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

Methods: 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. Results: 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). Discussion: 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. Conclusion: 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.