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 ( r 2 < 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.
Yang et al. (Fri,) studied this question.
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