Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis.
Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or low-trauma osteoporotic fractures (OF), both of which have strong genetic determination. The specific genes influencing these phenotypic traits, however, are largely unknown. Using the Affymetrix 500K array set, we performed a case-control genome-wide association study (GWAS) in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip OF and 516 controls. We found that a SNP, rs13182402 within the ALDH7A1 gene on chromosome 5q31, was strongly associated with OF with evidence combined GWAS and replication studies (P = 2.08x10(-9), odds ratio = 2.25). In order to explore the target risk factors and potential mechanism underlying hip OF risk, we further examined this candidate SNP's relevance to hip BMD both in Chinese and Caucasian populations involving 9,962 additional subjects. This SNP was confirmed as consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians (combined P = 6.39x10(-6)), further attesting to its potential effect on osteoporosis. ALDH7A1 degrades and detoxifies acetaldehyde, which inhibits osteoblast proliferation and results in decreased bone formation. Our findings may provide new insights into the pathogenesis of osteoporosis.
Guo
Yan
Y
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, People's Republic of China.
Tan
Li-Jun
LJ
Lei
Shu-Feng
SF
Yang
Tie-Lin
TL
Chen
Xiang-Ding
XD
Zhang
Feng
F
Chen
Yuan
Y
Pan
Feng
F
Yan
Han
H
Liu
Xiaogang
X
Tian
Qing
Q
Zhang
Zhi-Xin
ZX
Zhou
Qi
Q
Qiu
Chuan
C
Dong
Shan-Shan
SS
Xu
Xiang-Hong
XH
Guo
Yan-Fang
YF
Zhu
Xue-Zhen
XZ
Liu
Shan-Lin
SL
Wang
Xiang-Li
XL
Li
Xi
X
Luo
Yi
Y
Zhang
Li-Shu
LS
Li
Meng
M
Wang
Jin-Tang
JT
Wen
Ting
T
Drees
Betty
B
Hamilton
James
J
Papasian
Christopher J
CJ
Recker
Robert R
RR
Song
Xiao-Ping
XP
Cheng
Jing
J
Deng
Hong-Wen
HW
D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015519:Bone Density; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase