Causal Effects Between Antibody-Mediated Immune Responses and Parkinson's Disease: Insights from Genetic Studies

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder with a complex etiology. Increasing evidence suggests that antibody-mediated immune responses elicited by prior infectious exposures may contribute to its pathogenesis; however, whether these associations reflect true causal relationships remains unresolved, largely due to confounding and other inherent limitations of observational study designs.

We conducted a two-sample Mendelian randomization (MR) analysis to interrogate the causal associations between 46 antibody-mediated immune responses and PD risk, leveraging Genome-wide association study (GWAS) summary statistics for antibody-related traits and PD data from the FinnGen consortium (5,861 cases and 494,487 controls of European ancestry). Independent genetic variants reaching genome-wide significance were selected as instrumental variables. Causal estimates were primarily derived using the inverse-variance weighted approach, with complementary analyses conducted using the weighted median, MR-Egger regression, and both simple and weighted mode methods. Bayesian weighted MR, together with a series of sensitivity analyses, was employed to evaluate the robustness of the findings and interrogate potential heterogeneity and horizontal pleiotropy.

Among the 46 antibody-mediated immune responses analyzed, two showed statistically significant causal associations with PD after Bonferroni correction. Genetically predicted elevated antibody levels against Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) were significantly associated with an increased risk of PD (odds ratio (OR) = 1.154, 95% confidence interval (CI): 1.098-1.214, P < 1.09 × 10^-4). In contrast, genetically predicted seropositivity for anti-polyomavirus 2 IgG was associated with a reduced risk of PD ( OR = 0.897, 95% CI: 0.865-0.930, P < 1.09 × 10^-4). Sensitivity analyses revealed no evidence of significant heterogeneity or horizontal pleiotropy.

This MR study offers genetic evidence supporting a potential causal involvement of specific antibody-mediated immune responses in the pathogenesis of PD. Elevated EBNA-1 antibody levels are associated with an increased risk of PD, whereas anti-polyomavirus 2 IgG seropositivity appears to confer a protective effect. These findings provide new insights into the immunological mechanisms underlying PD and underscore the potential of immune-related biomarkers and therapeutic targets.