Immune Cell-Specific Genetic Regulation in Graves' Disease: An Integrative Mendelian Randomization Study

Graves' disease (GD) is an autoimmune form of hyperthyroidism. We integrated GD GWAS summary statistics with immune-cell eQTLs to prioritize cell-type-specific genes with potential relevance to GD susceptibility.

We analyzed European-ancestry GD GWAS summary statistics from FinnGen Release 12 together with cis-eQTLs from 14 peripheral immune-cell subsets in the OneK1K single-cell resource (982 donors). We prioritized associations using SMR and HEIDI filtering, and Bayesian colocalization (COLOC) analysis was then performed to assess whether eQTL and GD association signals were likely to share a causal variant. Differential expression analysis using GSE71956 was used as additional transcriptomic support.

After harmonization, 5,048 instrument-gene pairs were retained. MR identified 173 nonredundant genes (FDR < 0.05); SMR plus HEIDI retained 159 genes across the 14 immune subsets. COLOC highlighted 33 high-confidence colocalized signals (PPH4 > 0.90), including ARID5B in CD4+ naïve/central memory T cells, PRSS16 in CD4+ effector-memory T cells, HIST1H2BI in CD8+ effector-memory T cells, and FCRL3 in NK cells. In GSE71956, several prioritized genes showed differential expression, and ARID5B was expressed at lower levels in GD samples than in controls.

Concordant evidence across methods supports these signals, but residual pleiotropy and the European-only design remain important caveats. Differences from prior reports may reflect cell-type context and disease stage.

Immune subset-resolved eQTL-GWAS integration points to specific genes and pathways that may contribute to GD susceptibility and helps narrow candidates for follow-up studies.