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. 2022 Mar 1:16:817067.
doi: 10.3389/fnins.2022.817067. eCollection 2022.

Mendelian Randomization Analysis Suggests No Associations of Herpes Simplex Virus Infections With Multiple Sclerosis

Wan Zhang  1   2 , Pengfei Wu  2   3 , Rui Yin  4 , Meichen Sun  5 , Rongsen Zhang  6 , Xiaoyao Liao  7 , Yuhong Lin  8 , Hui Lu  5
Affiliations

Mendelian Randomization Analysis Suggests No Associations of Herpes Simplex Virus Infections With Multiple Sclerosis

Wan Zhang et al. Front Neurosci. .

Abstract

Previous studies have suggested an association between infection with herpes simplex virus (HSV) and liability to multiple sclerosis (MS), but it remains largely unknown whether the effect is causal. We performed a two-sample Mendelian randomization (MR) study to explore the relationship between genetically predicted HSV infection and MS risk. Genetic instrumental variables for diagnosed infections with HSV (p < 5 × 10-6) were retrieved from the FinnGen study, and single nucleotide polymorphisms associated with circulating immunoglobulin G (IgG) levels of HSV-1 and HSV-2 and corresponding summary-level statistics of MS were obtained from genome-wide association studies of the European-ancestry. Inverse-variance weighted MR was employed as the primary method and multiple sensitivity analyses were performed. Genetically proxied infection with HSV was not associated with the risk of MS (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.90-1.02; p = 0.22) per one-unit increase in log-OR of herpes viral infections. MR results provided no evidence for the relationship between circulating HSV-1 IgG levels and MS risks (OR = 0.91; 95% CI, 0.81-1.03; p = 0.37), and suggested no causal effect of HSV-2 IgG (OR = 1.04; 95% CI, 0.96-1.13; p = 0.32). Additional sensitivity analyses confirmed the robustness of these null findings. The MR study did not support the causal relationship between genetic susceptibly to HSV and MS in the European population. Further studies are still warranted to provide informative knowledge, and triangulating evidence across multiple lines of evidence are necessary to plan interventions for the treatment and prevention of MS.

Keywords: Mendelian randomization; causal risk factors; genetic epidemiology; herpes simplex virus; multiple sclerosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram of the Mendelian randomization study. HSV, herpes simplex virus; MR, Mendelian randomization; MS, multiple sclerosis; SNP, single nucleotide polymorphism.
FIGURE 2
FIGURE 2
Scatter plot (A) and leave-one-out plot (B) in the Mendelian randomization analysis of HSV infection on MS risk. HSV, herpes simplex virus; MR, Mendelian randomization; MS, multiple sclerosis.
FIGURE 3
FIGURE 3
Scatter plot (A) and leave-one-out plot (B) in the Mendelian randomization analysis of HSV-1 IgG levels on multiple sclerosis. MR-PRESSO outlier-corrected estimate was calculated with the removal of rs3132935 as an outlying variant, while the raw estimate was not delineated since it was nearly the same as the value given by inverse-variance-weighted method. HSV, herpes simplex virus; MR, Mendelian randomization; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; MS, multiple sclerosis.
FIGURE 4
FIGURE 4
Scatter plot (A) and leave-one-out plot (B) in the Mendelian randomization analysis of HSV-2 IgG on MS risk. HSV, herpes simplex virus; MR, Mendelian randomization; MS, multiple sclerosis.
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