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Article(id=1322954303874413265, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322954253676979072, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202506083, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751126400000, receivedDateStr=2025-06-29, revisedDate=1762444800000, revisedDateStr=2025-11-07, acceptedDate=null, acceptedDateStr=null, onlineDate=1793346485291, onlineDateStr=2026-10-30, pubDate=1764432000000, pubDateStr=2025-11-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793346485291, onlineIssueDateStr=2026-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793346485291, creator=13701087609, updateTime=1793346485291, updator=13701087609, issue=Issue{id=1322954253676979072, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='22', pageStart='2725', pageEnd='2880', issueExtLink='null', onlineDate='null', pubDate='1764432000000', pubDateStr='2025-11-30', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793346473378, creator='13701087609', updateTime=1793346473378, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=2725, endPage=2734, ext={EN=ArticleExt(id=1322954304335786706, articleId=1322954303874413265, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Causal association between intrahepatic cholestasis of pregnancy and offspring neurodevelopmental disorders and mediating roles of lipoproteins and ATPase: A Mendelian randomization study, columnId=1320435149808980440, journalTitle=Journal of Army Medical University, columnName=Neuroscience, runingTitle=null, highlight=null, articleAbstract=
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.

, authors=Zhengdong CHEN, Qingqi RAN, Minghui XIAO, Qinyi YU, Wenjie PENG, Zhangxue HU, authorsList=Zhengdong CHEN, Qingqi RAN, Minghui XIAO, Qinyi YU, Wenjie PENG, Zhangxue HU, authorCompany=null, correspAuthors=Wenjie PENG, Zhangxue HU, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322954306416161499, articleId=1322954303874413265, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=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, columnId=1320435149964169690, journalTitle=陆军军医大学学报, columnName=论著·神经科学, runingTitle=null, highlight=null, articleAbstract=
目的

探究妊娠期肝内胆汁淤积症 （intrahepatic cholestasis of pregnancy，ICP）和子代注意缺陷多动障碍（attention-deficit hyperactivity disorder，ADHD）和妥瑞氏综合征（Tourette’s Syndrome，TS）之间的因果关联以及潜在机制。

方法

数据均来源于公共数据库全基因组关联研究（genome wide association study，GWAS）。其中暴露为ICP（n=123 579），来源于芬兰数据库；结局为ADHD与TS及其他抽动障碍（n=23 918），来源于GWAS Catalog数据库。中介分子中，高密度脂蛋白里的总胆固醇含量（n=21 558）来源于人类血浆蛋白质组的基因图谱，Obg样ATP酶1来源于循环代谢物全基因组研究（n=3 301）。本研究选择满足MR假设的工具变量。双样本MR分析主要方法为逆方差加权（inverse variance weighted，IVW），MR-Egger回归、加权中位数法、加权众数法、简单模式也被采用进行稳健性分析。Cochran’s Q 检验、MR-Egger 截距检验和留一法等敏感性分析用来验证结果的可靠性，统计显著性设定为P<0.05。使用中介MR时，从暴露到中介的第一步采用双样本MR，第二步采用多变量MR，此时条件F值被采用检测工具变量的强度。最后使用乘积分布检验验证中介效应的显著性。

结果

ICP与ADHD和TS及其他抽动障碍显著相关（IVW：OR=1.003，95%CI：1.000~1.006，P=0.035），敏感性分析证实了结果的稳健性。可能的中介分子包括高密度脂蛋白中总胆固醇含量［总效应 （total effect，TE）=2.855×10-3；中介效应（mediated effect，ME）=8.628×10-4；中介效应占比（mediated proportion，MP）=30.217%，95%CI：0.878%~73.954%）］ 和Obg样ATP酶1（TE=2.855×10-3；ME=1.216×10-3； MP=42.572%，95%CI：6.356%~90.195%）。

结论

ICP可能通过高密度脂蛋白中总胆固醇含量和Obg样ATP酶1的减少来增加子代ADHD和TS及其他抽动障碍的发病率。

, authors=陈正东, 冉清琦, 肖明辉, 余沁怡, 彭文杰, 胡章雪, authorsList=陈正东, 冉清琦, 肖明辉, 余沁怡, 彭文杰, 胡章雪, authorCompany=null, correspAuthors=彭文杰, 胡章雪, authorNote=

同等贡献者

CHEN Zhengdong and RAN Qingqi contributed equally to the article.

