Gliomas are characterized by a high degree of malignancy, aggressiveness, and morbidity [43]. Researchers have focused on the diagnosis, treatment, and recurrence of gliomas, but less attention has been given to their etiology. Limited by methodological, ethical, and multiple factors, exploring the etiology of gliomas, the most common primary tumors of the central nervous system, is difficult and complex. Viral infection is known to be a risk factor for many cancers, including nasopharyngeal carcinoma and cervical cancer [10]. The results of a previous research indicated that genetic predisposition toward increased seroreactivity to EBV ZEBRA was associated with a decreased overall glioma risk [44]. Despite previous studies, the association between viral infection and glioma incidence remains controversial [15]. In general, establishing causal relationships is difficult due to the limitations of small sample sizes and inherent biases. As a result, very few studies have explored causal relationships between viral infection and glioma. We sought to apply MR, which can overcome the methodological obstacles mentioned above, to elucidate such causality. MR is an analytic research technique using genetic variation as a proxy for exposure. We used MR analysis to investigate a range of viral infection factors and their causation with cancer risk. To date, our work is the most comprehensive MR study to illustrate the causal relationship between viral infection and glioma. Our MR results confirm that genetically predicted herpes zoster is significantly associated with lower risk of LGG after correcting for multiple tests (FDR < 0.05) and sensitivity analysis. Additionally, we found that genetically predicted GBM has suggestive causality with lower risk of acute poliomyelitis (OR = 0.69, P = 0.01, FDR = 0.13); genetically predicted LGG also shows suggestive causality with higher risk of herpes zoster (OR = 1.11, P = 0.01, FDR = 0.11).

The association between genetically predicted herpes zoster and glioma

Our MR results confirmed that genetically predicted herpes zoster was significantly associated with lower risk of LGG. Interestingly, the causal associations for GBM and LGG were completely opposite: our MR analysis indicated that herpes zoster increased risk of GBM (OR = 1.11, P = 0.01, FDR = 0.13) but decreased that of LGG (OR = 0.85, P = 0.01, FDR = 0.04). Based on the results of the leave-one-out method, the MR analysis of herpes zoster and LGG was responsible, and single SNPs did not affect the results. However, this trend with GBM failed to remain consistent in leave-one-out tests, which indicated that it was driven by one SNP in ABCB11, rs75043801. ABCB11, also known as BSEP, encodes bile salt outlet pump (BSEP), which plays an important role in transporting bile acid (BA). Our results suggest that this particular SNP in ABCB11 may dominate the estimation of the causal effect of herpes zoster on GBM, which means the selection of SNPs in the GWAS may influence the soundness of the results.

In previous studies, VZV was the only virus found to be negatively related to glioma. One of the largest studies on the subject to date, International Case–Control Study of Glioma (GICC) collected data for 8704 individuals from several countries and confirmed the negative association between history of chickenpox and glioma [31]. The results showed that varicella history was associated with lower risk of glioma (OR = 0.79, 95% CI: 0.65–0.96) [45]. More specifically, the authors demonstrated that VZV infection provides a strong protective effect against GBM. The same results were validated in other cohorts: Sjostrom et al. investigated three large cohorts consisting of prediagnostic samples and found that anti-VZV IgG levels are related to reduced glioma risk (OR = 0.63, 95% CI: 0.37–1.08) [19]. Additionally, it has been reported that the level of VZV IgG is significantly low (OR = 0.68, 95% CI: 0.41–1.13) in glioma patients [32]. However, without further establishing causality, these studies remain at the stage of simple observation. More bench research focusing on validating the causation between VZV infection and glioma is needed to elucidate the underlying mechanism. Our MR results substantiate the causal relationship between herpes zoster and glioma, providing further reinforcement to the previous perspective.

Potential mechanism

It is not clear by what biological mechanism VZV infection protects against LGG, but several hypotheses have been proposed [46, 47]. Previous studies have found that immune-related diseases such as allergies and asthma reduce risk of glioma, suggesting that activation of the immune system might play an important protective role in suppressing glioma development [46]. Similarly, we propose that VZV may share epitopes with LGG tumor cells and that its antibodies may be cross-reactive with tumor cells, allowing the immune system to mount protective immune responses against tumor cells. Additionally, some studies have found that VZV infection changes the systemic immune effect, recruits NK cells and T lymphocytes, and increases inflammatory factors [47, 48], which are also known mechanisms of oncolytic viruses [49]. After primary infection, VZV maintains latency in the nervous system. After reactivation, VZV may help to destroy tumor cells and enhance the local immune response against them. All of these anti glioma characteristics suggest that VZV is a better vector for oncolytic virus development than other virus vectors. Henning Leske et al. studied the oncolytic potential of VZV in glioma cell cultures and the tumor-targeting potential of human mesenchymal stem cells infected by VZV. Their results showed that VZV replicates rapidly in all glioma cells studied and dissolves tumors in vitro. Additionally, it was found that human mesenchymal stem cells were able to target varicella-zoster virus to tumor growth sites. Overall, VZV shows great oncolytic capacity in glioma cell cultures and may be an ideal candidate for glioma virus therapy.

