Shared genetic architecture across fibrotic diseases

Fibrosis contributes to clinically distinct diseases across anatomical sites, but their convergence on shared molecular pathways remains unclear. We include genome-wide meta-analyses across five cohorts (Copenhagen Hospital Biobank, Danish Blood Donor Study, UK Biobank, FinnGen, and Million Veteran Program) across 18 selected fibrosis-relevant traits: nine prototypical fibrotic diseases, five organ-diseases with partial fibrotic components, and four imaging-derived fibrotic phenotypes. We assess genetic overlaps using genetic correlations, while locus-wide overlaps are investigated using colocalization and clustering. Case sample sizes range from 4,559-126,358 individuals. We identify 654 genome-wide significant associations, of which 139 represent previously unreported associations for their respective traits. Clustering broadly distinguishes organ diseases with partial fibrotic components, prototypical fibrotic diseases, and imaging-derived fibrotic phenotypes. The strongest correlation is between carpal tunnel syndrome and trigger finger (rg = 0.60, P = 1.25×10−63). We identify 38 colocalizing loci, of which 11 overlap with three or more diseases. Candidate genes implicate gene families with established roles in fibrosis, including Wnt signaling (WNT7B, TCF7L2, and WNT2), extracellular matrix (COL11A1, MMP14 and P4HA2), fibroblast growth factors (FGFR2 and FGF21), and inflammation (IRF5, STAT3, and TNFAIP3). These findings identify novel genetic associations and support a shared genetic predisposition for fibrosis, converging on extracellular matrix remodeling, immune regulation, and developmental signaling. The authors map the genetic architecture of 18 fibrosis-related conditions and find that fibrosis affecting anatomically distant parts shares genetic similarities, particularly in pathways involved in tissue remodeling, immune regulation and development.