Knee Osteoarthritis as a Causal Risk Factor for Parkinson's Disease: Converging Evidence From a National Survey and...

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.

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.

The cross-sectional analysis used a nationally representative U.S. population sample. The MR analysis used summary statistics from large international genetic consortia.

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.

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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.

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.

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.