, correspAuthorsNote=
胡章雪，Email：
彭文杰，Email：
HU Zhangxue，E-mail：
PENG Wenjie，E-mail：
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Brain Sci，2017，8（1）：3., articleTitle=A prospective birth cohort study on maternal cholesterol levels and offspring attention deficit hyperactivity disorder：new insight on sex differences, refAbstract=null), Reference(id=1322954313324180279, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, doi=10.1096/fj.10-175448, pmid=null, pmcid=null, year=2011, volume=25, issue=5, pageStart=1641, pageEnd=1652, url=null, language=null, rfNumber=28, rfOrder=28, authorNames=KIM Y K, WASSEF L, CHUNG S, journalName=FASEB J, refType=null, unstructuredReference=KIM Y K，WASSEF L，CHUNG S，et al. β-Carotene and its cleavage enzyme β-carotene-15，15'-oxygenase （CMOI） affect retinoid metabolism in developing tissues［J］. 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PLoS Genet，2022，18（6）：e1010219., articleTitle=OLA-1，an Obg-like ATPase，integrates hunger with temperature information in sensory neurons in C. elegans, refAbstract=null), Reference(id=1322954313676501819, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, doi=10.5114/ceji.2014.43723, pmid=null, pmcid=null, year=2014, volume=39, issue=2, pageStart=198, pageEnd=202, url=null, language=null, rfNumber=32, rfOrder=32, authorNames=OZLER A, UCMAK D, EVSEN M S, journalName=Cent Eur J Immunol, refType=null, unstructuredReference=OZLER A，UCMAK D，EVSEN M S，et al. Immune mechanisms and the role of oxidative stress in intrahepatic cholestasis of pregnancy［J］. Cent Eur J Immunol，2014，39（2）：198-202., articleTitle=Immune mechanisms and the role of oxidative stress in intrahepatic cholestasis of pregnancy, refAbstract=null), Reference(id=1322954313777165116, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, doi=10.1038/cddis.2013.23, pmid=null, pmcid=null, year=2013, volume=4, issue=2, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=33, rfOrder=33, authorNames=MAO R F, RUBIO V, CHEN H, journalName=Cell Death Dis, refType=null, unstructuredReference=MAO R F，RUBIO V，CHEN H，et al. OLA1 protects cells in heat shock by stabilizing HSP70［J］. Cell Death Dis，2013，4（2）：e491., articleTitle=OLA1 protects cells in heat shock by stabilizing HSP70, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322954306873340636, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, xref=1, ext=[AuthorCompanyExt(id=1322954306885923549, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, companyId=1322954306873340636, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Pediatrics，Daping Hospital，Army Medical University，Chongqing，China), AuthorCompanyExt(id=1322954306902700766, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, companyId=1322954306873340636, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学大坪医院儿科，重庆)])], figs=[ArticleFig(id=1322954309549306633, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Figure 1, caption=Workflow of this study, figureFileSmall=HQ7pZzgrVj0ZFEA1bfWwYQ==, figureFileBig=p/28Xz5aUZ5+lwHAFzPH3Q==, tableContent=null), ArticleFig(id=1322954309645775626, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=图1, caption=研究流程图, figureFileSmall=HQ7pZzgrVj0ZFEA1bfWwYQ==, figureFileBig=p/28Xz5aUZ5+lwHAFzPH3Q==, tableContent=null), ArticleFig(id=1322954309855490827, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Figure 2, caption=Scatter plot and leave-one-out analysis of the MR analysis from ICP to ADHD and TS and other tic disorders, figureFileSmall=/P2Ra5BDVh4RgKHWwL0iLg==, figureFileBig=H1CF3x+F5G/zI4QYtkc+PA==, tableContent=null), ArticleFig(id=1322954309914211084, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=图2, caption=ICP与子代ADHD和TS及其他抽动障碍双样本MR的散点图和留一法分析

