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

Richard Gill, Daniel R. Lu, Ittai Eres, Jiamiao Lu, Jixin Cui, Chen Wang, Zhongsheng J. Yu, Tracy Yamawaki, Hong Zhou, Baikang Pei, Junedh M. Amrute, Yen-Sin Ang, Songli Wang, Kory J. Lavine, Brandon Ason, Chi-Ming Li () and Yi-Hsiang Hsu ()
Additional contact information
Richard Gill: Amgen Global Research
Daniel R. Lu: Amgen Global Research
Ittai Eres: Amgen Global Research
Jiamiao Lu: Amgen Global Research
Jixin Cui: Amgen Global Research
Chen Wang: Amgen Global Research
Zhongsheng J. Yu: Amgen Global Research
Tracy Yamawaki: Amgen Global Research
Hong Zhou: Amgen Global Research
Baikang Pei: Amgen Global Research
Junedh M. Amrute: Amgen Global Research
Yen-Sin Ang: Amgen Global Research
Songli Wang: Amgen Global Research
Kory J. Lavine: Washington University School of Medicine
Brandon Ason: Amgen Global Research
Chi-Ming Li: Amgen R&D Postdoctoral Fellow Program
Yi-Hsiang Hsu: Amgen Global Research

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64070-1

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