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. 2025 Aug 15;104(33):e43656. doi: 10.1097/MD.0000000000043656

Human herpes virus infection and vestibular neuritis: A Mendelian randomization study

Long Luo a, Ronghe Yang b, Yixuan He c, Ling Zhu a,*
PMCID: PMC12366938  PMID: 40826744

Abstract

Human herpes virus infection is thought to be associated with the development of vestibular neuritis (VN); however, the causal relationship is unclear. Large-scale genome-wide association studies were used in bidirectional Mendelian randomization (MR) analyses to evaluate the causal relationship between human herpes virus infections and VN in a cohort of 434,070 individuals. Inverse variance weighting, MR-Egger, and weighted median methods were used to estimate causality. These results were then validated through multiple sensitivity analyses. In forward MR inverse variance weighting analysis, genetically predicted herpes simplex virus (HSV) infections (odds ratio [OR] = 1.01; 95% confidence interval [CI]: 0.90–1.14; P = .814), HSV keratitis and keratoconjunctivitis (OR = 0.97; 95% CI: 0.87–1.08; P = .593), anogenital HSV infection (OR = 0.96; 95% CI: 0.87–1.06; P = .410), HSV-1 IgG (OR = 1.05; 95% CI: 0.59–1.88; P = .860), HSV-2 IgG (OR = 1.01; 95% CI: 0.90–1.14; P = .839), varicella-zoster virus infection (OR = 1.05; 95% CI: 0.97–1.14; P = .222), Epstein–Barr virus infection (OR = 1.00; 95% CI: 0.91–1.09; P = .944), and cytomegalovirus IgG (OR = 0.93; 95% CI: 0.79–1.10; P = .414), were not causally associated with VN. Moreover, no causality was found in the reverse MR analysis. Sensitivity analyses confirmed the reliability and validity of our findings. Our MR analysis revealed no significant causal effect of HSV-1, HSV-2, varicella-zoster virus, Epstein–Barr virus, and cytomegalovirus infections on the development of VN. These findings need to be further validated in larger, more diverse populations, and subgroup analyses will further reveal potential trends and differences in the study data.

Keywords: HHV, human herpes virus, Mendelian randomization study, MR, vestibular neuritis, VN

1. Introduction

Vestibular neuritis (VN) has an incidence of 3.5/100,000 to 15.5/100,000,[1,2] accounting for approximately 0.5% to 9% of patients in specialized vertigo clinics or neurology outpatient departments,[3] and is a relatively common disorder of peripheral vestibular vertigo, second to benign paroxysmal positional vertigo. The exact etiology of VN is unknown but viral infection is now widely accepted as one of the possible causes.

Human herpes virus (HHV) are neurotropic viruses classified into 3 main subfamilies (α, β, and γ). The α herpes viruses include herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV). HSV infections have body site attributes: HSV-1 is commonly associated with oropharyngeal herpes and herpetic keratoconjunctivitis,[4] while HSV-2 is a major cause of genital ulcers.[5] The β herpes viruses include HHV-5 (cytomegalovirus, CMV), HHV-6, and HHV-7. The γ herpes viruses include HHV-4 (Epstein–Barr virus, EBV) and HHV-8.[6] Infectious mononucleosis and Kaposi sarcoma are almost always caused by EBV and HHV-8 infection, respectively.[7,8] These infections are highly prevalent, affecting approximately 80% to 90% of adults worldwide.[9] Evidence suggests that HHVs are associated with various neurological disorders, including facial neuritis, VN, and multiple sclerosis.[10,11] Clinical,[2,12] experimental,[13,14] and pathologic[10,15] evidence suggests that HSV-1 infection may be the cause of VN. In addition to HSV-1, HHV that have been reported to be clinically associated with VN include HSV- 2, VZV, CMV, and EBV.[16,17] However, the viral hypothesis has also been questioned, with multiple studies showing that antiviral therapy is ineffective against VN.[18,19]

Whether some of the associations between HHV and VN are coincidental or causal has not been clarified. Mendelian randomization (MR) analysis offers a distinct advantage over observational studies because it minimizes confounding factors.[20] MR uses genetic variations as instrumental variables (IVs) assigned randomly at conception, similar to randomized controlled trials. In addition, MR achieves better results than traditional clinical trials for rare diseases by using a much larger sample size. Therefore, in the present study, we used MR to assess the causal relationship between HHV and VN; HHV-6, HHV-7, and HHV-8 were not included in this study due to the lack of reports of their association with VN.

2. Methods

2.1. MR methods

Bidirectional MR analyses of HHV and VN were performed using the largest genome-wide association study (GWAS) database. The analysis was based on the following 3 hypotheses. (1) Single-nucleotide polymorphisms (SNPs) as IVs are strongly associated with exposure. (2) SNPs as IVs are independent of confounding factors that affect the relationship between HHV and VN. (3) SNPs as IVs affect outcomes only through their effect on exposure and not through other pathways. The bidirectional MR design is illustrated in Figure 1A.