A：Scatter plot of MR analysis from ICP to ADHD and TS and other tic disorders； B：Leave-one-out analysis of MR analysis from ICP to ADHD and TS and other tic disorders. ICP：Intrahepatic cholestasis of pregnancy； ADHD：Attention-deficit hyperactivity disorder； TS：Tourette’s syndrome； MR：Mendelian randomization

, figureFileSmall=/P2Ra5BDVh4RgKHWwL0iLg==, figureFileBig=H1CF3x+F5G/zI4QYtkc+PA==, tableContent=null), ArticleFig(id=1322954310019068685, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Figure 3, caption=Forest plot of analysis describing the two-sample MR analysis of ICP with ADHD and TS as well as other tic disorders, figureFileSmall=oS9SagwhExbCGEw3Qv5IRg==, figureFileBig=R4cvrXr0L3FTDe2eVpbI/Q==, tableContent=null), ArticleFig(id=1322954310081983246, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=图3, caption=ICP与ADHD和TS及其他抽动障碍双样本MR分析的森林图

MR：Mendelian randomization； ICP：Intrahepatic cholestasis of pregnancy； ADHD：Attention-deficit hyperactivity disorder； TS：Tourette’s syndrome

, figureFileSmall=oS9SagwhExbCGEw3Qv5IRg==, figureFileBig=R4cvrXr0L3FTDe2eVpbI/Q==, tableContent=null), ArticleFig(id=1322954310165869327, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Figure 4, caption=Forest plot of the mediators and its mediated proportions of ICP with ADHD and TS as well as other tic disorders, figureFileSmall=1uuvDFFcsLHABNGu9NCs+w==, figureFileBig=cWQ9MiW4MYt8vcplMLSQuQ==, tableContent=null), ArticleFig(id=1322954310241366800, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=图4, caption=ICP与ADHD和TS和其他抽动障碍之间的中介及其中介效应占比森林图

ICP：Intrahepatic cholestasis of pregnancy； ADHD：Attention-deficit hyperactivity disorder； TS：Tourette’s syndrome

, figureFileSmall=1uuvDFFcsLHABNGu9NCs+w==, figureFileBig=cWQ9MiW4MYt8vcplMLSQuQ==, tableContent=null), ArticleFig(id=1322954310337835793, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Table 1, caption=

Information of GWAS data for MR analysis

, figureFileSmall=null, figureFileBig=null, tableContent=
TraitsGWAS IDNSNPSample sizeAncestryReference
ICPfinn-b-O15_ICP_WIDE16 379 784123 579European［12］
ADHD vs TS and other tic disordersebi-a-GCST900165985 604 39023 918European［13］
Obg-like ATPase 1prot-a-214310 534 7353 301European［14］
TC in HDLmet-c-89811 864 11821 558European［15］
), ArticleFig(id=1322954310400750354, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=表1, caption=

MR研究GWAS数据的信息

, figureFileSmall=null, figureFileBig=null, tableContent=
TraitsGWAS IDNSNPSample sizeAncestryReference
ICPfinn-b-O15_ICP_WIDE16 379 784123 579European［12］
ADHD vs TS and other tic disordersebi-a-GCST900165985 604 39023 918European［13］
Obg-like ATPase 1prot-a-214310 534 7353 301European［14］
TC in HDLmet-c-89811 864 11821 558European［15］
), ArticleFig(id=1322954310463664915, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Table 2, caption=

Conditions applied for mediation analysis of ICP with ADHD and TS as well as other tic disorders

, figureFileSmall=null, figureFileBig=null, tableContent=
MediatorsGWAS IDParametersMethodsOutcome
TC in HDLmet-c-898P1=5E-08
P2 threshold =7E-08
P3=5E-06		MVMRADHD vs TS and other tic disorders
Obg-like ATPase 1prot-a-2143P1=5E-08
P2=5E-06
P3=5E-06		MVMR
), ArticleFig(id=1322954310526579476, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=表2, caption=

