Causal associations of dietary habits and blood metabolites with Parkinson's disease risk.

Parkinson's disease (PD) is a neurodegenerative disorder with unclear etiology, though dietary factors and metabolic alterations are implicated. This study employed two-sample mendelian randomization (MR) to evaluate causal relationships between dietary habits, blood metabolites, and PD risk. Using GWAS summary data from the UK Biobank (17 dietary habits, N = 421 764-462 436), KORA/Twins UK cohorts (452 metabolites, N = 7824), and the International PD Genomics Consortium (PD outcomes, N = 482 730), we applied inverse-variance weighted (IVW) methods and sensitivity analyses (MR-Egger, MR-RAPS) along with mediation analysis. Higher alcohol intake frequency was inversely associated with PD risk (OR 0.77, 95% CI 0.65-0.92), while grain and dried fruit intake increased risk (OR 1.15 and 1.70, respectively). Of 452 metabolites, 23 showed causal associations with PD: 12 increased risk (e.g., CMPF, epiandrosterone sulfate) and 11 were protective (e.g., X-01911, mannose). Mediation analysis revealed 8.63-15.30% of dietary effects on PD were mediated by metabolites, including CMPF and X-01911. Sensitivity analyses confirmed robustness for most associations. This MR study identifies modifiable dietary factors and metabolites influencing PD risk, highlighting metabolic pathways linking diet to neurodegeneration and suggesting targets for precision nutrition.