Pathway-Based Genome-Wide Association Analysis Identified the Importance of Regulation-of-Autophagy Pathway for Ultradistal Radius BMD

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