Genetic evidence linking anti-polyomavirus 2 IgG seropositivity to ovarian cancer risk

Antibody-related immune phenotypes reflect long-term host-pathogen interactions and immunogenetic regulation, and have been increasingly implicated in cancer susceptibility. In ovarian cancer, observational associations between immune responses and disease risk remain difficult to interpret due to confounding and potential reverse causation. Genetic analyses may help clarify whether specific antibody immune response profiles are linked to ovarian cancer risk. We investigated the associations between 46 genetically predicted antibody immune response phenotypes and ovarian cancer using a 2-sample Mendelian randomization framework. Genetic instruments for antibody traits were obtained from large genome-wide association studies, while ovarian cancer summary statistics were derived independently from the FinnGen R12 and OpenGWAS resources. Causal estimates were derived primarily using inverse-variance weighted models and subsequently synthesized across datasets to improve precision. Multiple testing adjustment was applied, and additional analyses were conducted to assess robustness and causal directionality. Across the evaluated antibody phenotypes, most showed no evidence of a causal association with ovarian cancer risk. After meta-analysis and correction for multiple comparisons, genetically predicted anti-polyomavirus 2 immunoglobulin G (IgG) seropositivity was associated with a modest increase in ovarian cancer risk (odds ratio = 1.062, 95% confidence interval: 1.027-1.099). Sensitivity analyses did not indicate substantial pleiotropic bias, and reverse-direction analyses provided no support for ovarian cancer influencing anti-polyomavirus 2 IgG levels. These findings suggest that genetic liability to anti-polyomavirus 2 IgG seropositivity, as a marker of immune response rather than active infection, is modestly associated with ovarian cancer risk in individuals of European ancestry. Although the effect size is small, the results highlight a potential role for antibody-mediated immune processes in ovarian cancer etiology and warrant further investigation in diverse populations and experimental settings.