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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)417-427
Number of pages11
JournalAmerican Journal of Human Genetics
Volume101
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

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Dupuytren Contracture
Genome-Wide Association Study
Fibrosis
Connective Tissue Diseases
Myofibroblasts
Fascia
Contracture
Research
Extracellular Matrix
Genotype
Inflammation
Physicians
Genes

Cite this

Ng, Michael ; Thakkar, Dipti ; Southam, Lorraine ; Werker, Paul M. ; Ophoff, Roel ; Becker, Kerstin ; Nothnagel, Michael ; Franke, Andre ; Nürnberg, Peter ; Espirito-Santo, Ana Isabel ; Izadi, David ; Hennies, Hans ; Nanchahal, Jagdeep ; Zeggini, Eleftheria ; Furniss, Dominic. / A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. In: American Journal of Human Genetics. 2017 ; Vol. 101, No. 3. pp. 417-427.
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abstract = "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.",
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Ng, M, Thakkar, D, Southam, L, Werker, PM, Ophoff, R, Becker, K, Nothnagel, M, Franke, A, Nürnberg, P, Espirito-Santo, AI, Izadi, D, Hennies, H, Nanchahal, J, Zeggini, E & Furniss, D 2017, 'A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis', American Journal of Human Genetics, vol. 101, no. 3, pp. 417-427. https://doi.org/10.1016/j.ajhg.2017.08.006

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. / Ng, Michael; Thakkar, Dipti; Southam, Lorraine; Werker, Paul M.; Ophoff, Roel; Becker, Kerstin; Nothnagel, Michael; Franke, Andre; Nürnberg, Peter; Espirito-Santo, Ana Isabel; Izadi, David; Hennies, Hans; Nanchahal, Jagdeep; Zeggini, Eleftheria; Furniss, Dominic.

In: American Journal of Human Genetics, Vol. 101, No. 3, 07.09.2017, p. 417-427.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis

AU - Ng, Michael

AU - Thakkar, Dipti

AU - Southam, Lorraine

AU - Werker, Paul M.

AU - Ophoff, Roel

AU - Becker, Kerstin

AU - Nothnagel, Michael

AU - Franke, Andre

AU - Nürnberg, Peter

AU - Espirito-Santo, Ana Isabel

AU - Izadi, David

AU - Hennies, Hans

AU - Nanchahal, Jagdeep

AU - Zeggini, Eleftheria

AU - Furniss, Dominic

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - Depuytren disease

KW - Fibrosis

KW - Genetics

KW - GWAS

KW - Hand surgery

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