Abstract
Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease.
Highlights
Dupuytren’s disease (DD; OMIM 126900) is among the most common genetic diseases of connective tissues
In a network analysis based on protein-protein interaction data we identified functional modules of genes/proteins with shared characteristics that were overrepresented in our DD case/control data sets
Several new loci of suggestive evidence again contain genes related to Wnt signalling. These genes include WNT5A on chromosome 3p14.3, which is a ligand of frizzled receptors; EBF2 on 8p21.2, which acts in synergy with the Wnt-responsive LEF-1/β-catenin pathway; SMAD3 on 15q22.33, which is involved in positive regulation of the canonical Wnt signalling pathway; and AXIN1 on 16p13.3, which is a component of the β-catenin destruction complex. These observations clearly support the notion that the suggestive loci identified in this study may be true signals, they corroborate the outstanding importance of Wnt signalling in the susceptibility for DD and meet the expectation that Wnt signalling pathway related genes were located in genomic regions with weaker association signals
Summary
Dupuytren’s disease (DD; OMIM 126900) is among the most common genetic diseases of connective tissues. DD is a fibroproliferative disorder that affects the palmar aponeurosis and the cutaneous retinacula of the hand. It manifests first through the formation of subcutaneous nodules, fibrotic cords are found afterwards, and flexion contractures of single fingers can occur. The prevalence of DD has been estimated as around 4% in England [1] and 2.5% in Germany [2] It increases significantly with age [3, 4] and was determined as 22% in a cross-sectional study of the population aged over 50 years in the northern part of the Netherlands [5] and 30% in the Norwegian population over 60 years of age [6]. The disease shows a progressive clinical behaviour with frequent local recurrence
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