title: Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk.
abstract: To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis.
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Dong
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Chen
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Ying-Aisha
authors.initials: YA
authors.lastname: Jing
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Man
authors.initials: M
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University New Orleans, LA 70112, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, P. R. China.
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, P. R. China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Tan
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University New Orleans, LA 70112, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University New Orleans, LA 70112, USA.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016208:Databases, Factual; D057890:Epigenomics / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D010024:Osteoporosis / Q000235:genetics; D058866:Osteoporotic Fractures / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; C579455:BDNF protein, human