Pathogenic genes associated with immune-related genes in graves’ disease: a multi-omics Mendelian randomization analysis

Immune-related genes (IRGs) have been implicated in autoimmune diseases, but their causal role in GD remains unclear. We conducted a multi-omics Mendelian randomization (MR) analysis integrating genome-wide association study (GWAS) data from GD patients with blood-based methylation quantitative trait loci(mQTLs), expression QTLs(eQTLs), and protein QTLs(pQTLs). SMR analysis was performed to assess the causal associations between IRGs and GD, followed by HEIDI tests to screen for pleiotropy. Colocalization analysis identified shared genetic determinants. We further validated the findings in Finngen R10 and GWAS catalog dataset and explored the regulatory associations between mQTLs, eQTLs, and pQTLs. Through SMR analysis (P-SMR-multi < 0.05, P-SMR < 0.05, P-HEIDI > 0.01), we identified 301 mQTLs, 27 eQTLs, and 11 pQTLs associated with the risk of GD in our discovery cohort. The validation cohort and colocalization analysis (PP.H4 > 0.5) confirmed 79 mQTLs, 5 eQTLs, and 1 pQTL (MMP9). Integrating mQTL and eQTL data, we identified 6 genes with potential causal associations (TNFRSF4, HLA-H, BACH2, TSHR, IL32, MMP9). Integrating eQTL and pQTL data, we identified FGFRL1. Crucially, a functional enrichment analysis of our candidate genes revealed significant enrichment in key immune pathways, providing strong biological support for our findings. IRGs, particularly FGFRL1, play a causal role in the pathogenesis of GD, providing insights into the molecular mechanisms of GD and potential therapeutic targets for future research.