Integrative analysis of GWASs, human protein interaction and gene expression identified gene modules associated with BMD

We designed our study from a systems-level perspective by integrating GWASs, human protein-protein interaction (PPI) network and gene expression to identify gene subnetworks contributing to osteoporosis risk.

First we searched for modules significantly enriched with BMD-associated genes in human PPI network by using two large meta-analysis GWAS datasets through a dense module search algorithm. One was an imputation-based meta-analysis (Meta7). The other was the second GWAS meta-analysis from Genetic Factors for Osteoporosis Consortium (GEFOS-2). One was assigned as a discovery dataset and the other as an evaluation dataset, and vice versa. Through the discovery-evaluation strategy, in total 42 modules and 129 modules were identified significantly in both Meta7 and GEFOS2 dataset, for FN and SPN BMD respectively. There were 3340 modules identified for Hip BMD only in Meta7. As candidate modules, they were assessed the biological relevance to BMD by gene set enrichment analysis (GSEA) in two independent microarray expression datasets from circulating monocytes isolated and purified in subjects with low versus high BMD values. There were two modules significantly enriched in monocytes from low BMD group in both gene expression datasets (p value < 0.05). Two modules overlapped in their gene content and had 16 nonredundant genes, including ESR1, LRP5, TNFRSF11B, SMAD3, SFRP1, SFRP2, MDFI, LRP5, WNT1, WNT4 and DKK1,etc. Functional enrichment analysis further revealed that both modules were enriched for genes involved in Wnt receptor signaling and osteoblast differentiation.

We highlighted two modules as well as genes in modules playing important roles in the regulation of bone mass.