A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease

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...

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Vydané v:	Nature communications Ročník 15; číslo 1; s. 199 - 11
Hlavní autori:	Riesmeijer, Sophie A., Kamali, Zoha, Ng, Michael, Drichel, Dmitriy, Piersma, Bram, Becker, Kerstin, Layton, Thomas B., Nanchahal, Jagdeep, Nothnagel, Michael, Vaez, Ahmad, Hennies, Hans Christian, Werker, Paul M. N., Furniss, Dominic, Nolte, Ilja M.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 03.01.2024 Nature Publishing Group Nature Portfolio
Predmet:	45 45/43 45/47 631/208/205 631/208/457 692/699/1670/122 Animals Dupuytren Contracture - genetics Dupuytren Contracture - metabolism Fibrosis Gene loci Genetic Loci Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study Genomes Hedgehog protein Hedgehogs - genetics Humanities and Social Sciences Humans Joint diseases Meta-analysis multidisciplinary Nucleotides Polymorphism, Single Nucleotide Science Science (multidisciplinary) Shoulder Signal transduction Single-nucleotide polymorphism Therapeutic targets Wnt protein Wnt Signaling Pathway
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. In this meta-analysis of the fibrotic hand disorder Dupuytren’s disease, the authors identify genetic risk variants, study them for their functional consequences and implicate two signaling pathways involved in the disease mechanism of this debilitating disorder.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-44451-0