Common and Rare Variants in the Exons and Regulatory Regions of Osteoporosis-Related Genes Improve Osteoporotic Fracture Risk Prediction

Context: Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. Objective: To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. Design and Setting: This cross-sectional study was conducted in three clinical units in Korea. Participants: Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. Main Outcome Measure: We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Results: Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 gene...