The causal relationship between diabetes mellitus and hashimoto thyroiditis: A two-sample mendelian randomization...

This study aims to investigate the genetic correlation and potential causal relationship between diabetes mellitus (DM) and Hashimoto thyroiditis (HT), and to assess the effects of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) on HT risk, with the goal of informing thyroid-function monitoring in patients with DM and improving HT management. We used linkage disequilibrium score regression (LDSC) to estimate the genetic correlation between DM and HT. We then performed two-sample Mendelian randomization (TSMR) using data from genome-wide association studies (GWAS) to evaluate potential causal effects of DM subtypes on HT. We selected single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) and applied the inverse-variance weighted (IVW) method along with complementary sensitivity analyses to estimate causal effects. We assessed heterogeneity using Cochran's Q test and identified outlier SNPs with MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier). We used the MR-Egger intercept to test for directional pleiotropy. Finally, we performed a leave-one-out analysis to evaluate whether any single SNP unduly influenced the MR estimates. LDSC showed a significant negative genetic correlation between DM and HT (rG = -0.3285, SE = 0.062, P = 1.20 × 10-7), with evidence of nonzero SNP heritability (h2P < .005). In two-sample MR analyses of DM overall, the IVW estimate suggested increased HT risk in UK Biobank (OR = 7.26, 95% CI = 1.95-27.11, P < .05) and was directionally consistent in FinnGen (OR = 1.08, 95% CI = 1.02-1.14, P < .05). Subtype-specific MR analyses supported a causal effect of T2DM on HT (OR = 1.10, 95% CI = 1.05-1.16, P < .05), whereas there was no evidence for a causal effect of T1DM (OR = 1.04, 95% CI = 0.97-1.12, P > .05). We provide genetic support for a causal relationship between T2DM liability and higher HT risk, with no evidence of a direct causal effect for T1DM. These findings motivate periodic thyroid-function assessment and integrated endocrine-metabolic care in T2DM, and warrant multi-ancestry and mechanistic studies to refine risk prediction and identify actionable biology.