Abstract
Gestational diabetes mellitus (GDM) is a common metabolic disorder during pregnancy and a significant risk factor for maternal and neonatal complications. Although management strategies have improved, early identification of high-risk cases remains challenging. This study aimed to clarify whether GDM exerts a causal effect on intrahepatic cholestasis of pregnancy (ICP), a hepatic disorder associated with adverse perinatal outcomes. We performed a 2-sample Mendelian randomization (MR) analysis using summary data from the genome-wide association study of the FinnGen consortium. Genetic variants strongly associated with GDM at a predefined significance threshold (P < 5 × 10-6) were selected as instrumental variables. Linkage disequilibrium clumping was applied (r2< 0.001, 10,000 kb window), and weak instruments with F < 10 were excluded. Multiple MR approaches, including inverse variance weighted, weighted median, MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier, were employed to ensure robustness. Inverse variance weighted analysis demonstrated a significant causal association between genetically predicted GDM and ICP (odds ratio [OR] = 1.30, 95% confidence interval [CI] 1.08-1.56, P = .005). The weighted median method yielded similar results (OR = 1.36, 95% CI 1.06-1.74, P = .014). Sensitivity analyses showed no evidence of heterogeneity or horizontal pleiotropy, and the MR-Steiger test confirmed the direction of causality from GDM to ICP. These findings provide genetic evidence supporting a causal effect of GDM on ICP risk and suggest that women with GDM may benefit from closer monitoring of liver function and bile acid levels during pregnancy.