ICP与子代ADHD和TS及其他抽动障碍之间的中介效应采纳条件

, figureFileSmall=null, figureFileBig=null, tableContent=
MediatorsGWAS IDParametersMethodsOutcome
TC in HDLmet-c-898P1=5E-08
P2 threshold =7E-08
P3=5E-06		MVMRADHD vs TS and other tic disorders
Obg-like ATPase 1prot-a-2143P1=5E-08
P2=5E-06
P3=5E-06		MVMR
), ArticleFig(id=1322954310602076949, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Table 3, caption=

Detailed information of SNPs enrolled in two-sample MR from ICP and ADHD and TS as well as other tic disorders

, figureFileSmall=null, figureFileBig=null, tableContent=
SNPsEffect AlleleOther AlleleEffect Allele
Frequency		ExposureOutcomer2F
βSEPβSEP
rs1046356TC0.0370.5360.1111.47E-060.0070.0030.0450.020151.427
rs10768940GA0.865-0.2890.0612.55E-063.00E-040.0030.9300.019144.312
rs117766456TC0.0500.4570.0983.11E-060.0060.0030.0610.020146.347
rs118123046AG0.0130.9920.2061.38E-06-0.0010.0030.7400.025185.185
rs11881404GA0.678-0.2830.0441.55E-100.0020.0030.6300.035262.607
rs17209837CT0.135-0.5160.0634.26E-160.0050.0030.1600.062481.864
rs1800961TC0.0450.7750.1062.40E-130.0010.0030.8500.052397.584
rs1983127TG0.284-0.2480.0468.14E-080.0030.0030.4600.025186.044
rs2016886CT0.616-0.3620.0432.42E-174.80E-040.0030.8900.062480.349
rs28929474TC0.0201.4590.1651.04E-180.0060.0030.0920.082645.570
rs296393CT0.8480.4040.0601.39E-113.70E-040.0030.9100.042318.772
rs4665972CT0.6240.2680.0433.71E-100.0020.0030.5100.034253.090
rs62489733AG0.138-0.3230.0611.20E-07-0.0010.0030.7900.025184.070
rs6748810GA0.444-0.5040.0425.72E-330.0010.0030.8400.1251 040.578
rs6873506TC0.1330.3010.0617.73E-07-0.0010.0030.8300.021154.915
rs78417535TC0.0360.6010.1194.38E-070.0040.0030.2600.025185.393
rs79598313TC0.0350.6470.1195.35E-080.0070.0030.0320.028209.909
), ArticleFig(id=1322954310690157334, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=表3, caption=

ICP与ADHD和TS及其他抽动障碍双样本MR分析纳入SNPs的详细信息

, figureFileSmall=null, figureFileBig=null, tableContent=
SNPsEffect AlleleOther AlleleEffect Allele
Frequency		ExposureOutcomer2F
βSEPβSEP
rs1046356TC0.0370.5360.1111.47E-060.0070.0030.0450.020151.427
rs10768940GA0.865-0.2890.0612.55E-063.00E-040.0030.9300.019144.312
rs117766456TC0.0500.4570.0983.11E-060.0060.0030.0610.020146.347
rs118123046AG0.0130.9920.2061.38E-06-0.0010.0030.7400.025185.185
rs11881404GA0.678-0.2830.0441.55E-100.0020.0030.6300.035262.607
rs17209837CT0.135-0.5160.0634.26E-160.0050.0030.1600.062481.864
rs1800961TC0.0450.7750.1062.40E-130.0010.0030.8500.052397.584
rs1983127TG0.284-0.2480.0468.14E-080.0030.0030.4600.025186.044
rs2016886CT0.616-0.3620.0432.42E-174.80E-040.0030.8900.062480.349
rs28929474TC0.0201.4590.1651.04E-180.0060.0030.0920.082645.570
rs296393CT0.8480.4040.0601.39E-113.70E-040.0030.9100.042318.772
rs4665972CT0.6240.2680.0433.71E-100.0020.0030.5100.034253.090
rs62489733AG0.138-0.3230.0611.20E-07-0.0010.0030.7900.025184.070
rs6748810GA0.444-0.5040.0425.72E-330.0010.0030.8400.1251 040.578
rs6873506TC0.1330.3010.0617.73E-07-0.0010.0030.8300.021154.915
rs78417535TC0.0360.6010.1194.38E-070.0040.0030.2600.025185.393
rs79598313TC0.0350.6470.1195.35E-080.0070.0030.0320.028209.909
), ArticleFig(id=1322954310782432023, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Table 4, caption=

