Exploring the possible causal role of the immune response to varicella-zoster virus on multiple traits: a phenome-wide Mendelian randomization study

Background: The immune response to infections could be largely driven by the individuals genes, especially in the major histocompatibility complex (MHC) region. Varicella-zoster virus (VZV) is a highly communicable pathogen. In addition to infection, the re-activations of VZV can be a potential causal factor for multiple traits. Identification of VZV immune response-related health conditions can therefore help elucidate the aetiology of certain diseases. Methods A phenome-wide Mendelian randomization study (MR-PheWAS) of anti-VZV Immunoglobulin G (IgG) level with 1,370 traits was conducted to explore the potential causal role of VZV-specific immunity on multiple traits using the UK Biobank cohort. For each trait, we performed Mendelian randomization (MR) analyses using five methods with or without instrumental variables (IVs) in the MHC region. Results We identified 49 single nucleotide polymorphisms (SNPs) associated with anti-VZV IgG level as IVs, five of which were located in the MHC region. Statistical evidence for a causal effect of anti-VZV IgG level on 75 traits was found in at least three of the MR methods, 60 traits if IVs in the MHC region were removed from MR analysis. With or without the MHC IVs, we found that a higher anti-VZV IgG level led to increased risk of 14 diseases and lower risks of 9 diseases. In addition, anti-VZV IgG level was causally associated with 5 biomarker-related traits. Conclusions Anti-VZV IgG was causally associated with multiple traits. MHC IVs had a substantial impact on MR causal inference, and therefore, should not be neglected from analysis.