Shared genetic architecture across fibrotic diseases

Fibrotic diseases show common pathophysiological features irrespective of their anatomical locations. By mapping the genomic landscape behind selected fibrotic diseases, we aim to investigate the genome-wide and locus-wide genetic overlap across fibrotic diseases. We conducted genome-wide meta-analyses using five genetic cohorts (Copenhagen Hospital Biobank (CHB), the Danish Blood Donor Study (DBDS), UK Biobank (UKB), FinnGen, the Million Veteran Program (MVP)) across 17 fibrotic traits comprising nine prototypical fibrotic diseases (e.g. carpal tunnel syndrome and idiopathic pulmonary fibrosis), four organ-diseases with known fibrotic components (e.g. heart failure and chronic kidney disease), and four imaging-derived fibrotic phenotypes. Global genetic correlations across fibrotic traits were estimated using linkage disequilibrium score regression (LDSC) and Locus-wide genetic overlaps were evaluated using colocalization analyses. Across 17 fibrotic traits with case sample sizes ranging from 4,559 for Peyronie’s disease to 126,358 for chronic kidney disease, we identified 645 genome-wide significant associations, of which 136 had not been reported previously for the respective trait. Using genetic correlation and hierarchical clustering, we found that fibrotic diseases clustered mainly into organ and non-organ specific clusters. The strongest correlations were between carpal tunnel syndrome and trigger finger ( r _g  = 0.60, P  = 1.1 × 10 ⁻⁶³ ) and between chronic kidney disease and heart failure ( r _g  = 0.51, P  = 9.5 × 10 ⁻⁸⁷ ). We identified 64 loci that colocalized across traits, of which 12 overlapped with three or more diseases. Many of the colocalizing genes belonged to gene families with established roles in fibrosis, including WNT signaling ( WNT7B , TCF7L2 , and WNT2 ), extracellular matrix ( COL11A1, MMP14 and P4HA2 ), fibroblast growth factors ( FGFR2, FGF21 ), and inflammation ( IRF5, STAT3 , and TNFAIP3 ). Our findings identified novel genetic variants and provide strong evidence for a shared genetic predisposition across fibrotic traits, converging on key biological pathways including extracellular matrix remodeling, immune regulation, and developmental signaling.