Figures (4)  Tables (2)

    • Figure 1. 

      Mendelian randomization analyses of inflammatory proteins on Graves' ophthalmopathy (a) and of thyrotropin receptor antibodies on inflammatory proteins (b) identified in the VA Million Veteran Program. FDR, false discovery rate; OR, odds ratio; CI, confidence interval; TRAb, thyrotropin receptor antibody; SNP, single-nucleotide polymorphism.

    • Figure 2. 

      Mendelian randomization analyses of inflammatory proteins on Graves' ophthalmopathy (a) and of thyrotropin receptor antibodies on inflammatory proteins (b) identified in the UK Biobank. FDR, false discovery rate; OR, odds ratio; CI, confidence interval; TRAb, thyrotropin receptor antibody; SNP, single-nucleotide polymorphism.

    • Figure 3. 

      Radial plots and corresponding radial regression analyses for CX3CL1, CXCL10, and TNFRSF9.

    • Figure 4. 

      Interaction network analysis of the identified inflammatory proteins.

    • Exposure Outcome study Method Number of SNPs OR (95% CI) p-Value
      Thyrotropin receptor antibody VA Million Veteran Program Inverse variance weighted 43 2.42 (1.26–4.66) 0.008
      Thyrotropin receptor antibody UK Biobank Inverse variance weighted 33 7.96 (1.85–34.28) 0.005
      SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

      Table 1. 

      Association between genetically predicted thyrotropin receptor antibody and the risk of Graves' ophthalmopathy.

    • Dataset Mediator β overall β1 β2 Mediation proportion p-Value Exposure-outcome pleiotropy test Exposure-mediator pleiotropy test Mediator-outcome pleiotropy test
      VA Million Veteran Program CX3CL1 0.88 (0.23–1.54) 0.18 (0.04–0.32) 0.37 (0.13–0.60) 0.07 (0–0.15) 0.048 0.212 0.430 0.102
      UK Biobank CX3CL1 2.07 (0.61–3.53) 0.18 (0.04–0.32) 1.14 (0.59–1.70) 0.10 (0.01–0.19) 0.029 0.230 0.430 0.012
      CXCL10 0.20 (0.08–0.31) 1.23 (0.67–1.79) 0.12 (0.03–0.20) 0.008 0.230 0.205 0.030
      CXCL9 0.15 (0.05–0.25) 0.99 (0.44–1.54) 0.07 (0.01–0.14) 0.024 0.230 0.610 0.178
      TNF-β 0.14 (0.04–0.23) 0.47 (0.32–0.63) 0.03 (0.01–0.06) 0.012 0.230 0.291 0.093
      TNFRSF9 0.27 (0.16–0.38) 1.28 (0.65–1.90) 0.17 (0.06–0.27) 0.002 0.230 0.782 < 0.001
      The values of β overall, β1, and β2 represent the overall causal effect of TRAb on GO, the effect of TRAb on inflammatory proteins, and the effect of inflammatory proteins on GO, respectively. The indirect (mediated) effect is calculated as the product of β1 and β2, quantifying the portion of the TRAb–GO association mediated by inflammatory proteins.

      Table 2. 

      Mediation analysis of inflammatory proteins in the causal pathway linking thyrotropin receptor antibody to Graves' ophthalmopathy.