Pathogen Antibodies and Parkinson's Disease: A Two-sample Mendelian Randomization Study

Parkinson's disease (PD) is a prototypical neurodegenerative disease. Evidence suggests infection-induced immune responses contribute to the pathogenesis of PD; however, establishing causality from observational studies remains challenging. To explore the causal relationship between pathogen-derived antibodies and PD, we conducted a two-sample Mendelian randomization (MR) analysis.

Genetic variants were derived from publicly available genome-wide association study (GWAS) summary statistics, including data on 46 pathogen antibodies and PD (N = 5,861 cases). The inverse variance weighted (IVW) method served as our primary analysis. Robustness was assessed using MR-Egger, weighted median, and sensitivity analyses, including Cochran's Q test for heterogeneity and the MR-Egger intercept test for directional pleiotropy.

Of the 46 pathogen antibodies tested, human herpesvirus 6 (HHV-6) p101k antibody levels demonstrated a significant association with increased PD risk (OR: 1.08, 95% CI: 1.01- 1.15, p = 0.026). Suggestive, albeit less robust evidence for potential protective associations is found involving Helicobacter pylori GroEL (OR: 0.87, 95% CI: 0.76-0.99, p = 0.041) and Merkel cell polyomavirus (MCPyV) VP1 antibodies (OR: 0.89, 95% CI: 0.79-1.00, p = 0.049).

Our findings suggest potential roles for pathogen-specific immune responses in PD etiology. The association between HHV-6 p101k antibodies and PD risk may reflect virusinduced neuroinflammatory pathways, while the inverse associations observed for Helicobacter pylori GroEL and MCPyV VP1 antibodies warrant further investigation to confirm.

Our study provides genetic evidence that implicates specific pathogen antibody responses. These findings underscore the importance of investigating immune and neurovascular pathways in PD and may inform future therapeutic strategies.