Causal association between intrahepatic cholestasis of pregnancy and offspring neurodevelopmental disorders and mediating roles of lipoproteins and ATPase: A Mendelian randomization study

To explore the callsal association between intrahepatic cholestasis of pregnancy (ICP) and offspring attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome (TS) and its potential mechanisms.

Genome wide association study (GWAS) in public datasets was used to extract data. Among them, exposure was ICP (n=123579), which stems from FinnGen dataset. Outcome was defined as ADHD, TS and other tic disorders (n=23918), which is extracted from GWAS Catalog. Among mediators, total cholesterol in high-density lipoprotein (TC in HDL) were from the genetic map of the human plasma proteinome (n=21558), and Obg-like ATPase 1 was from whole-genome study of circulating metabolites (n=3301). In this study, we chose instrumental variables (IVs) that meets the Mendelian randomization (MR) hypothesis. When using two-sample MR, inverse variance weighted (IVW) was adopted as the primary method, and MR-Egger regression, weighted median, weighted mode, and simple mode were also utilized to analyse the robustness. Cochran's Q test, MR-Egger intercept test and leave-one-out sensitivity analysis were performed to verify the reliability. Significant threshold was set up as P<0.05. When using two-step MR, the first step is two-sample MR from exposure to mediator, and the second step is multivariable MR (MVMR), which is from mediator to outcome. At this time, conditional F-statistic was adopted to test the strength of IVs. At last, product distribution test was applied to determine the significance of mediation effects.

ICP was significantly related to ADHD and TS as well as other tic disorders in offspring (IVW: OR=1.003, 95%CI: 1.000~1.006, P=0.035), and sensitivity analysis verified the robustness of the results. The potential positive mediators included TC in HDL [total effect (TE) =2.855×10^-3; mediated effect (ME) =8.628×10^-4; mediated proportion (MP) =30.217%, 95%CI: 0.878%~73.954%], and Obg-like ATPase 1 (TE=2.855×10^-3; ME=1.216×10^-3; MP=42.572%, 95%CI: 6.356%~90.195%).

ICP is possible to elevate the incidence rate of ADHD and TS and other tic disorders via reducing TC in HDL and Obg-like ATPase 1.