Multigenomics Reveals the Causal Effect of Herpes Simplex Virus in Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

Abstract

In recent years, the herpes virus infectious hypothesis for Alzheimer’s disease (AD) has gained support from an increasing number of researchers. Herpes simplex virus (HSV) is a potential risk factor associated with AD. This study assessed whether HSV has a causal relationship with AD using a two-sample Mendelian randomization analysis model. Six single-nucleotide polymorphisms (SNPs) associated with HSV-1 and thirteen SNPs associated with HSV-2 were used as instrumental variables in the MR analysis. We estimated MR values of relevance between exposure and the risk of AD using inverse-variance weighted (IVW) method, MR-Egger regression (Egger), and weighted median estimator (WME). To make the conclusion more robust and reliable, sensitivity analyses and RadialMR were performed to evaluate the pleiotropy and heterogeneity. We found that anti-HSV-1 IgG measurements were not associated with risk of AD (OR, 0.96; 95% CI, 0.79–1.18; p = 0.736), and the same was true for HSV-2 (OR, 1.03; 95% CI, 0.94–1.12; p = 0.533). The findings indicated that any HSV infection does not appear to be a genetically valid target of intervention in AD.

Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus

“…Second, though we used the F ‐statistic to define strong instruments, distortion caused by weak instruments may appear. This might be because our instrumental variables were selected based on the relaxed significance threshold 1 × 10 −5 rather than classical 5 × 10 −8 in the forward MR to guarantee the existence of IVs for all research subjects 50 . Third, limited IVs caused by limited sample size, especially for HSV IgG, might affect the statistical power of the causal estimates.…”

“…rather than classical 5 × 10 −8 in the forward MR to guarantee the existence of IVs for all research subjects 50. Third, limited IVs caused by limited sample size, especially for HSV IgG, might affect the statistical power of the causal estimates.…”

Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study

“…We performed a replicate MR analysis for significant results and a meta‐analysis to explore the combined effect. All statistical analyses were performed by using the “TwoSampleMR” (Hemani et al., 2018), “MR‐PRESSO” (Verbanck et al., 2018) and “RadialMR” packages (Zhang et al., 2021) in R (version 4.2.1.) and Reviewer Manager software (Version 5.4.1).…”

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

“…Those equivocal results might be caused by methodological shortcomings of observational studies, such as residual confounding and reverse causality. Confined by these limitations, observational research is unable to deduce the causal role of HSV infection in the development of MS. With the exponential growth in and widespread availability of genotype data, Mendelian randomization (MR) approach as an epidemiologic study designed to establish causality between exposures and outcomes has gained its popularity in the last two decades ( Zhuang et al, 2019 ; Huang et al, 2021 ; Kwok and Schooling, 2021 ; Zhang et al, 2021 ). MR utilizes germline genetic variants as proxies.…”