title: Integrative analysis of GWASs, human protein interaction, and gene expression identified gene modules associated with BMDs.
abstract: BACKGROUND
  To date, few systems genetics studies in the bone field have been performed. We designed our study from a systems-level perspective by integrating genome-wide association studies (GWASs), human protein-protein interaction (PPI) network, and gene expression to identify gene modules contributing to osteoporosis risk.
  
  
  METHODS
  First we searched for modules significantly enriched with bone mineral density (BMD)-associated genes in human PPI network by using 2 large meta-analysis GWAS datasets through a dense module search algorithm. One included 7 individual GWAS samples (Meta7). The other was from the Genetic Factors for Osteoporosis Consortium (GEFOS2). One was assigned as a discovery dataset and the other as an evaluation dataset, and vice versa.
  
  
  RESULTS
  In total, 42 modules and 129 modules were identified significantly in both Meta7 and GEFOS2 datasets for femoral neck and spine BMD, respectively. There were 3340 modules identified for hip BMD only in Meta7. As candidate modules, they were assessed for the biological relevance to BMD by gene set enrichment analysis in 2 expression profiles generated from circulating monocytes in subjects with low versus high BMD values. Interestingly, there were 2 modules significantly enriched in monocytes from the low BMD group in both gene expression datasets (nominal P value <.05). Two modules had 16 nonredundant genes. Functional enrichment analysis revealed that both modules were enriched for genes involved in Wnt receptor signaling and osteoblast differentiation.
  
  
  CONCLUSIONS
  We highlighted 2 modules and novel genes playing important roles in the regulation of bone mass, providing important clues for therapeutic approaches for osteoporosis.
authors.affiliation: Center of Genomics and Bioinformatics and Department of Biostatistics and Bioinformatics (H.H., L.Z., J.L., Y.-P.W., J.-G.Z., H.-W.D.), Tulane University, New Orleans, Louisiana 70112; Biomedical Engineering Department (Y.-P.W.), Tulane University, New Orleans, Louisiana 70118; and Third Affiliated Hospital (J.S., Y.-F.G., H.-W.D.), China Southern Medical University, Guang Zhou 510000, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D015519:Bone Density / Q000235:genetics*; D030541:Databases, Genetic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D010024:Osteoporosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide