Exploring the Causal Links Between Toxoplasma gondii Infection and Risk of Brain Tumors: A Bidirectional Mendelian...

Toxoplasma gondii (T. gondii) is a ubiquitous protozoan parasite capable of establishing lifelong latent infections in the central nervous system. Previous epidemiological studies have suggested a potential association between T. gondii infection and an increased risk of brain cancer, but the causal relationship remains unclear.

We conducted a bidirectional Mendelian randomization (MR) study to assess the causal relationship between T. gondii infection and brain tumor risk. Genetic instruments for T. gondii seropositivity were derived from a genome-wide association study (GWAS) in the UK Biobank, while genetic data for brain tumors were obtained from the FinnGen R12 dataset. Standard MR methods, including inverse-variance weighted (IVW), weighted median, and MR-Egger, were applied to infer causality, with generalized summary Mendelian randomization (GSMR) used for further validation. Sensitivity analyses, including heterogeneity and pleiotropy assessments, were performed to ensure robustness. Additionally, reverse MR analyses were conducted to evaluate whether brain tumors influence genetic liability to T. gondii seropositivity.

Our MR analyses found no evidence of a causal relationship between genetic liability to T. gondii seropositivity, as indicated by P22 and SAG1 antibody levels, and the risk of brain tumors. Across all tumor subtypes, IVW, weighted median, MR-Egger, and GSMR analyses consistently yielded non-significant results. However, reverse MR analysis suggested that genetic liability to malignant brain tumors is associated with increased odds of T. gondii seropositivity. For P22, a strong association was observed across methods (IVW: OR = 1.234, p = 0.004; GSMR: OR = 1.228, p = 0.006). In contrast, for SAG1 the evidence was weaker, with IVW indicating a suggestive association (OR = 1.094, p = 0.048) and GSMR showing a borderline association (OR = 1.088, p = 0.052). Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or pleiotropy. No significant associations were observed for meningioma, glioblastoma, or benign brain tumors.

Our study provides no evidence for a causal relationship between genetic liability to T. gondii seropositivity and brain tumor risk. However, reverse MR suggests that genetic liability to malignant brain tumors may be associated with increased odds of T. gondii infection.