Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for Osteoporosis

Tie Lin Yang, Xiang Ding Chen, Yan Guo, Shu Feng Lei, Jin Tang Wang, Qi Zhou, Feng Pan, Yuan Chen, Zhi Xin Zhang, Shan Shan Dong, Xiang Hong Xu, Han Yan, Xiaogang Liu, Chuan Qiu, Xue Zhen Zhu, Teng Chen, Meng Li, Hong Zhang, Liang Zhang, Betty M. Drees & 6 others James J. Hamilton, Christopher J. Papasian, Robert R. Recker, Xiao Ping Song, Jing Cheng, Hong Wen Deng

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Abstract

Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 × 10-4, Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 × 10-4 -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.

Original languageEnglish
Pages (from-to)663-674
Number of pages12
JournalAmerican Journal of Human Genetics
Volume83
Issue number6
DOIs
StatePublished - Dec 12 2008

Fingerprint

Osteoporotic Fractures
Osteoporosis
Genome
Genes
Hip Fractures
Bone Density
Testosterone
Estradiol
Pelvic Bones
Femur Neck
Bone Fractures
Electrophoresis
Real-Time Polymerase Chain Reaction
Odds Ratio
Steroids
Hormones
Bone and Bones
Polymerase Chain Reaction
Enzymes
Serum

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for Osteoporosis. / Yang, Tie Lin; Chen, Xiang Ding; Guo, Yan; Lei, Shu Feng; Wang, Jin Tang; Zhou, Qi; Pan, Feng; Chen, Yuan; Zhang, Zhi Xin; Dong, Shan Shan; Xu, Xiang Hong; Yan, Han; Liu, Xiaogang; Qiu, Chuan; Zhu, Xue Zhen; Chen, Teng; Li, Meng; Zhang, Hong; Zhang, Liang; Drees, Betty M.; Hamilton, James J.; Papasian, Christopher J.; Recker, Robert R.; Song, Xiao Ping; Cheng, Jing; Deng, Hong Wen.

In: American Journal of Human Genetics, Vol. 83, No. 6, 12.12.2008, p. 663-674.

Research output: Contribution to journalArticle

Yang, TL, Chen, XD, Guo, Y, Lei, SF, Wang, JT, Zhou, Q, Pan, F, Chen, Y, Zhang, ZX, Dong, SS, Xu, XH, Yan, H, Liu, X, Qiu, C, Zhu, XZ, Chen, T, Li, M, Zhang, H, Zhang, L, Drees, BM, Hamilton, JJ, Papasian, CJ, Recker, RR, Song, XP, Cheng, J & Deng, HW 2008, 'Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for Osteoporosis', American Journal of Human Genetics, vol. 83, no. 6, pp. 663-674. https://doi.org/10.1016/j.ajhg.2008.10.006
Yang, Tie Lin ; Chen, Xiang Ding ; Guo, Yan ; Lei, Shu Feng ; Wang, Jin Tang ; Zhou, Qi ; Pan, Feng ; Chen, Yuan ; Zhang, Zhi Xin ; Dong, Shan Shan ; Xu, Xiang Hong ; Yan, Han ; Liu, Xiaogang ; Qiu, Chuan ; Zhu, Xue Zhen ; Chen, Teng ; Li, Meng ; Zhang, Hong ; Zhang, Liang ; Drees, Betty M. ; Hamilton, James J. ; Papasian, Christopher J. ; Recker, Robert R. ; Song, Xiao Ping ; Cheng, Jing ; Deng, Hong Wen. / Genome-wide Copy-Number-Variation Study Identified a Susceptibility Gene, UGT2B17, for Osteoporosis. In: American Journal of Human Genetics. 2008 ; Vol. 83, No. 6. pp. 663-674.
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AU - Yang, Tie Lin

AU - Chen, Xiang Ding

AU - Guo, Yan

AU - Lei, Shu Feng

AU - Wang, Jin Tang

AU - Zhou, Qi

AU - Pan, Feng

AU - Chen, Yuan

AU - Zhang, Zhi Xin

AU - Dong, Shan Shan

AU - Xu, Xiang Hong

AU - Yan, Han

AU - Liu, Xiaogang

AU - Qiu, Chuan

AU - Zhu, Xue Zhen

AU - Chen, Teng

AU - Li, Meng

AU - Zhang, Hong

AU - Zhang, Liang

AU - Drees, Betty M.

AU - Hamilton, James J.

AU - Papasian, Christopher J.

AU - Recker, Robert R.

AU - Song, Xiao Ping

AU - Cheng, Jing

AU - Deng, Hong Wen

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N2 - Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 × 10-4, Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 × 10-4 -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.

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