Integrative Analysis of GWASs, Human Protein Interaction, and Gene Expression Identified Gene Modules Associated With BMDs

He, Hao; Zhang, Lei; Li, Jian; Wang, Yuping; Zhang, Jigang; Shen, Jie; Guo, Yan-Fang; Deng, Hong−Wen

doi:10.1210/jc.2014-2563

Cited by 10 publications

(12 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The systems genetics approach for BMD has been applied in recent studies by integrating genomic data and coexpression networks of other genomics data. (15)(16)(17) Farber and colleagues carried out the first two systems-level studies for BMD based on monocyte transcriptional gene expression network with a relatively small sample size. He and colleagues performed a system analysis on BMD by integrating GWAS data and known human protein interactions.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

“…Both studies integrated GWAS data with weighted gene coexpression network analysis (WGCNA) and set up a good example of identification of functional connections between genes through disease‐relevant microarray gene expression data. Another network‐assisted study for BMD was reported by He and colleagues by using GWAS data, gene expression data, and human protein‐protein interaction data . Their work highlighted two modules and genes in those modules associated with BMD.…”

Section: Introductionmentioning

confidence: 99%

“…Another network-assisted study for BMD was reported by He and colleagues by using GWAS data, gene expression data, and human protein-protein interaction data. (17) Their work highlighted two modules and genes in those modules associated with BMD. Further enrichment analysis suggested that both modules were associated with Wnt receptor signaling.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females

Chen

Guo

et al. 2016

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

Osteoporosis is known to be highly heritable. However, to date, the findings from more than 20 genome-wide association studies (GWASs) have explained less than 6% of genetic risks. Studies suggest that the missing heritability data may be because of joint effects among genes. To identify novel heritability for osteoporosis, we performed a system-level study on bone mineral density (BMD) by weighted gene coexpression network analysis (WGCNA), using the largest GWAS data set for BMD in the field, Genetic Factors for Osteoporosis Consortium (GEFOS-2), and a transcriptomic gene expression data set generated from transiliac bone biopsies in women. A weighted gene coexpression network was generated for 1574 genes with GWAS nominal evidence of association (p 0.05) based on dissimilarity measurement on the expression data. Twelve distinct gene modules were identified, and four modules showed nominally significant associations with BMD (p 0.05), but only one module, the yellow module, demonstrated a good correlation between module membership (MM) and gene significance (GS), suggesting that the yellow module serves an important biological role in bone regulation. Interestingly, through characterization of module content and topology, the yellow module was found to be significantly enriched with contractile fiber part (GO:044449), which is widely recognized as having a close relationship between muscle and bone. Furthermore, detailed submodule analyses of important candidate genes (HOMER1, SPTBN1) by all edges within the yellow module implied significant enrichment of functional connections between bone and cytoskeletal protein binding. Our study yielded novel information from system genetics analyses of GWAS data jointly with transcriptomic data. The findings highlighted a module and several genes in the model as playing important roles in the regulation of bone mass in females, which may yield novel insights into the genetic basis of osteoporosis.

show abstract

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females

Chen

Guo

et al. 2016

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Through the evaluation of module content and topology, they identified a number of novel candidate genes/subnetworks for osteoporosis susceptibility and revealed functional connections between novel genes with evidence of association and those with a previously established role in the regulation of bone metabolism [109]. We also conducted a study, integrating GWASs, human protein-protein interaction (PPI) network, and gene expression from high versus low BMD subjects, and found two modules of genes contributing to osteoporosis risk [111]. The two modules were enriched with BMD-associated genes in human PPI network and were identified significantly in the GWASs for BMD.…”

