Identification of pleiotropic genetic variants affecting osteoporosis risk in a Korean elderly cohort

Pleiotropy has important implications for understanding the genetic basis and risk assessment of osteoporosis. Our aim was to identify pleiotropic genetic variants associated with the development of osteoporosis and predict osteoporosis risk by leveraging pleiotropic variants. We evaluated the effects of 21 conventional risk factors and 185 single-nucleotide polymorphisms (SNPs) in 63 inflammation- and metabolism-related genes on osteoporosis risk in a community-based Korean cohort study of 1025 participants, the Hallym Aging Study. Ten nongenetic factors, including sex (female) and hematocrit level, and 12 SNPs across ten genes showed evidence of association with incident osteoporosis in 270 initially osteoporosis-free subjects who completed a 6-year follow up. Three gene variants, rs1801282 (PPARG-Pro12Ala, hazard ratio (HR) = 3.26, P = 0.008), rs1408282 (near EPHA7, HR = 1.87, P = 0.002), and rs2076212 (PNPLA3-Gly115Cys, HR = 2.24, P = 0.024), were associated with significant differences in survival among the three genotype groups (P_diff = 0.042, 0.003, and 0.048, respectively). Individuals in the highest polygenic risk score tertile were 27.9 fold more likely to develop osteoporosis than those in the lowest tertile (P = 0.004). The PPARG gene in particular was a hub pleiotropic gene in the epistasis network. Our findings highlight pleiotropic modulations of metabolism- and inflammation-related genes in the development of osteoporosis and demonstrate the contribution of pleiotropic genetic variants in prediction of osteoporosis risk.