Integrative clinical and genomic analyses reveal a causal role of GPNMB in the bone-brain axis of Parkinson’s disease

Osteokines, primarily secreted by bone, have been implicated in brain function and Parkinson's disease (PD) pathogenesis, yet their circulating levels in PD and potential role in the relationship between bone mineral density (BMD) and PD remain unclear. 80 participants (40 PD patients and 40 controls) were enrolled to measure plasma levels of eight osteokines (GPNMB, OPN, SOST, DKK1, RANKL, FGF23, BMP2, and BMP4) and assess their associations with clinical scales. Mendelian randomization (MR), SMR, and colocalization analyses were performed to evaluate causal relationships between osteokines and PD. Restricted cubic spline (RCS) models were applied to explore nonlinear associations between BMD, osteokines, and PD. GPNMB levels were significantly elevated in PD patients and showed a linear association with PD risk. Higher GPNMB levels were associated with worse cognitive performance and clinical severity, while higher SOST levels correlated with milder symptoms. Genetic analyses consistently supported a causal and colocalized relationship between GPNMB and PD. Total coxa BMD and T-score were lower in PD, but not statistically significant. RCS analysis revealed an "n-shaped" association between total coxa T-score and both PD and GPNMB levels. Overall, GPNMB appears causally linked to PD risk and may mediate the bone-brain axis connecting BMD with PD susceptibility.