functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. We identify several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and FURIN). We perform Perturb-seq in immortalized male cardiac fibroblasts to knock out putative regulatory elements, confirming regulatory relationships involving GJA1, CXCL12, and FURIN. Our results demonstrate that multi-omic approaches can delineate pathophysiologically relevant regulatory circuits connecting protein-coding genes to non-coding genetic variants associated with disease.