title: Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD.
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, 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.
authors.affiliation: Institute of Bioscience and Biotechnology, School of Science, Beijing Jiaotong University, Beijing, People's Republic of China.
authors.forename: Lishu
authors.initials: L
authors.lastname: Zhang
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Dong-Hai
authors.initials: DH
authors.lastname: Xiong
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: 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