Heterogeneity test and pleiotropy test of the two-sample MR from ICP to ADHD and TS as well as other tic disorders

, figureFileSmall=null, figureFileBig=null, tableContent=
MethodsHeterogeneityPleiotropy test
QQ_dfQ_Pegger_interceptSEP
MR Egger14.815150.465-8.576E-040.0020.611
IVW15.084160.518
), ArticleFig(id=1322954310849540888, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=表4, caption=

ICP与子代ADHD和TS及其他抽动障碍双样本MR异质性和多效性检验

, figureFileSmall=null, figureFileBig=null, tableContent=
MethodsHeterogeneityPleiotropy test
QQ_dfQ_Pegger_interceptSEP
MR Egger14.815150.465-8.576E-040.0020.611
IVW15.084160.518
), ArticleFig(id=1322954310933426969, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=EN, label=Table 5, caption=

Results of each step of mediation analysis （without outliers）

, figureFileSmall=null, figureFileBig=null, tableContent=
MediatorsStep 1 （Without outliers）Step 2
βSEPβSEP
TC in HDL-0.0250.0100.009-0.0340.0160.031
Obg-0.0940.024<0.001-0.0130.0050.018
), ArticleFig(id=1322954311004730138, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322954303874413265, language=CN, label=表5, caption=

剔除离群SNP后的中介分析分步结果

, figureFileSmall=null, figureFileBig=null, tableContent=
MediatorsStep 1 （Without outliers）Step 2
βSEPβSEP
TC in HDL-0.0250.0100.009-0.0340.0160.031
Obg-0.0940.024<0.001-0.0130.0050.018
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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
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陈正东 , 冉清琦 , 肖明辉 , 余沁怡 , 彭文杰 , 胡章雪
陆军军医大学学报 | 论著·神经科学 2025,47(22): 2725-2734
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陆军军医大学学报 |论著·神经科学 2025 , 47 (22) : 2725 -2734
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
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陈正东, 冉清琦, 肖明辉, 余沁怡, 彭文杰 , 胡章雪
作者信息
  • 1陆军军医大学大坪医院儿科，重庆
通讯作者:
胡章雪，Email：
彭文杰，Email：
HU Zhangxue，E-mail：
PENG Wenjie，E-mail：
作者简介:

同等贡献者

CHEN Zhengdong and RAN Qingqi contributed equally to the article.

Causal association between intrahepatic cholestasis of pregnancy and offspring neurodevelopmental disorders and mediating roles of lipoproteins and ATPase: A Mendelian randomization study
Zhengdong CHEN, Qingqi RAN, Minghui XIAO, Qinyi YU, Wenjie PENG , Zhangxue HU
Affiliations
  • 1Department of Pediatrics，Daping Hospital，Army Medical University，Chongqing，China
出版时间: 2025-11-30 doi: 10.16016/j.2097-0927.202506083
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摘要
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目的

探究妊娠期肝内胆汁淤积症 （intrahepatic cholestasis of pregnancy，ICP）和子代注意缺陷多动障碍（attention-deficit hyperactivity disorder，ADHD）和妥瑞氏综合征（Tourette’s Syndrome，TS）之间的因果关联以及潜在机制。