Section: Using Pbms As a Working Cell Model To Study For Bone Diseasesmentioning

confidence: 99%

Circulating monocytes: an appropriate model for bone-related study

2015

View full text Add to dashboard Cite

Peripheral blood monocytes (PBMs) are an important source of precursors of osteoclasts, the bone-resorbing cells and the cytokines produced by PBMs that have profound effects on osteoclast differentiation, activation, and apoptosis. So PBMs represent a highly valuable and unique working cell model for bone-related study. Finding an appropriate working cell model for clinical and (epi-)genomic studies of human skeletal disorders is a challenge. Peripheral blood monocytes (PBMs) can give rise to osteoclasts, the bone-resorbing cells. Particularly, PBMs provide the sole source of osteoclast precursors for adult peripheral skeleton where the bone marrow is normally hematopoietically inactive. PBMs can secrete potent pro- and anti-inflammatory cytokines, which are important for osteoclast differentiation, activation, and apoptosis. Reduced production of PBM cytokines represents a major mechanism for the inhibitory effects of sex hormones on osteoclastogenesis and bone resorption. Abnormalities in PBMs have been linked to various skeletal disorders/traits, strongly supporting for the biological relevance of PBMs with bone metabolism and disorders. Here, we briefly review the origin and further differentiation of PBMs. In particular, we discuss the close relationship between PBMs and osteoclasts, and highlight the utility of PBMs in study the pathophysiological mechanisms underlying various skeletal disorders.

show abstract

“…Recently, our group [9] and Farber [10] independently illustrated that PBM transcriptomic data can be used to extract additional biological functional information from GWAS datasets, allowing for discovery of novel osteoporosis-associated genes and prioritization of genes and SNPs for replication studies. Our group also conducted another in silico study, integrating GWASs, human protein-protein interaction (PPI) network, and monocytic gene expression from high vs. low BMD subjects, and found two modules of genes contributing to osteoporosis risk by participating in Wnt receptor signaling and osteoblast differentiation, respectively [11]. Together, these studies indicate that PBMs represent a valuable working cell model for studying mechanistic differences occurring in bone metabolism between health and disease conditions.…”

Section: Introductionmentioning

confidence: 99%

Cytosolic proteome profiling of monocytes for male osteoporosis

Zhu

Shen

et al. 2016

Osteoporos Int

View full text Add to dashboard Cite

Summary In male Caucasians with discordant hip bone mineral density (BMD), we applied the subcellular separation and proteome profiling to investigate the monocytic cytosol. Three BMD-associated proteins (ALDOA, MYH14, and Rap1B) were identified based on multiple omics evidence, and they may influence the pathogenic mechanisms of osteoporosis by regulating the activities of monocytes. Introduction Osteoporosis is a serious public health problem, leading to significant mortality not only in aging females but also in males. Peripheral blood monocytes (PBMs) play important roles in bone metabolism by acting as precursors of osteoclasts and producing cytokines important for osteoclast development. The first cytosolic sub-proteome profiling analysis was performed in male PBMs to identify differentially expressed proteins (DEPs) that are associated with BMDs and risk of osteoporosis. Methods Here, we conducted a comparative proteomics analysis in PBMs from Caucasian male subjects with discordant hip BMD (29 low BMD vs. 30 high BMD). To decrease the proteome complexity and expand the coverage range of the cellular proteome, we separated the PBM proteome into several subcellular compartments and focused on the cytosolic fractions, which are involved in a wide range of fundamental biochemical processes. Results Of the total of 3796 detected cytosolic proteins, we identified 16 significant (P < 0.05) and an additional 22 suggestive (P < 0.1) DEPs between samples with low vs. high hip BMDs. Some of the genes for DEPs, including ALDOA, MYH14, and Rap1B, showed an association with BMD in multiple omics studies (proteomic, transcriptomic, and genomic). Further bioinformatics analysis revealed the enrichment of DEPs in functional terms for monocyte proliferation, differentiation, and migration. Conclusions The combination strategy of subcellular separation and proteome profiling allows an in-depth and refined investigation into the composition and functions of cytosolic proteome, which may shed light on the monocyte-mediated pathogenic mechanisms of osteoporosis.

show abstract

Integrative Analysis of GWASs, Human Protein Interaction, and Gene Expression Identified Gene Modules Associated With BMDs

Cited by 10 publications

References 38 publications

Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females

Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females

Circulating monocytes: an appropriate model for bone-related study

Cytosolic proteome profiling of monocytes for male osteoporosis

Contact Info

Product

Resources

About