title: Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups.
abstract: To identify and validate genes associated with bone mineral density (BMD), which is a prominent osteoporosis risk factor, we tested 379,319 SNPs in 1000 unrelated white U.S. subjects for associations with BMD. For replication, we genotyped the most significant SNPs in 593 white U.S. families (1972 subjects), a Chinese hip fracture (HF) sample (350 cases, 350 controls), a Chinese BMD sample (2955 subjects), and a Tobago cohort of African ancestry (908 males). Publicly available Framingham genome-wide association study (GWAS) data (2953 whites) were also used for in silico replication. The GWAS detected two BMD candidate genes, ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif, 18) and TGFBR3 (transforming growth factor, beta receptor III). Replication studies verified the significant findings by GWAS. We also detected significant associations with hip fracture for ADAMTS18 SNPs in the Chinese HF sample. Meta-analyses supported the significant associations of ADAMTS18 and TGFBR3 with BMD (p values: 2.56 x 10(-5) to 2.13 x 10(-8); total sample size: n = 5925 to 9828). Electrophoretic mobility shift assay suggested that the minor allele of one significant ADAMTS18 SNP might promote binding of the TEL2 factor, which may repress ADAMTS18 expression. The data from NCBI GEO expression profiles also showed that ADAMTS18 and TGFBR3 genes were differentially expressed in subjects with normal skeletal fracture versus subjects with nonunion skeletal fracture. Overall, the evidence supports that ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups.
authors.affiliation: Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Dong-Hai
authors.initials: DH
authors.lastname: Xiong
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Liu
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Tan
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Bao-Yong
authors.initials: BY
authors.lastname: Sha
authors.forename: Zi-Hui
authors.initials: ZH
authors.lastname: Tang
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges
authors.forename: Xue-Zen
authors.initials: XZ
authors.lastname: Zhu
authors.forename: Victor W
authors.initials: VW
authors.lastname: Wheeler
authors.forename: Alan L
authors.initials: AL
authors.lastname: Patrick
authors.forename: ClareAnn H
authors.initials: CH
authors.lastname: Bunker
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.forename: Yin-Pin
authors.initials: YP
authors.lastname: Zhang
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.forename: Y Wang
authors.initials: YW
authors.lastname: Lundberg
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000328:Adult; D000368:Aged; D044466:Asian People; D044383:Black People; D015519:Bone Density / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006620:Hip Fractures / Q000208:ethnology / Q000209:etiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000150:complications / Q000208:ethnology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D044465:White People; D055815:Young Adult
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C510099:ADAMTS18 protein, human