Causal association between intrahepatic cholestasis of pregnancy and offspring neurodevelopmental disorders and mediating roles of lipoproteins and ATPase:A Mendelian randomization study
10.16016/j.2097-0927.202506083
- VernacularTitle:妊娠期肝内胆汁淤积症与子代神经发育障碍的因果关联及脂蛋白与ATP酶的中介作用:一项孟德尔随机化研究
- Author:
Zhengdong CHEN
1
;
Qingqi RAN
;
Minghui XIAO
;
Qinyi YU
;
Wenjie PENG
;
Zhangxue HU
Author Information
1. 陆军军医大学大坪医院儿科
- Keywords:
attention-deficit disorder with hyperactivity;
Tourette's syndrome;
intrahepatic cholestasis of pregnancy;
Mendelian randomization analysis;
mediating factor
- From:
Journal of Army Medical University
2025;47(22):2725-2734
- CountryChina
- Language:Chinese
-
Abstract:
Objective 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.Methods Genome wide association study(GWAS)in public datasets was used to extract data.Among them,exposure was ICP(n=123 579),which stems from FinnGen dataset.Outcome was defined as ADHD,TS and other tic disorders(n=23 918),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=21 558),and Obg-like ATPase 1 was from whole-genome study of circulating metabolites(n=3 301).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.Results 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%).Conclusion 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.
