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

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.

Integrative analysis of Dupuytren’s disease identifies novel risk locus and reveals a shared genetic etiology with BMI

“…Results from a GWAS of DD in UK Europeans (3,871 cases and 4,686 controls) were previously reported 4 . This GWAS summary data contained association statistics for 7,218,238 SNPs, with 6,991,033 SNPs that were imputed from individuals of European ancestry in the Haplotype Reference Consortium 19 .…”

“…Recent twin studies estimate the heritability (i.e., proportion of phenotypic variation explained by genetics) of DD to be ~80% 3 . The largest previous genome-wide association study (GWAS) of DD in individuals of European ancestry identified 26 genome-wide significant single-nucleotide polymorphism (SNP) associations in 24 independent risk regions 4 , and estimated the proportion of phenotypic variance attributable to additive effects of common variants (i.e., SNP-heritability) to be 0.53 4,5 . The vast majority (23 of 24) of DD associations lie in non-coding genomic regions with only one located in an intron 4 , thus the biological implications of these associations are not immediately clear.…”

“…The largest previous genome-wide association study (GWAS) of DD in individuals of European ancestry identified 26 genome-wide significant single-nucleotide polymorphism (SNP) associations in 24 independent risk regions 4 , and estimated the proportion of phenotypic variance attributable to additive effects of common variants (i.e., SNP-heritability) to be 0.53 4,5 . The vast majority (23 of 24) of DD associations lie in non-coding genomic regions with only one located in an intron 4 , thus the biological implications of these associations are not immediately clear. Investigations into the mechanisms behind the strongest GWAS association, rs16879765 ( P GWAS = 7.2 × 10 −41 ), located in the intron of EPDR1 , revealed an effect on expression and protein secretion of the nearby gene SFRP4 4 but implicated EPDR1 functionally 6 .…”

“…The vast majority (23 of 24) of DD associations lie in non-coding genomic regions with only one located in an intron 4 , thus the biological implications of these associations are not immediately clear. Investigations into the mechanisms behind the strongest GWAS association, rs16879765 ( P GWAS = 7.2 × 10 −41 ), located in the intron of EPDR1 , revealed an effect on expression and protein secretion of the nearby gene SFRP4 4 but implicated EPDR1 functionally 6 . Overall, the regulatory mechanisms driving signal at the GWAS associations on DD remains unknown.…”

“…Recently, transcriptome-wide association studies 7,8 (TWAS) have emerged as a way to identify associations between gene expression and a trait. We performed a multi-tissue TWAS by combining a recent DD GWAS 4 with expression quantitative trait loci 9–14 (eQTL), integrating gene expression from five consortia in 43 unique tissues, to test for association between expression and DD in 15,198 genes. We identified 43 associations between tissue-specific gene expression and DD, including one novel risk region on chromosome 17.…”