Abstract
BACKGROUND: Type 1 diabetes (T1D) and autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are characterized by immune-mediated damage. Prior observational studies have reported associations between these conditions, but definitive causal relationships remain elusive. This study leverages genetic data to clarify the nature of these associations. METHODS: We conducted a bidirectional Mendelian randomization (MR) analysis using summary-level data from large-scale genome-wide association studies. The inverse variance weighted was the primary method, supplemented by diverse sensitivity analyses (MR-Egger, weighted median, weighted mode, cML-MA, BWMR, MR-PRESSO, and CAUSE) to rigorously assess causality and address potential pleiotropy. We assessed genetic correlation using linkage disequilibrium score regression and performed colocalization to evaluate shared causal variants. RESULTS: Our findings revealed a causal effect of genetically predicted T1D on an increased risk of AIH (OR = 1.32, 95% CI: 1.16-1.50, P = 2.72 × 10⁻⁵), robustly supported by sensitivity analyses and replicated in an independent cohort. Evidence for a potential bidirectional causal relationship emerged between T1D and PBC, where genetically predicted T1D increased PBC risk (OR = 1.10; 95% CI: 1.02-1.20; P = 0.014), and genetically predicted PBC also increased T1D risk (OR = 1.13; 95% CI: 1.09-1.17; P = 3.45 × 10⁻¹¹), albeit with potential pleiotropy. No evidence for a genetic causal relationship was observed between T1D and PSC (IVW, P = 0.695). Significant genetic correlations were present between T1D and all AILDs, but colocalization did not support shared causal variants. CONCLUSIONS: This study provides genetic evidence for a causal effect of T1D on AIH and a likely bidirectional relationship between T1D and PBC. These findings refine our understanding of their comorbidity, suggesting the need for heightened clinical surveillance and warranting further mechanistic investigation to elucidate the biological pathways.