A Genome-Wide Association Meta-Analysis Implicates Hedgehog and Notch Signaling in Dupuytren’S Disease Publisher Pubmed



Riesmeijer SA^{1, 2} ; Kamali Z^{2, 3} ; Ng M⁴ ; Drichel D^{5, 6} ; Piersma B⁷ ; Becker K⁵ ; Layton TB⁸ ; Nanchahal J⁸ ; Nothnagel M^{5, 6} ; Vaez A^{2, 3} ; Hennies HC^{6, 9} ; Werker PMN¹ ; Furniss D⁴ ; Nolte IM² Show Affiliations
Source: Nature Communications Published:2024

Abstract

Dupuytren’s disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3–38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function. © 2024, The Author(s).