方法

数据均来源于公共数据库全基因组关联研究（genome wide association study，GWAS）。其中暴露为ICP（n=123 579），来源于芬兰数据库；结局为ADHD与TS及其他抽动障碍（n=23 918），来源于GWAS Catalog数据库。中介分子中，高密度脂蛋白里的总胆固醇含量（n=21 558）来源于人类血浆蛋白质组的基因图谱，Obg样ATP酶1来源于循环代谢物全基因组研究（n=3 301）。本研究选择满足MR假设的工具变量。双样本MR分析主要方法为逆方差加权（inverse variance weighted，IVW），MR-Egger回归、加权中位数法、加权众数法、简单模式也被采用进行稳健性分析。Cochran’s Q 检验、MR-Egger 截距检验和留一法等敏感性分析用来验证结果的可靠性，统计显著性设定为P<0.05。使用中介MR时，从暴露到中介的第一步采用双样本MR，第二步采用多变量MR，此时条件F值被采用检测工具变量的强度。最后使用乘积分布检验验证中介效应的显著性。

结果

ICP与ADHD和TS及其他抽动障碍显著相关（IVW：OR=1.003，95%CI：1.000~1.006，P=0.035），敏感性分析证实了结果的稳健性。可能的中介分子包括高密度脂蛋白中总胆固醇含量［总效应 （total effect，TE）=2.855×10-3；中介效应（mediated effect，ME）=8.628×10-4；中介效应占比（mediated proportion，MP）=30.217%，95%CI：0.878%~73.954%）］ 和Obg样ATP酶1（TE=2.855×10-3；ME=1.216×10-3； MP=42.572%，95%CI：6.356%~90.195%）。

结论

ICP可能通过高密度脂蛋白中总胆固醇含量和Obg样ATP酶1的减少来增加子代ADHD和TS及其他抽动障碍的发病率。

注意缺陷多动障碍  /  妥瑞氏综合征  /  妊娠期肝内胆汁淤积症  /  孟德尔随机化研究  /  中介因素
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.

