Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups.
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.
Xiong
Dong-Hai
DH
Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Liu
Xiao-Gang
XG
Guo
Yan-Fang
YF
Tan
Li-Jun
LJ
Wang
Liang
L
Sha
Bao-Yong
BY
Tang
Zi-Hui
ZH
Pan
Feng
F
Yang
Tie-Lin
TL
Chen
Xiang-Ding
XD
Lei
Shu-Feng
SF
Yerges
Laura M
LM
Zhu
Xue-Zen
XZ
Wheeler
Victor W
VW
Patrick
Alan L
AL
Bunker
ClareAnn H
CH
Guo
Yan
Y
Yan
Han
H
Pei
Yu-Fang
YF
Zhang
Yin-Pin
YP
Levy
Shawn
S
Papasian
Christopher J
CJ
Xiao
Peng
P
Lundberg
Y Wang
YW
Recker
Robert R
RR
Liu
Yao-Zhong
YZ
Liu
Yong-Jun
YJ
Zmuda
Joseph M
JM
Deng
Hong-Wen
HW
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
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C510099:ADAMTS18 protein, human