Exploring the 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 individual's genes, especially in the major histocompatibility complex (MHC) region. Varicella-zoster virus (VZV) is a highly communicable pathogen. In addition to infection, the reactivations 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 (MR) study of anti-VZV immunoglobulin G (IgG) levels with 1370 traits was conducted to explore the potential causal role of VZV-specific immune response on multiple traits using the UK Biobank cohort. For the robustness of the results, we performed MR analyses using five different methods. To investigate the impact of the MHC region on MR results, the analyses were conducted using instrumental variables (IVs) inside (IV_mhc) and outside (IV_no.mhc) the MHC region or all together (IV_full).

Results: Forty-nine single nucleotide polymorphisms (IV_full) were associated with anti-VZV IgG levels, of which five (IV_mhc) were located in the MHC region and 44 (IV_no.mhc) were not. Statistical evidence (false discovery rate < 0.05 in at least three of the five MR methods) for a causal effect of anti-VZV IgG levels was found on 22 traits using IV_mhc, while no evidence was found when using IV_no.mhc or IV_full. The reactivations of VZV increased the risk of Dupuytren disease, mononeuropathies of the upper limb, sarcoidosis, coeliac disease, teeth problems and earlier onset of allergic rhinitis, which evidence was concordant with the literature. Suggestive causal evidence (P < 0.05 in at least three of five MR methods) using IV_full, IV_mhc and IV_no.mhc was detected in 92, 194 and 56 traits, respectively. MR results from IV_full correlated with those from IV_mhc or IV_no.mhc. However, the results between IV_mhc and IV_no.mhc were noticeably different, as evidenced by causal associations in opposite directions between anti-VZV IgG and ten traits.

Conclusions: In this exploratory study, anti-VZV IgG was causally associated with multiple traits. IVs in the MHC region might have a substantial impact on MR, and therefore, could be potentially considered in future MR studies.