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.

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Journal
Nature Communications
Published
2026-10-31
DOI
https://doi.org/10.1038/s41467-026-79052-0
Primary Topic
Genetic Associations and Epidemiology
Type
article
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article

Shared genetic architecture across fibrotic diseases

Mie Topholm Bruun, Lotte Hindhede, Christina Mikkelsen, Bitten Aagaard Jensen et al.
Nature Communications
Genetic Associations and Epidemiology
article

Shared genetic architecture across fibrotic diseases

Mie Topholm Bruun, Lotte Hindhede, Christina Mikkelsen, Bitten Aagaard Jensen, Mette Kongstad, Niels Vejlstrup, Andrea Barghetti, Thomas Folkmann Hansen, Hreinn Stefánsson, Søren Brunak, Søren Albertsen Rand, Susan Mikkelsen, David Westergaard, Lea Arregui Nordahl Christoffersen, Henrik Ullum, Erik Sørensen, Kāri Stefánsson, Mette Skou Bentsen, Maria Didriksen, Liam James Elgaard Quinn, Steffen Ullitz Thorsen, Andrew Joseph Schork, Henrik Hjalgrim, Josephine Gladov, Laura Barrett Ryø, Joseph Dowsett, Jens Kjærgaard Boldsen, Daniel Fannar Gudbjartsson, Nanna Brøns, Lisette J. A. Kogelman, Michael Schwinn, Unnur Þorsteinsdóttir, Jakob Thaning Bay, Mette Nyegaard, Ingileif Jónsdóttir, Lars Dyrskjøt, Henning Bundgaard, Johan Skov Bundgaard, Ole Birger Pedersen, Aeron Small, Jonas Ghouse, Sisse Rye Ostrowski, Kathrine Agergård Kaspersen, Bertram Dalskov Kjerulff, Karina Banasik, Þórunn Rafnar, Patrick Sulem, Bitten Aagaard, Janna Nissen, Khoa Manh Dinh, Henrik Hager, Christian Erikstrup, Ole H. Larsen, Søren Jacobsen, Klaus Rostgaard, Stefan Stender, Frederikke Byron Pedersen, Dorte Helenius Mikkelsen, Thomas M. Werge, Alfonso Buil Demur, Jacob Træholt, Maya Borchardt, Maiken Astrup, Line Hjorth Sjernholm Nielsen, Jakob Hjorth von Stemann, Hildur Knútsdóttir
article en

Abstract

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.

Nature Communications
Statens Serum Institut (DK), University of Copenhagen (DK), Brigham and Women's Hospital (US), deCODE Genetics (Iceland) (IS), Harvard University (US), Aarhus University (DK), Aalborg University Hospital (DK), Sankt Hans Hospital (DK), Novo Nordisk Foundation (DK), Odense University Hospital (DK), Hvidovre Hospital (DK), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Danish Cancer Society (DK), Zealand University Hospital Køge (DK), Aalborg University (DK)
Openalex Percentile: Top 14%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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