title: Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females.
abstract: 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. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Yuan-Cheng
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.|Institute of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou, PR China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.affiliation: Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.|Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Xia-Fang
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Rou
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Dao-Yan
authors.initials: DY
authors.lastname: Pan
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.|Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D015519:Bone Density / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D059467:Transcriptome
keywords: BMD; HOMER1; OSTEOPOROSIS; SYSTEM GENETICS