Background: While observational studies have suggested associations between viral infections and lymphoma risk, causal relationships remain unclear. This pan-lymphoma analysis aims to comprehensively explore the role of common viral infections, including HBV, HCV, EBV, CMV, HIV, HSV, HTLV and VZV, in lymphoma development. Methods: We performed a two-sample bi-directional Mendelian randomization (MR) analysis using GWAS summary statistics from the GWAS Catalog and FinnGen R11 databases. This analysis examined genetically predicted viral infections and their association with various lymphoma types, including Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), non-follicular lymphoma (NFL), non-Hodgkin's lymphoma (NHL), other non-specific NHL, mature T/NK cell lymphoma (TNK), and chronic lymphocytic leukemia (CLL). Sample sizes for the lymphomas ranged from 345,238 to 348,252, while sample sizes for viral infections ranged from 683 to 352,013. Causal effects were evaluated using the inverse variance-weighted method and validated through sensitivity analyses, including MR-PRESSO, MR-Egger, and leave-one-out analysis. For external validation, we performed chi-square tests and survival analyses on the data from the UK Biobank. Results: MR analysis revealed a negative causal association between CMV IgG seropositivity and HL (OR 0.86, 95% CI 0.76-0.98, P < 0.05) and between CMV pp52 antibody levels and non-follicular lymphoma (non-FL) (OR 0.88, 95% CI 0.79-0.99, P = 0.026). EBV IgG seropositivity was associated with a potential protective effect against FL (OR 0.91, 95% CI 0.85-0.99, P < 0.05) and WM (OR 0.75, 95% CI 0.59-0.95, P < 0.05). EBV EBNA-1 antibody levels were negatively associated with HL (OR 0.72, 95% CI 0.53-0.97, P < 0.05). Elevated EBV EA-D antibody levels increased the risk of WM (OR 2.23, 95% CI 1.09-4.54, P < 0.05), while EBV VCA p18 antibody levels showed an inverse relationship with WM (OR 0.97, 95% CI 0.94-0.99, P = 0.039). HIV infection was linked to an increased risk of MCL (OR 1.01, 95% CI 1.00-1.02, P < 0.05). HSV-1 mgG-1 antibody levels (OR 1.72, 95% CI 1.05-2.82, P < 0.05), HSV-2 mgG-1 antibody levels (OR 1.38, 95% CI 1.01-1.88, P < 0.05), and HSV-2 IgG seropositivity (OR 1.45, 95% CI 1.05-2.01, P < 0.05) were associated with a higher risk of WM. Increased HSV-1 mgG-1 antibody levels were also linked to an increased risk of MZL (OR 1.52, 95% CI 1.08-2.14, P < 0.05) and a decreased risk of mature TNK lymphoma (OR 0.75, 95% CI 0.58-0.99, P < 0.05). HSV-2 IgG seropositivity was associated with an increased risk of HL (OR 1.14, 95% CI 1.03-1.27, P < 0.05), while increased HSV-1 IgG levels were found to be protective against non-specific NHL (OR 0.93, 95% CI 0.87-0.99, P < 0.05). In external validation, we found that the disease occurrence and survival of WM were associated with EBV infection (P - value of chi - square test = 0.025, P - value of survival analysis = 0.00054), HCV infection (P - value of chi - square test = 0.015, P - value of survival analysis < 0.0001), and HIV infection (P - value of chi - square test = 0.010, P - value of survival analysis < 0.0001). HBV (P - value of chi - square test = 0.118, P - value of survival analysis = 0.011) and HTLV (P - value of chi - square test = 0.076, P - value of survival analysis = 0.00081) were associated with the survival of WM patients but not with the disease occurrence. The survival of patients with NAS was found to be associated with HCV infection (P - value of chi - square test = 0.080, P - value of survival analysis = 0.00064) and HIV infection (P - value of chi - square test = 0.05, P - value of survival analysis < 0.0001). Additionally, EBV infection was associated with the survival of TNK (P - value of chi - square test = 0.103, P - value of survival analysis = 0.0047), and HTLV infection was associated with both the disease occurrence and survival of HL (P - value of chi - square test = 0.003, P - value of survival analysis < 0.0001). Conclusions: Our findings provide evidence for the causative role of various viral infections in the development of different lymphoma types. These results offer new insights into the pathogenesis of lymphoma and suggest potential viral prophylactic targets for lymphoma prevention.

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2025
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