Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD

Lishu Zhang, Yan Fang Guo, Yao Zhong Liu, Yong Jun Liu, Dong Hai Xiong, Xiao Gang Liu, Liang Wang, Tie Lin Yang, Shu Feng Lei, Yan Guo, Han Yan, Yu Fang Pei, Feng Zhang, Christopher J. Papasian, Robert R. Recker, Hong Wen Deng

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Abstract

Wrist fracture is not only one of the most common osteoporotic fractures but also a predictor of future fractures at other sites. Wrist bone mineral density (BMD) is an important determinant of wrist fracture risk, with high heritability. Specific genes underlying wrist BMD variation are largely unknown. Most published genome-wide association studies (GWASs) have focused only on a few top-ranking single-nucleotide polymorphisms (SNPs)/genes and considered each of the identified SNPs/genes independently. To identify biologic pathways important to wrist BMD variation, we used a novel pathway-based analysis approach in our GWAS of wrist ultradistal radius (UD) BMD, examining approximately 500,000 SNPs genome-wide from 984 unrelated whites. A total of 963 biologic pathways/gene sets were analyzed. We identified the regulation-of-autophagy (ROA) pathway that achieved the most significant result ( p=.005, qfdr=0.043, pfwer=0.016) for association with UD BMD. The ROA pathway also showed significant association with arm BMD in the Framingham Heart Study sample containing 2187 subjects, which further confirmed our findings in the discovery cohort. Earlier studies indicated that during endochondral ossification, autophagy occurs prior to apoptosis of hypertrophic chondrocytes, and it also has been shown that some genes in the ROA pathway (e.g., INFG) may play important roles in osteoblastogenesis or osteoclastogenesis. Our study supports the potential role of the ROA pathway in human wrist BMD variation and osteoporosis. Further functional evaluation of this pathway to determine the mechanism by which it regulates wrist BMD should be pursued to provide new insights into the pathogenesis of wrist osteoporosis.

Original languageEnglish
Pages (from-to)1572-1580
Number of pages9
JournalJournal of Bone and Mineral Research
Volume25
Issue number7
DOIs
StatePublished - Jul 2010

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Genome-Wide Association Study
Autophagy
Wrist
Bone Density
Single Nucleotide Polymorphism
Genes
Osteogenesis
Osteoporosis
Arm Bones
Osteoporotic Fractures
Chondrocytes
Genome
Apoptosis

All Science Journal Classification (ASJC) codes

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. / Zhang, Lishu; Guo, Yan Fang; Liu, Yao Zhong; Liu, Yong Jun; Xiong, Dong Hai; Liu, Xiao Gang; Wang, Liang; Yang, Tie Lin; Lei, Shu Feng; Guo, Yan; Yan, Han; Pei, Yu Fang; Zhang, Feng; Papasian, Christopher J.; Recker, Robert R.; Deng, Hong Wen.

In: Journal of Bone and Mineral Research, Vol. 25, No. 7, 07.2010, p. 1572-1580.

Research output: Contribution to journalArticle

Zhang, L, Guo, YF, Liu, YZ, Liu, YJ, Xiong, DH, Liu, XG, Wang, L, Yang, TL, Lei, SF, Guo, Y, Yan, H, Pei, YF, Zhang, F, Papasian, CJ, Recker, RR & Deng, HW 2010, 'Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD', Journal of Bone and Mineral Research, vol. 25, no. 7, pp. 1572-1580. https://doi.org/10.1002/jbmr.36
Zhang, Lishu ; Guo, Yan Fang ; Liu, Yao Zhong ; Liu, Yong Jun ; Xiong, Dong Hai ; Liu, Xiao Gang ; Wang, Liang ; Yang, Tie Lin ; Lei, Shu Feng ; Guo, Yan ; Yan, Han ; Pei, Yu Fang ; Zhang, Feng ; Papasian, Christopher J. ; Recker, Robert R. ; Deng, Hong Wen. / Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. In: Journal of Bone and Mineral Research. 2010 ; Vol. 25, No. 7. pp. 1572-1580.
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abstract = "Wrist fracture is not only one of the most common osteoporotic fractures but also a predictor of future fractures at other sites. Wrist bone mineral density (BMD) is an important determinant of wrist fracture risk, with high heritability. Specific genes underlying wrist BMD variation are largely unknown. Most published genome-wide association studies (GWASs) have focused only on a few top-ranking single-nucleotide polymorphisms (SNPs)/genes and considered each of the identified SNPs/genes independently. To identify biologic pathways important to wrist BMD variation, we used a novel pathway-based analysis approach in our GWAS of wrist ultradistal radius (UD) BMD, examining approximately 500,000 SNPs genome-wide from 984 unrelated whites. A total of 963 biologic pathways/gene sets were analyzed. We identified the regulation-of-autophagy (ROA) pathway that achieved the most significant result ( p=.005, qfdr=0.043, pfwer=0.016) for association with UD BMD. The ROA pathway also showed significant association with arm BMD in the Framingham Heart Study sample containing 2187 subjects, which further confirmed our findings in the discovery cohort. Earlier studies indicated that during endochondral ossification, autophagy occurs prior to apoptosis of hypertrophic chondrocytes, and it also has been shown that some genes in the ROA pathway (e.g., INFG) may play important roles in osteoblastogenesis or osteoclastogenesis. Our study supports the potential role of the ROA pathway in human wrist BMD variation and osteoporosis. Further functional evaluation of this pathway to determine the mechanism by which it regulates wrist BMD should be pursued to provide new insights into the pathogenesis of wrist osteoporosis.",
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AU - Liu, Yong Jun

AU - Xiong, Dong Hai

AU - Liu, Xiao Gang

AU - Wang, Liang

AU - Yang, Tie Lin

AU - Lei, Shu Feng

AU - Guo, Yan

AU - Yan, Han

AU - Pei, Yu Fang

AU - Zhang, Feng

AU - Papasian, Christopher J.

AU - Recker, Robert R.

AU - Deng, Hong Wen

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