Figure 1.

Figure 1.

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Flowchart. (A) Study design in bidirectional Mendelian randomization; (B) MR analysis flow. HHV = human herpes virus, IVs = instrumental variables, IVW = inverse variance weighting, SNPs = single-nucleotide polymorphisms, VN = vestibular neuritis.

Candidate SNPs were selected based on the following criteria: (1) the strength of the association of SNP with exposure needed to reach a statistical significance threshold of P < 5 × 10−6, (2) SNPs with associations were removed by “chain disequilibrium” analysis (r2 < 0.001, 10,000 kb), (3) potential SNPs required an F-statistic > 10 to exclude weak IVs, (4) during harmonization, SNPs with inconsistent alleles and palindromic SNPs with unclear strand orientation were either corrected or omitted, and (5) SNPs associated with confounders (including smoking, alcohol consumption) were identified using LDtrait (https://ldlink.nih.gov/?tab=ldtrait), and excluded in subsequent analyses.[21] SNPs that fit these requirements were used as IVs (Fig. 1B). The inverse variance-weighted (IVW), MR-Egger, and weighted median methods are the main analytical methods used in this MR study. Of these, the IVW method was used as the foundational method because of its superior statistical power.[22] The remaining 2 methods were used as supplements. To minimize the possibility of false positives (type I errors), we used bonferroni correction to adjust the significance level, considering that forward and reverse MR analyses were performed 8 times, and the critical value of P was set at 0.05/8 (0.00625). P < .05 was taken as nominal significance.[23] In R software (v 4.3.3) and Rstudio software (v 2023.12.1.402), TwoSampleMR (v 0.5.11), and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) (v 1.0) packages were used to perform the analysis.

Sensitivity analyses were performed to ensure the stability of the results. First, Cochran Q statistic was used to assess heterogeneity, with P ≥ .05 indicating no heterogeneity.[24] Second, the MR-PRESSO global test and MR-Egger regression intercept compared with 0 were used to assess horizontal pleiotropy, with P ≥ .05 indicating no horizontal pleiotropy.[25,26]

Furthermore, the MR-PRESSO method also excludes outliers. Third, a leave-one-out analysis was performed to assess the effect of each SNP on causal signaling.[27] Funnel plots were constructed to check for horizontal pleiotropy during MR analysis (Fig. 1(B)).

2.2. GWAS data sources

We used publicly available summary-level GWAS data from the FinnGen and IEU Open GWAS Project publicly available databases and no additional ethical approvals were obtained. Details of the data sources are presented in Table 1.

Table 1.

Details of the genome-wide association studies and datasets used in this study.

Exposure and outcome GWAS ID Registry filters Sample size Cases Controls Ancestry Access link
HSV infections finn-b-AB1_HERPES_SIMPLEX ICD-10 B00; ICD-9 05 [4]; ICD-8 05 [4] 440,031 4159 435,872 European https://r11.finngen.fi
HSV keratitis and keratoconjunctivitis finn-b-H7_HERPESKERATITIS ICD-10 H19.1*, H19.1*B00.5 430,800 1404 429,396 European https://r11.finngen.fi
Anogenital HSV infection finn-b-AB1_ANOGENITAL_HERPES_SIMPLEX ICD-10 A60; ICD-9 0541A; ICD-8 5402 442,603 2236 440,367 European https://r11.finngen.fi
HSV-1 IgG ebi-a-GCST006346 – 645 – – European https://gwas.mrcieu.ac.uk/datasets/
HSV-2 IgG ebi-a-GCST006347 – 208 – – European https://gwas.mrcieu.ac.uk/datasets/
VZV infection finn-b-AB1_VARICELLA ICD-10 B01; ICD-9 05 [2]; ICD-8 05 [2] 437,516 1644 435,872 European https://r11.finngen.fi
EBV infection finn-b-AB1_EBV ICD-10 B27; ICD-9 07 [5]; ICD-8 07 [5] 444,478 3439 441,039 European https://r11.finngen.fi
CMV IgG ieu-b-4900 – 5010 – – European https://gwas.mrcieu.ac.uk/datasets/
VN finn-b-H8_VESTIBNEUR ICD-10 H81.2; ICD-9 3861 434,070 2951 431,119 European https://r11.finngen.fi
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EBV = Epstein–Barr virus, CMV = cytomegalovirus, HSV = herpes simplex virus, SNP = single-nucleotide polymorphism, VN = vestibular neuritis, VZV = varicella-zoster virus.

