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. © 2010 American Society for Bone and Mineral Research.
Highlights
Osteoporosis (MIM 166710) is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase of bone fragility and susceptibility to fractures.[1]
To identify novel biologic pathways contributing to wrist osteoporosis and Colles’ fractures, we performed a pathwaybased genome-wide association (GWA) analysis on Bone mineral density (BMD) variation at the wrist ultradistal radius (UD) using the method proposed by Wang and colleagues.[14]. We identified a significant association, at the pathwaywise level, between UD BMD and the regulation-of-autophagy (ROA) pathway
The ROA pathway was shown to be significantly associated with wrist UD BMD ( p 1⁄4 .005) and was the only pathway, among a total of 963 pathways tested, that achieved statistically significant FDR and FWER values
Summary
Osteoporosis (MIM 166710) is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase of bone fragility and susceptibility to fractures.[1]. Bone mineral density (BMD) at the distal forearm is the main determinant of susceptibility to Colles’ fracture.[4]. GWASs can systematically survey the whole genome for causal genetic variants for complex traits/diseases and are powerful tools for dissecting the genetic basis for osteoporosis. Several promising candidate genes for osteoporosis or related traits have been identified by GWASs.[10,11,12,13]
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