Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis

Yan Guo, Li Jun Tan, Shu Feng Lei, Tie Lin Yang, Xiang Ding Chen, Feng Zhang, Yuan Chen, Feng Pan, Han Yan, Xiaogang Liu, Qing Tian, Zhi Xin Zhang, Qi Zhou, Chuan Qiu, Shan Shan Dong, Xiang Hong Xu, Yan Fang Guo, Xue Zhen Zhu, Shan Lin Liu, Xiang Li WangXi Li, Yi Luo, Li Shu Zhang, Meng Li, Jin Tang Wang, Ting Wen, Betty Drees, James Hamilton, Christopher J. Papasian, Robert R. Recker, Xiao Ping Song, Jing Cheng, Hong Wen Deng

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Abstract

Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or lowtrauma 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 genomewide 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 = 2.08×10-9, 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 = 6.39×10 -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.

Original languageEnglish (US)
Article numbere1000806
JournalPLoS genetics
Volume6
Issue number1
DOIs
StatePublished - Jan 2010

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Guo, Y., Tan, L. J., Lei, S. F., Yang, T. L., Chen, X. D., Zhang, F., Chen, Y., Pan, F., Yan, H., Liu, X., Tian, Q., Zhang, Z. X., Zhou, Q., Qiu, C., Dong, S. S., Xu, X. H., Guo, Y. F., Zhu, X. Z., Liu, S. L., ... Deng, H. W. (2010). Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS genetics, 6(1), [e1000806]. https://doi.org/10.1371/journal.pgen.1000806