Identification of Novel Protein Biomarkers and Lifestyle-Modifiable Targets for Osteoporosis: Evidence from Mendelian Randomization and Colocalization Analyses
Danyang Zhao, Lidong Su, Jiubo Fan, Ziyan Guo, Xingguang Luo, Yimin Kang, Fan WangAbstract
Background
Osteoporosis (OP), a degenerative bone disease prevalent in aging populations, can lead to various complications and significantly impair the quality of life of elderly patients. We aimed to identify OP-related protein biomarkers and modifiable lifestyle factors for OP prevention in older adults.
Methods
Summary-data-based Mendelian randomization (SMR) and colocalization analyses were conducted to assess the possible causal effects of plasma protein on OP. Genetic data for plasma proteins were derived from the deCODE (4907 proteins) and UK Biobank-PPP (2923 proteins) datasets. OP summary statistics were obtained from the FinnGen study (10,461 cases). Two-sample Mendelian randomization (TSMR) analyses were subsequently performed to evaluate the effects of lifestyle factors on OP-related proteins.
Results
Primary SMR analysis identified 31 and 24 OP-related proteins in the deCODE and UKB-PPP cohorts, respectively. Cross-analysis of both datasets identified nine OP-related plasma protein targets. Among them, RSPO3 showed moderate evidence of colocalization with OP (PP.H4 = 0.643). TSMR analysis suggested that genetically predicted higher body mass index (BMI) was associated with increased RSPO3 levels (β = 0.08, 95% CI 0.02 to 0.14, p = 0.001), whereas type 2 diabetes (T2DM) was associated with lower RSPO3 levels (β = -5.71, 95% CI -11.16 to -0.26, p = 0.045).
Conclusions
This study identified nine plasma protein biomarkers with genetic evidence supporting their association with OP risk, with RSPO3 showing the strongest supportive evidence among the prioritized targets. These findings offer new insights into OP etiology and highlight how metabolic traits may influence bone health via specific protein mediators.