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 Langer & 10 others Wolfgang 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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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 < 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
Volume11
Issue number7
DOIs
Publication statusPublished - 28 Jul 2016

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Dupuytren Contracture
Genome-Wide Association Study
Electric network analysis
meta-analysis
Gene expression
Meta-Analysis
Genes
Gene Expression
gene expression
loci
Wnt Signaling Pathway
Wnt Proteins
Genome
Catenins
Genetic Loci
Fibroma
Gene Regulatory Networks
Transcriptome
genome
genes

Cite this

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 ; Bleuler, Peter E. ; Damert, Hans Georg ; Frank, Werner ; Hohendorff, Bernd ; Kühnel, Florian ; Langer, Martin ; Lenze, Wolfgang ; Lienert, Andrea ; Meinel, Albrecht ; Nick, Hans Elmar ; Rößler, Jörg ; Spicher, Rüdiger ; Staub, Frank ; Wach, Wolfgang ; Weinand, Christian ; German Dupuytren Study Group. / 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. In: PLoS One. 2016 ; Vol. 11, No. 7.
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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 < 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.",
author = "Kerstin Becker and Sabine Siegert and Toliat, {Mohammad Reza} and Juanjiangmeng Du and Ramona Casper and Dolmans, {Guido H.} and Werker, {Paul M.} and Sigrid Tinschert and Andre Franke and Christian Gieger and Konstantin Strauch and Michael Nothnagel and Peter N{\"u}rnberg and Hennies, {Hans Christian} and Bleuler, {Peter E.} and Damert, {Hans Georg} and Werner Frank and Bernd Hohendorff and Florian K{\"u}hnel and Martin Langer and Wolfgang Lenze and Andrea Lienert and Albrecht Meinel and Nick, {Hans Elmar} and J{\"o}rg R{\"o}{\ss}ler and R{\"u}diger Spicher and Frank Staub and Wolfgang Wach and Christian Weinand and {German Dupuytren Study Group}",
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Becker, K, Siegert, S, Toliat, MR, Du, J, Casper, R, Dolmans, GH, Werker, PM, Tinschert, S, Franke, A, Gieger, C, Strauch, K, Nothnagel, M, Nürnberg, P, Hennies, HC, Bleuler, PE, Damert, HG, Frank, W, Hohendorff, B, Kühnel, F, Langer, M, Lenze, W, Lienert, A, Meinel, A, Nick, HE, Rößler, J, Spicher, R, Staub, F, Wach, W, Weinand, C & German Dupuytren Study Group 2016, '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', PLoS One, vol. 11, no. 7, e0158101. https://doi.org/10.1371/journal.pone.0158101

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. / 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; Bleuler, Peter E.; Damert, Hans Georg; Frank, Werner; Hohendorff, Bernd; Kühnel, Florian; Langer, Martin; Lenze, Wolfgang; Lienert, Andrea; Meinel, Albrecht; Nick, Hans Elmar; Rößler, Jörg; Spicher, Rüdiger; Staub, Frank; Wach, Wolfgang; Weinand, Christian; German Dupuytren Study Group.

In: PLoS One, Vol. 11, No. 7, e0158101, 28.07.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Becker, Kerstin

AU - Siegert, Sabine

AU - Toliat, Mohammad Reza

AU - Du, Juanjiangmeng

AU - Casper, Ramona

AU - Dolmans, Guido H.

AU - Werker, Paul M.

AU - Tinschert, Sigrid

AU - Franke, Andre

AU - Gieger, Christian

AU - Strauch, Konstantin

AU - Nothnagel, Michael

AU - Nürnberg, Peter

AU - Hennies, Hans Christian

AU - Bleuler, Peter E.

AU - Damert, Hans Georg

AU - Frank, Werner

AU - Hohendorff, Bernd

AU - Kühnel, Florian

AU - Langer, Martin

AU - Lenze, Wolfgang

AU - Lienert, Andrea

AU - Meinel, Albrecht

AU - Nick, Hans Elmar

AU - Rößler, Jörg

AU - Spicher, Rüdiger

AU - Staub, Frank

AU - Wach, Wolfgang

AU - Weinand, Christian

AU - German Dupuytren Study Group

PY - 2016/7/28

Y1 - 2016/7/28

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pone.0158101

DO - 10.1371/journal.pone.0158101

M3 - Article

VL - 11

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e0158101

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