Genome-wide Association and Follow-Up Replication Studies Identified ADAMTS18 and TGFBR3 as Bone Mass Candidate Genes in Different Ethnic Groups

Dong Hai Xiong, Xiao Gang Liu, Yan Fang Guo, Li Jun Tan, Liang Wang, Bao Yong Sha, Zi Hui Tang, Feng Pan, Tie Lin Yang, Xiang Ding Chen, Shu Feng Lei, Laura M. Yerges, Xue Zen Zhu, Victor W. Wheeler, Alan L. Patrick, ClareAnn H. Bunker, Yan Guo, Han Yan, Yu Fang Pei, Yin Pin ZhangShawn Levy, Christopher J. Papasian, Peng Xiao, Yunxia W Lundberg, Robert R. Recker, Yao Zhong Liu, Yong Jun Liu, Joseph M. Zmuda, Hong Wen Deng

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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 × 10-5 to 2.13 × 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.

Original languageEnglish (US)
Pages (from-to)388-398
Number of pages11
JournalAmerican Journal of Human Genetics
Volume84
Issue number3
DOIs
StatePublished - Mar 13 2009

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Ethnic Groups
Bone Density
Genome
Bone and Bones
Single Nucleotide Polymorphism
Genome-Wide Association Study
Hip Fractures
Genes
Trinidad and Tobago
Thrombospondin 1
Metalloproteases
Electrophoretic Mobility Shift Assay
Computer Simulation
Sample Size
Osteoporosis
Meta-Analysis
betaglycan
Alleles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide Association and Follow-Up Replication Studies Identified ADAMTS18 and TGFBR3 as Bone Mass Candidate Genes in Different Ethnic Groups. / Xiong, Dong Hai; Liu, Xiao Gang; Guo, Yan Fang; Tan, Li Jun; Wang, Liang; Sha, Bao Yong; Tang, Zi Hui; Pan, Feng; Yang, Tie Lin; Chen, Xiang Ding; Lei, Shu Feng; Yerges, Laura M.; Zhu, Xue Zen; Wheeler, Victor W.; Patrick, Alan L.; Bunker, ClareAnn H.; Guo, Yan; Yan, Han; Pei, Yu Fang; Zhang, Yin Pin; Levy, Shawn; Papasian, Christopher J.; Xiao, Peng; Lundberg, Yunxia W; Recker, Robert R.; Liu, Yao Zhong; Liu, Yong Jun; Zmuda, Joseph M.; Deng, Hong Wen.

In: American Journal of Human Genetics, Vol. 84, No. 3, 13.03.2009, p. 388-398.

Research output: Contribution to journalArticle

Xiong, DH, Liu, XG, Guo, YF, Tan, LJ, Wang, L, Sha, BY, Tang, ZH, Pan, F, Yang, TL, Chen, XD, Lei, SF, Yerges, LM, Zhu, XZ, Wheeler, VW, Patrick, AL, Bunker, CH, Guo, Y, Yan, H, Pei, YF, Zhang, YP, Levy, S, Papasian, CJ, Xiao, P, Lundberg, YW, Recker, RR, Liu, YZ, Liu, YJ, Zmuda, JM & Deng, HW 2009, 'Genome-wide Association and Follow-Up Replication Studies Identified ADAMTS18 and TGFBR3 as Bone Mass Candidate Genes in Different Ethnic Groups', American Journal of Human Genetics, vol. 84, no. 3, pp. 388-398. https://doi.org/10.1016/j.ajhg.2009.01.025
Xiong, Dong Hai ; Liu, Xiao Gang ; Guo, Yan Fang ; Tan, Li Jun ; Wang, Liang ; Sha, Bao Yong ; Tang, Zi Hui ; Pan, Feng ; Yang, Tie Lin ; Chen, Xiang Ding ; Lei, Shu Feng ; Yerges, Laura M. ; Zhu, Xue Zen ; Wheeler, Victor W. ; Patrick, Alan L. ; Bunker, ClareAnn H. ; Guo, Yan ; Yan, Han ; Pei, Yu Fang ; Zhang, Yin Pin ; Levy, Shawn ; Papasian, Christopher J. ; Xiao, Peng ; Lundberg, Yunxia W ; Recker, Robert R. ; Liu, Yao Zhong ; Liu, Yong Jun ; Zmuda, Joseph M. ; Deng, Hong Wen. / Genome-wide Association and Follow-Up Replication Studies Identified ADAMTS18 and TGFBR3 as Bone Mass Candidate Genes in Different Ethnic Groups. In: American Journal of Human Genetics. 2009 ; Vol. 84, No. 3. pp. 388-398.
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AU - Xiong, Dong Hai

AU - Liu, Xiao Gang

AU - Guo, Yan Fang

AU - Tan, Li Jun

AU - Wang, Liang

AU - Sha, Bao Yong

AU - Tang, Zi Hui

AU - Pan, Feng

AU - Yang, Tie Lin

AU - Chen, Xiang Ding

AU - Lei, Shu Feng

AU - Yerges, Laura M.

AU - Zhu, Xue Zen

AU - Wheeler, Victor W.

AU - Patrick, Alan L.

AU - Bunker, ClareAnn H.

AU - Guo, Yan

AU - Yan, Han

AU - Pei, Yu Fang

AU - Zhang, Yin Pin

AU - Levy, Shawn

AU - Papasian, Christopher J.

AU - Xiao, Peng

AU - Lundberg, Yunxia W

AU - Recker, Robert R.

AU - Liu, Yao Zhong

AU - Liu, Yong Jun

AU - Zmuda, Joseph M.

AU - Deng, Hong Wen

PY - 2009/3/13

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N2 - 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 × 10-5 to 2.13 × 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.

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