3. Results

3.1. Effects of HHV on VN

The results of the forward MR and sensitivity analyses for HHV and VN are presented in Figure 2. The findings from the fixed-effects IVW method are as follows. HSV infection was not causally associated with VN (odds ratio [OR] = 1.01; P = .814). Similarly, HSV keratitis and keratoconjunctivitis (OR = 0.97; P = .593), anogenital HSV infection (OR = 0.96; P = .410), HSV-1 IgG (OR = 1.05; P = .860), HSV-2 IgG (OR = 1.01; P = .839), VZV infection (OR = 1.05; P = .222), EBV infection (OR = 1.00; P = .944), and CMV IgG (OR = 0.93; P = .414), did not show a significant association with VN. These results were corroborated using the MR-Egger and weighted median methods (Fig. 2 and Figure S1, Supplemental Digital Content, https://links.lww.com/MD/P594). The MR analyses detected no significant heterogeneity (P ≥ .05, Cochran Q) or horizontal pleiotropy (P ≥ .05, intercept; P ≥ .05, MR- PRESSO global test). The funnel plots of the IVs in the IVW analysis showed a symmetric distribution, indicating no significant heterogeneity (Figure S3, Supplemental Digital Content, https://links.lww.com/MD/P594); no individual SNP was found to affect the correlation in the leave-one-out analysis (Figure S2, Supplemental Digital Content, https://links.lww.com/MD/P594); the forest plot (Figure S4, Supplemental Digital Content, https://links.lww.com/MD/P594) summarizes the MR estimates for HHV subtypes and VN risk. These results indicate that the MR analysis was highly valid and robust.

Figure 2.

Figure 2.

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The causal relationship between human herpes viruses (exposure) and vestibular neuritis (outcome) determined through two-sample Mendelian randomization is shown, including results from sensitivity analyses.

3.2. Effects of VN on HHVs

The results of our reverse MR analysis for each HHV using VN as exposure are shown in Figure 3. The findings from the fixed-effects IVW method are as follows. VN was not found to be causally associated with HSV infections (OR = 0.95; P = .276). Similarly, no causal associations were found for HSV keratitis and keratoconjunctivitis (OR = 0.95; P = .511), anogenital HSV infection (OR = 0.98; P = .749), HSV-1 IgG (OR = 1.07; P = .182), HSV-2 IgG (OR = 1.04; P = .725), VZV infection (OR = 0.92; P = .228), EBV infection (OR = 1.08; P = .102), and CMV IgG (OR = 0.99; P = .887). The MR-Egger and weighted median methods corroborated these findings (Fig. 3 and Figure S5, Supplemental Digital Content, https://links.lww.com/MD/P594). These MR analyses detected no significant heterogeneity (P ≥ .05, Cochran Q) or horizontal pleiotropy (P ≥ .05, intercept; P ≥ .05, MR-PRESSO global test). In addition, the funnel plots were symmetrically distributed and showed no significant heterogeneity (Figure S7, Supplemental Digital Content, https://links.lww.com/MD/P594). Furthermore, the exclusion of any single SNP in the leave-one-out analysis did not significantly affect the results (Figure S6, Supplemental Digital Content, https://links.lww.com/MD/P594). The forest plot (Figure S8, Supplemental Digital Content, https://links.lww.com/MD/P594) summarizes the MR estimates for VN and HHV subtypes risk.

Figure 3.

Figure 3.

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The causal relationship between vestibular neuritis (exposure) and human herpes viruses (outcome) determined through two-sample Mendelian randomization is shown, including results from sensitivity analyses.

4. Discussion

To the best of our knowledge, this MR study is the first to investigate the causal relationship between HHV and VN. We found no causal relationship between HHV and VN.