The potential association between other genetically predicted virus infections and gliomasHSV infection

Additionally, we demonstrated by MR that HSV infection increases risk of LGG in genetically susceptible patients. Our MR analysis results indicated a suggestive causal relationship between HSV infection and glioma, though it did not remain robust in the validation test. Specifically, leave-one-out analysis revealed that the relationship was driven by the SNPs rs34264769, rs4885004 (in SNORA68), and rs9289557 (in MRAS). When any one of these SNPs was removed, no suggestive association remained, which means the MR results lack robustness due to the presence of these SNPs. SNORA68 is a small nucleolar RNA (snoRNA) located at p13.1 on chromosome 19 (19p13.1) that is associated with susceptibility to ovarian and breast cancer in individuals with BRCA1 or BRCA2 mutation [50]. Bolton et al. found that two SNPs at 19p13.1, rs8170 and rs2363956, are associated with patient survival in a cohort of 8,951 cases. In addition, high expression of SNORA68 is related to poor prognosis in several cancers, including ovarian cancer and non-small cell lung cancer (NSCLC) [51]. MRAS is similar to classical RAS oncoproteins, with many similar regulatory functions. It plays a vital role in cell differentiation and proliferation as well as cell polarity. However, in stark contrast to RAS, activating mutations in MRAS are rarely found in cancer [52]. Nonetheless, dysregulation of MRAS expression might be a contributing factor to tumorigenesis in some cases [53, 54]. Large-scale GWAS have identified MRAS sites as risk factors for cardiovascular disease [55]. Several observational studies have reached the same conclusion that HSV infection may increase risk of glioma: most GBM patients are serologically positive for HSV antibodies, suggesting that HSV may participate in the pathogenesis of glioma [17, 56]. Regardless, few studies have confirmed any causal relationship. HSV, as part of the Herpesviridae family, can remain latent in the nervous system and is well known for its neurovirulence [57]. Previous research proposed a possible mechanism by which miRNA-H16 encoded by HSV-1 induces NOTCH signaling pathway overactivation, which plays crucial roles in glioma cell survival and progression, thereby initiating glioma tumorigenesis [58, 59].

MeV infection

We also found suggestive evidence for the association between MeV infection and glioma. MeV infection reduced risk of GBM and all-glioma in patients genetically susceptible to MeV, which contradicts previous epidemiological study results [60]. Possible explanations for this discrepancy include that the underlying link obtained from previous case–control studies might be correlational but not causal and that such studies usually suffer from recall bias. Another possible explanation is the existence of reverse causality. Specifically, patients with glioblastoma may be immunocompromised [61], and more susceptible to measles virus infection, leading to the association between measles virus infection and glioma that we observed. In addition, our reverse MR estimate revealed no causal relationship between glioma and MeV infection. In recent years, oncolytic measles virus has been reported to be a novel treatment for glioma, and Cory Allen has proved that measles virus derivatives have significant antitumor activity against glioma-derived stem cells both in vitro and in vivo [62]. Therefore, further research is needed to examine the association between actual measles virus infection and glioma risk.

SARS-CoV-2 infection

As the pandemic progresses, the sequelae of COVID-19, including cardiovascular, pulmonary, and neurological diseases, are raising concerns about the long-term outcomes of SARS-CoV-2 infection, especially in heavily affected areas [63, 64]. Glial cells express SARS-COV-2 receptors such as angiotensin converting enzyme 2 (ACE2) and cathepsin L (CTSL), which may be responsible for making glioma patients more susceptible to SARS-CoV-2 infection and at higher risk for severe COVID-19 [65, 66]. However, the role of SARS-CoV-2 in glioma development remains unclear [67]. Our findings suggest that there is no causal association between SARS-COV-2 infection and glioma risk. Nevertheless, further research is necessary to substantiate that.

Strengths and limitations

Our study has several strengths. First, this is the first study to draw causal conclusions and eliminate confounding factors and reverse causality using the two-sample MR method to investigate the relationship between viral infection and glioma. Second, by using glioma data derived from the largest GWAS dataset (12,488 cases and 18,169 controls) and viral infection exposure data from credible large-scale GWAS databases (COVID-19 up to 1,887,658 individuals), our current study demonstrates solid validity and generalizability compared with traditional studies. Third, we included novel factors never studied before in our MR analysis, such as mumps and HPV infection. However, some limitations in this research need to be noted, including the lack of stratification of sex or age in the GWAS data and the lack of genetic data, as we were limited to using genome-wide association data of European ancestry only; ideally, we hope to expand the analysis to include all populations when possible. We use a suggestive genome-wide P-value threshold at 5 × 10−6, which may lead to false positive SNPs. But we additionally calculated F-statistics and R2 to transparently present the strength of our instruments. The F-statistics of all the selected SNPs are above the threshold of 10. And the R2 of the instrumental variables is calculated; SNPs selected as instrumental variables explain around 9.5% for herpes zoster. These results indicate that all the SNPs we selected are qualified and robust enough to carry out rigorous MR analyses. Besides, we do not find the association between herpes zoster and LGG risk by GRAPPLE method. We speculate that this may be related to GRAPPLE’s need for a separate GWAS cohort of exposure for selecting SNPs. Besides, the authors of GRAPPLE package also mentioned that in some areas, it is difficult to obtain multiple high-quality aggregated public GWAS statistics with non-overlapping cohorts in some areas [41].