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

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajhg.2009.01.025 Byline: Dong-Hai Xiong (1), Xiao-Gang Liu (2), Yan-Fang Guo (2), Li-Jun Tan (3), Liang Wang (2), Bao-Yong Sha (3), Zi-Hui Tang (3), Feng Pan (2), Tie-Lin Yang (2), Xiang-Ding Chen (3), Shu-Feng Lei (3), Laura M. Yerges (5), Xue-Zen Zhu (2), Victor W. Wheeler (7), Alan L. Patrick (7), ClareAnn H. Bunker (5), Yan Guo (2), Han Yan (2), Yu-Fang Pei (2), Yin-Pin Zhang (1), Shawn Levy (8), Christopher J. Papasian (1), Peng Xiao (4), Y. Wang Lundberg (9), Robert R. Recker (4), Yao-Zhong Liu (1), Yong-Jun Liu (1), Joseph M. Zmuda (5)(6), Hong-Wen Deng (1)(2)(3)(4) 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.sup.-5 to 2.13 x 10.sup.-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. Author Affiliation: (1) Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA (2) The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China (3) Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China (4) Osteoporosis Research Center, Creighton University, Omaha, NE 68131, USA (5) Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA (6) Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA (7) Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago (8) Vanderbilt Microarray Shared Resource, Vanderbilt University, Nashville, TN 37232, USA (9) Genetics Department, Boys Town National Research Hospital, Omaha, NE, 68131, USA Article History: Received 3 November 2008; Revised 17 January 2009; Accepted 30 January 2009 Article Note: (miscellaneous) Published online: February 26, 2009