Meta-analysis of genome-wide association studies and network analysis-based integration with gene expression data identify new suggestive loci and unravel a Wnt-centric network associated with Dupuytren's disease

Kerstin Becker, Sabine Siegert, Mohammad Reza Toliat, Juanjiangmeng Du, Ramona Casper, Guido H. Dolmans, Paul M. Werker, Sigrid Tinschert, Andre Franke, Christian Gieger, Konstantin Strauch, Michael Nothnagel, Peter Nürnberg, Hans Christian Hennies, Peter E. Bleuler, Hans Georg Damert, Werner Frank, Bernd Hohendorff, Florian Kühnel, Martin LangerWolfgang Lenze, Andrea Lienert, Albrecht Meinel, Hans Elmar Nick, Jörg Rößler, Rüdiger Spicher, Frank Staub, Wolfgang Wach, Christian Weinand, German Dupuytren Study Group

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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 < 5×10-8). 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.

Original languageEnglish
Article numbere0158101
Number of pages18
JournalPLoS One
Issue number7
Publication statusPublished - 28 Jul 2016


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