The causal relationship between antibody-mediated immune responses to infections and Graves’ disease: a bi-directional Mendelian randomization analysis

The pathogenesis of Graves’ disease (GD) has not been fully elucidated, and antibody-mediated immune responses following microbial infection may be involved in its development. We conducted a bidirectional two-sample Mendelian randomization analysis using genetic variants associated with GD and 46 antibody-mediated immune-response phenotypes obtained from large-scale genome-wide association studies. In the forward analysis, none of the antibody-mediated immune-response phenotypes was significantly associated with GD risk after Bonferroni or false discovery rate (FDR) correction. Three Epstein–Barr virus antibody phenotypes showed nominal inverse associations with GD under the inverse-variance weighted method, but these findings did not survive multiple-testing correction and showed evidence of heterogeneity, with additional evidence of horizontal pleiotropy for the ZEBRA antibody phenotype. In the reverse analysis, several associations survived multiple-testing correction, although sensitivity analyses indicated heterogeneity or horizontal pleiotropy for the corrected associations except anti-polyomavirus 2 IgG seropositivity. After jointly considering multiple-testing correction and sensitivity analyses, genetic liability to GD was associated with higher anti-polyomavirus 2 IgG seropositivity (OR = 1.156, 95% CI: 1.050–1.273; P = 0.003), which remained significant after FDR correction but did not reach the Bonferroni-corrected threshold. Four additional associations—lower cytomegalovirus pp52 and pp150 antibody levels and higher Helicobacter pylori UreA antibody levels and anti-Merkel cell polyomavirus IgG seropositivity—were nominally significant and should be considered hypothesis-generating. Overall, this bidirectional MR study suggests that genetic liability to GD may influence selected humoral immune-response phenotypes. Notably, the association with anti-polyomavirus 2 IgG seropositivity remained significant after FDR correction, while additional suggestive associations were observed for antibody responses related to CMV, Helicobacter pylori , and Merkel cell polyomavirus. These findings provide new genetic insights into the potential relationship between GD and infection-related humoral immunity, while the potential influence of antibody-mediated immune responses on GD risk warrants further investigation.