Mendelian randomization and national survey analyses indicate knee osteoarthritis—but not hip OA—is associated with increased Parkinson's disease risk, suggesting a potential causal, joint-specific link.

Highlights knee OA as a potentially modifiable risk factor that could steer mechanistic work on peripheral inflammation/systemic mediators and motivate prevention or repurposing strategies to lower PD risk.

OBJECTIVE: Osteoarthritis (OA) and Parkinson's disease (PD) are age-related degenerative conditions with potentially shared pathophysiological pathways. This study aimed to investigate the association and potential causal links between site-specific OA phenotypes and PD risk using a dual-method approach. DESIGN: We employed a dual-method approach combining cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) data with bidirectional two-sample Mendelian randomization (MR) analysis using large-scale genome-wide association study data. SETTING: The cross-sectional analysis used a nationally representative U.S. population sample. The MR analysis used summary statistics from large international genetic consortia. PARTICIPANTS: The NHANES analysis included 21,414 adults aged ≥40 years (1999-2016). The MR analysis utilized genetic data from hundreds of thousands of European individuals. INTERVENTION: None. MEASUREMENTS: In NHANES, OA and PD were based on self-reported physician diagnoses. In MR, genetic variants served as instrumental variables for OA phenotypes and PD. Multiple MR methods (inverse-variance weighted, weighted median, weighted mode, and MR-Egger) were used to assess potential causal links, with comprehensive sensitivity analyses performed. RESULTS: In the fully adjusted NHANES analysis, OA was significantly associated with higher odds of PD (OR=2.99, 95% CI: 1.92-4.65). MR analyses revealed that genetic predisposition to knee OA was associated with an increased PD risk (OR=1.49, 95% CI: 1.11-2.02), with a similar effect for combined hip/knee OA (OR=1.23, 95% CI: 1.03-1.47). In contrast, hip OA showed no significant association with PD. Reverse MR analyses found no evidence supporting causal effects of PD on any OA phenotype. CONCLUSIONS: Both observational and genetic evidence consistently suggest that knee OA, but not hip OA, may be a causal risk factor for PD, with no evidence of reverse causality. The phenotype-specific findings suggest joint-specific mechanisms linking OA to neurodegeneration.