title: 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.
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.
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Becker
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Siegert
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Juanjiangmeng
authors.initials: J
authors.lastname: Du
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Casper
authors.affiliation: University of Groningen and University Medical Center Groningen, Dept. of Plastic Surgery, Groningen, the Netherlands.
authors.forename: Guido H
authors.initials: GH
authors.lastname: Dolmans
authors.affiliation: University of Groningen and University Medical Center Groningen, Dept. of Plastic Surgery, Groningen, the Netherlands.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Werker
authors.affiliation: Div. of Human Genetics and Dept. of Dermatology, Medical University of Innsbruck, Innsbruck, Austria.|Inst. of Clinical Genetics, Dresden University of Technology, Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiologie II, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.|Div. of Human Genetics and Dept. of Dermatology, Medical University of Innsbruck, Innsbruck, Austria.|Dept. of Biological Sciences, University of Huddersfield, Huddersfield, United Kingdom.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
mesh_terms: D004387:Dupuytren Contracture / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide