AUTHOR=Zhang Xinwei , Xu Wenyu , Liu Zhou , Zhang Jinan , Yang Xiaorong 
  
TITLE=The causal relationship between antibody-mediated immune responses to infections and Graves’ disease: a bi-directional Mendelian randomization analysis
  
JOURNAL=Experimental Biology and Medicine
  
VOLUME=Volume 251 - 2026
  
YEAR=2026
  
URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2026.11238
  
DOI=10.3389/ebm.2026.11238
  
ISSN=1535-3699
  
ABSTRACT=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.