attention-deficit disorder with hyperactivity  /  Tourette’s syndrome  /  intrahepatic cholestasis of pregnancy  /  Mendelian randomization analysis  /  mediating factor
陈正东, 冉清琦, 肖明辉, 余沁怡, 彭文杰, 胡章雪. 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. 陆军军医大学学报, 2025 , 47 (22) : 2725 -2734 . DOI: 10.16016/j.2097-0927.202506083
Zhengdong CHEN, Qingqi RAN, Minghui XIAO, Qinyi YU, Wenjie PENG, Zhangxue HU. Causal association between intrahepatic cholestasis of pregnancy and offspring neurodevelopmental disorders and mediating roles of lipoproteins and ATPase: A Mendelian randomization study[J]. Journal of Army Medical University, 2025 , 47 (22) : 2725 -2734 . DOI: 10.16016/j.2097-0927.202506083
正文
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注意力缺陷多动障碍 （attention-deficit hyperactivity disorder，ADHD）是以注意力不集中、多动和冲动为特征的儿童神经发育障碍性疾病［1］，发病率约为5.3%。在青少年中，该疾病会导致教育和职业失败、同伴冲突和社会排斥、家庭冲突和意外伤害等［2］。妥瑞氏综合征 （Tourette’s Syndrome，TS）和其他抽动障碍也属于一类神经发育障碍，以不自主的重复动作（运动性抽动）和发声（发声性抽动）为主要特征，影响着大约1%的儿童［3］。患有ADHD的患儿常常合并其他精神类疾病，比如重度抑郁、焦虑障碍、双相情感障碍等，同时ADHD也会增加其他器质性疾病的患病概率，如肥胖、哮喘［2］，这些特征导致了该疾病对于家庭和社会的沉重负担。然而，它们的发病机制仍然不明。Meta分析和全基因组关联研究（genome-wide association studies，GWAS）分别表明ADHD和TS和其他抽动障碍的遗传倾向非常明显［2，4］。妊娠期胆汁淤积症 （Intrahepatic cholestasis of pregnancy，ICP） 是以瘙痒和血清胆汁酸 （Bile acid，BA） 水平升高为主的常见产科肝脏疾病［5］。近年来，ICP的发病率显著增加，在我国长江流域尤其是川渝地区发病率达到了6%［6］。该疾病可能导致子代多种不良结局，如胎儿窘迫、早产、不可预测的宫内死亡等［5］。而ICP引起的胆汁酸水平升高可能通过脐带血［7］，穿过胎儿不完整的血脑屏障影响胎儿神经系统的发育，从而导致精神疾病。最近的一项观察性队列研究显示，143 746名 （6.05%） 暴露于ICP的儿童被发现患有神经发育障碍性疾病，如ADHD、孤独症谱系障碍和智力障碍，且胎儿期暴露于ICP环境中的儿童比正常对照组罹患这些疾病的概率大17%［8］。但是，该队列研究仅表明ICP和神经发育障碍性疾病相关，没有阐明ICP导致神经发育障碍性疾病的机制。
孟德尔随机化 （mendelian randomization，MR） 分析利用来自不同GWAS的单核苷酸多态性 （single-nucleotide polymorphisms，SNPs），评估2个性状之间的关系。与传统的观察性临床研究相比，MR可以避免混杂因素的干扰，并评估危险因素的终身影响；此外，多变量MR （multivariable mendelian randomization，MVMR）和中介MR可用于探索暴露因素如何影响结局的机制［9］。因此，本研究通过双样本MR、MVMR和中介MR的方法，探讨了ICP与子代ADHD和TS和其他抽动障碍的因果关系，以及探讨潜在的中介机制。
1　材料和方法
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1.1　数据提取
本研究数据来源于IEU open GWAS（https://gwas.mrcieu.ac.uk/）。由于使用公共公开数据库，伦理审查被豁免。本研究遵循了《流行病学观察性研究报告加强指南（STROBE指南）》［10］。此外，仅欧洲人群被纳入，以避免人群异质性的偏差［11］。ICP作为暴露，ADHD和TS以及其他抽动障碍作为结局，且结局数据库为儿童队列数据。队列和GWAS数据库相关信息见表1。本研究采用两样本MR探究其因果关系，MVMR和两步MR探索潜在的中介途径。
1.2　工具变量筛选
工具变量从2个不重叠的GWAS数据库中筛选。MR分析的关键假设如下：① 相关性假设：工具变量 （Instrumental variables，IVs） 与暴露因素有强烈关联；② 独立性假设：混杂变量与MR推断过程的任何步骤无关；③排除限制假设：所选工具变量仅通过暴露因素影响结局 （图1）。为确保工具变量的强度，并同时保证SNP的数量足够，本研究参考全基因组显著性选择SNPs，使用的P值为5E-08、7E-08或者5E-06，详细信息见表2［11］。为避免连锁不平衡造成混杂，本研究对存在该问题的SNPs进行了剔除（区域宽度=10 000 kb，r2=0.001），与此同时回文SNP也被排除在外。随后，本研究采用F值评估工具变量的强度，公式如下：
