Research Article: A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis

Date Published: September 07, 2017

Publisher: Elsevier

Author(s): Michael Ng, Dipti Thakkar, Lorraine Southam, Paul Werker, Roel Ophoff, Kerstin Becker, Michael Nothnagel, Andre Franke, Peter Nürnberg, Ana Isabel Espirito-Santo, David Izadi, Hans Christian Hennies, Jagdeep Nanchahal, Eleftheria Zeggini, Dominic Furniss.


Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10−8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.

Partial Text

Dupuytren disease (DD [MIM: 126900]) is a progressive fibroproliferative disease of the palmar fascia and the most common inherited disorder of the connective tissue. It is the most frequent example of a tissue-specific fibrotic disease: others include pulmonary, renal, hepatic, and skin fibrosis. It is accepted that there are common features of all fibrotic diseases, but some pathologic pathways are likely to be tissue specific.1

We have completed the largest GWAS to date in DD, the most common inherited disorder of connective tissue. Our results have almost tripled the known loci associated with this localized fibrosis and have also highlighted the role of fundamental biological processes in the pathophysiology of fibrosis, in the context of DD. Several associated loci harbor potentially attractive drug targets and are the subject of active further research. While we acknowledge that the mechanistic link between associated SNPs and pathophysiological function can often be obscure and requires experimental validation, we think that certain biological processes deserve discussion.




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