Shared and Distinct Genetic Factors Underlying Bile Acid Regulation and Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated total bile acid (TBA) levels, leading to adverse maternal and fetal outcomes. While genetic factors contribute to ICP and bile acid metabolism, the underlying mechanisms remain incompletely understood, particularly in East Asian populations. We conducted a genome-wide association study (GWAS) in 13,357 pregnant women from a Chinese cohort to investigate genetic determinants of TBA levels and ICP. Meta-analysis was performed by combining our data with the Shenzhen cohort. Post-GWAS analyses included pathway enrichment, integrative analysis with liver single-cell RNA sequencing (scRNA-seq) data, and Mendelian randomization (MR). We identified genome-wide significant associations at CYP7A1 (rs4738680, p = 1.08 × 10^-10) and SLC39A9 (rs17107007, p = 3.46 × 10^-28) for TBA, and at SLC39A9 (rs17107007, p = 3.34 × 10^-16) for ICP. Pathway analysis highlighted bile acid synthesis and metabolism pathways for TBA and immune-related pathways for ICP. Integrative scRNA-seq analysis revealed enrichment of TBA-associated genes in hepatocytes and ICP-associated genes in neutrophils. MR analysis suggested a potential causal effect of estrone on TBA levels. Our findings provide novel insights into the genetic architecture of TBA and ICP, emphasizing the roles of bile acid metabolism in hepatocytes and immune dysregulation in ICP pathogenesis. The identified genetic loci and pathways may inform future research on risk prediction and targeted therapies for ICP.