Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD.
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, q(fdr) = 0.043, p(fwer) = 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.
Zhang
Lishu
L
Institute of Bioscience and Biotechnology, School of Science, Beijing Jiaotong University, Beijing, People's Republic of China.
Guo
Yan-Fang
YF
Liu
Yao-Zhong
YZ
Liu
Yong-Jun
YJ
Xiong
Dong-Hai
DH
Liu
Xiao-Gang
XG
Wang
Liang
L
Yang
Tie-Lin
TL
Lei
Shu-Feng
SF
Guo
Yan
Y
Yan
Han
H
Pei
Yu-Fang
YF
Zhang
Feng
F
Papasian
Christopher J
CJ
Recker
Robert R
RR
Deng
Hong-Wen
HW
D000328:Adult; D000368:Aged; D001343:Autophagy / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D005260:Female; D050723:Fractures, Bone / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D058866:Osteoporotic Fractures / Q000235:genetics*; D011884:Radius / Q000033:anatomy & histology / Q000502:physiology*; D044465:White People / Q000235:genetics