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
UR - http://www.sciencedirect.com/science/journal/00029297?sdc=1
U2 - 10.1016/j.ajhg.2017.08.006
DO - 10.1016/j.ajhg.2017.08.006
M3 - Article
VL - 101
SP - 417
EP - 427
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -