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

• Published in: PloS one Vol. 11; no. 7; p. e0158101
• Main Authors: Becker, Kerstin, Siegert, Sabine, Toliat, Mohammad Reza, Du, Juanjiangmeng, Casper, Ramona, Dolmans, Guido H, Werker, Paul M, Tinschert, Sigrid, Franke, Andre, Gieger, Christian, Strauch, Konstantin, Nothnagel, Michael, Nürnberg, Peter, Hennies, Hans Christian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.07.2016; Public Library of Science (PLoS)
• Subjects: Aging; Biology and Life Sciences; Computer and Information Sciences; Connective tissues; Data processing; Datasets; Deregulation; Dermatology; Disease; Dupuytren Contracture - genetics; Dupuytren's contracture; Epidemiology; Family medical history; Fibroblasts; Gene Expression; Genes; Genetic aspects; Genetic disorders; Genetic factors; Genetic Predisposition to Disease; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Health risks; Heritability; Humans; Loci; Meta-analysis; Network analysis; Physical Sciences; Plastic surgery; Polymorphism, Single Nucleotide; Proteins; Research and Analysis Methods; Signal transduction; Signaling; Wnt protein; Wnt proteins; β-Catenin; England; Austria; Netherlands; United Kingdom > UK; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158101

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.