VN is associated with infection; combined viral infections in VN have a prevalence of 43% to 46%.[28,29] Of these, HSV-1 has been most extensively studied in relation to VN. There are 3 states of HSV-1 in humans: primary infection, latent infection, and reactivation. Primary infection is usually subclinical and occurs before adolescence. The virus then becomes latent in the sensory ganglia, and stress, as well as endogenous and exogenous injury can lead to reactivation of the virus, ultimately resulting in the clinical manifestations of viral infection.[30] The peak period of primary infection with HSV-1 does not coincide with the peak incidence of VN, which occurs between the ages of 30 and 60 years.[2,31] Therefore, primary infection with HSV-1 is unlikely to contribute to VN. Reactivation of HSV-1 is hypothesized to be a potential cause of VN.[10] Notably, viral survival in the body is dynamic and related to viral factors[32,33] and the host immune response.[34] It has been shown that serum antibody titers to herpes simplex virus vary intermittently up to 4-fold in healthy individuals,[35] as of now there are no objective criteria to define HSV-1 reactivation. Since primary infection is usually subclinical and reactivation leads to clinical manifestations of viral infection,[30] herpes simplex virus keratitis and keratoconjunctivitis can be considered a form of HSV-1 reactivation. Based on MR analysis we did not find a causal association with VN, and the use of HSV-1 IgG as an exposure factor yielded consistent findings. Similarly, no causal association was found between other herpesviruses (including HSV-2, VZV, EBV, and CMV) and VN. These contrasts with previous findings, where observational studies have identified a possible association between HHV and VN,[16,17] and a GWAS found that HSV-1 reactivation may contribute to VN.[36] Furthermore, in animal studies, inoculation of HSV-1 into the rat auricle or middle ear resulted in vestibular dysfunction.[13,14] Possible reasons for the discrepancy in the results are as follows: (1) observational studies are usually unavoidably subject to selective bias, and causality cannot be inferred. (2) The subjects and outcome indicators selected for the studies are different, specifically, while the results of animal experiments are important references for human studies, there is no guarantee that all experimental conclusions are directly applicable to humans; previous genome-wide studies have focused on correlating functional genes,[36] whereas our study employs genetic data as a bridge to explore causal relationships. (3) Despite the use of herpes simplex virus keratitis and keratoconjunctivitis as surrogate indicators of HSV-1 reactivation, the survival status of HSV-1 in the vestibular ganglia remains uncertain. Viral reactivation in the vestibular ganglion deserves further investigation. Whether reduced host immunocompetence under specific circumstances, such as the use of immunosuppressive agents, can lead to viral reactivation, and consequently to VN, may be a direction for future research. (4) Ischemia and inflammation may be key factors in the development of VN, because of its acute onset and associated cardiovascular risk factors, thrombosis in the vestibular branch of the labyrinthine artery has been hypothesized to be involved in VN;[37,38] magnetic resonance imaging shows enhancement of the affected vestibular ganglion in patients with VN, suggesting inflammation in the vestibular nerve;[39] in addition, hormones, as an anti-inflammatory agent, seem to promote early recovery of vestibular function in patients with VN.[18,19] (5) HHV infection may be insufficient for VN development, which requires other genetic and environmental triggers, other biological factors facilitate viral replication, induction of chimerism, and edematous processes that cause secondary cellular damage to vestibular ganglion cells and axons in bone tubes.[40] Therefore, further studies on the function of HHV in VN pathogenesis and progression are necessary.

The main strengths of this study are the use of the latest genetic instruments to characterize HHV infections; we used large-scale GWAS data from European populations to increase power, and MR methods to avoid residual confounding compared with traditional observational studies. This study had several limitations. First, instrumental SNPs collectively explain only a fraction of the variation in exposure; their ability to identify small causal relationships is limited. Second, we used a relaxed value of significance (P < 5 × 10−6) rather than the classic GWAS tolerance (P < 5 × 10−8) to select the IVs. Third, we used summary-level GWAS data, and the lack of individual statistics for stratified analyses prevented us from performing in-depth analyses of subgroups, which may affect the interpretation and validity of the results for specific characteristics. Finally, this study was based on GWAS data that included only Europeans. Therefore, caution should be exercised when interpreting and generalizing the results to other populations.

In summary, this study found no causal relationship between HHV infection and VN. However, this conclusion should be interpreted with caution. Validation with a larger sample size and a wider population is required.

Acknowledgments

We want to acknowledge the participants and investigators of the FinnGen and IEU Open GWAS Project studies.

Author contributions

Conceptualization: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Data curation: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Formal analysis: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Investigation: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Methodology: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Project administration: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Resources: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Software: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Supervision: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Validation: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Visualization: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Writing – original draft: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Writing – review & editing: Long Luo, Ronghe Yang, Yixuan He, Ling Zhu.

Supplementary Material

Abbreviations:

CI
confidence interval
CMV
cytomegalovirus
EBV
Epstein–Barr virus
GWAS
genome-wide association study
HHV
human herpes virus
HSV
herpes simplex virus
IVs
instrumental variables
IVW
inverse variance weighting
MR
Mendelian randomization
MR-PRESSO
MR Pleiotropy Residual Sum and Outlier
OR
odds ratio
SNPs
single-nucleotide polymorphisms
VN
vestibular neuritis
VZV
varicella-zoster virus

All data sources used in this MR study (FinnGen and IEU Open GWAS Project) have been approved by the Human Experiment Ethics Standards Committee and informed consent has been obtained from all participants.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Luo L, Yang R, He Y, Zhu L. Human herpes virus infection and vestibular neuritis: A Mendelian randomization study. Medicine 2025;104:33(e43656).

Contributor Information

Long Luo, Email: luol01@126.com.

Ronghe Yang, Email: 469172070@qq.com.

Yixuan He, Email: 1010967139@qq.com.

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Supplementary Materials

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