F=R21-R2×N-K-1K
其中R2是由该SNP解释的性状变异的比例，N是GWAS数据纳入人群的样本量，K是该研究纳入的SNP的数量。R2使用以下公式评估：
R2=2×EAF×（1-EAF）×β2
EAF是SNP的效应等位基因频率，β是SNP对性状的估计效应［16］。F<10表示弱工具变量，需要排除在外。此外，本研究还使用了PhenoScannerV2（http://www.phenoscanner.medschl.cam.ac.uk/） 对潜在的混杂因素进行了排查［17］，任何与混杂因素有关的SNPs将会被排除。
1.3　异质性检验和水平多效性检验
若SNPs存在异质性，可能导致研究结果存在偏差。因此本研究使用了Cochrane’s Q检验来评估SNPs中的异质性。若有SNPs存在异质性，使用随机效应模型的逆方差加权法 （inverse variance-weighted，IVW）结果；若SNPs间异质性不显著，则使用固定效应模型的IVW结果。本研究使用留一法敏感性检验来判断MR结果的稳定性，即通过逐一排除SNP［11］，观察剔除前后的 MR 分析结果有无统计学差异。此外，本研究还使用MR多效性残差总和以及异常值R包 （MR pleiotropy residual sum and outlier，MR-PRESSO） 来获得每一个SNP的异质性P值，P<0.05的SNP被剔除［18］。MR-Egger 截距回归被采纳进行多效性检测，它不受SNPs有效性的影响，并检验了回归方程的截距与0的差异性，P<0.05的结果视为存在多效性，将不被采纳［11］。
1.4　统计学分析
使用R 4.3.1软件的TwoSample MR包（版本0.5.8） 分析。本研究的主要方法是经典的IVW法［19］。此外，本研究还补充了MR的加权中位数法、加权众数法、MR-Egger回归和简单模式［20］，以评估MR研究的可靠性。比值比 （odds ratio，OR） 表示结果的风险；标准误 （standard error，SE） 和95%置信区间 （confidence interval，CI） 表示估计值的不确定性［9］。
MVMR被用来寻找可能的中介。MVMR方法中，第一步考察ICP与中介因素（β1） 之间的关联。第二步采用MVMR，其中IVW方法被采用评估中介与ADHD和TS及其他抽动障碍的关联（β2），采用双样本法得出的关联性定义为总效应（β总），条件F统计量用于评估工具变量强度［9］。使用delta方法（即乘积分布检验，使用RMediation包版本1.2.2）评估中介效应［21］，公式如下：
=β1×β2β总
2　结果
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2.1　工具变量SNPs的筛选结果
经过关联性假设的筛选，该研究双样本MR纳入了17个SNPs，MVMR纳入了26个SNPs。双样本分析中F值均大于10，表明工具变量的强度是可信的，双样本MR的SNPs详细信息见表3。独立性假设筛选中，本研究逐一筛查了所有的SNP的可能混杂因素，包括单纯疱疹病毒2、母体感染、缺氧、羊水过多、早产、贫血等，发现这些SNPs和前述混杂因素相关：rs13071166、rs10008637、rs2742676、rs7660554、rs939678，并且进行了排除。因此独立性假设成立。
2.2　ICP与子代多动和抽动障碍具有关联
ICP与子代ADHD与TS和其他抽动障碍的双样本MR结果在排除混杂因素之后主要检验方法IVW结果显著（OR=1.003，95%CI：1.000~1.006，P=0.035），OR值大于1，表明ICP是子代多动与抽动障碍的危险因素，在图2A散点图的斜线方向也佐证了这一点。异质性检验、多效性检验不具有显著性，具体的检验数据见表4。留一法发现了SNPs具有潜在显著性。但是所有结果的平均值仍然在0右侧，仍然视为有效，见图2B。MR-Egger法（OR=1.004，95%CI：0.999~1.009，P=0.154）、加权中位数法（OR=1.003，95%CI：0.999~1.007，PIVW=0.123）、加权众数法（OR=1.003，95%CI：0.999~1.007，PIVW=0.190）、简单模式（OR=0.999，95%CI：0.996~1.006，PIVW=0.879）均不显著，见图3。
2.3　Obg样ATP酶1和中等大小的高密度脂蛋白中的总胆固醇为ICP和多动抽动障碍疾病之间的潜在中介
由于神经发育与能量代谢密切相关，且神经系统含有丰富的脂类物质，因此本研究选择能量代谢和脂类物质进行中介分析，并发现了2个潜在的中介变量（图4）：①中等大小的高密度脂蛋白 （High-density lipoprotein，HDL）中的总胆固醇（Total cholesterol，TC） ［总效应 （Total effect，TE）=2.855×10-3；中介效应 （Mediated effect，ME）=8.628×10-4；中介效应占比 （Mediated proportion，MP）=30.217%，95%CI：0.878%~73.954%］；②Obg样ATP酶1（TE=2.855×10-3；ME=1.216×10-3； MP=42.572%，95%CI：6.356%~90.195%）。所有双样本MR分析中的F值和MVMR分析中的条件F值均大于10 （中介为中等大小的HDL中的TC时：ICP的F=26.430，中等大小的HDL中的TC的F=22.220；中介为Obg样ATP酶1时：ICP的F=25.979，Obg样ATP酶1的F=12.254），表明不存在弱工具变量。但在第一步分析过程中，即ICP作为暴露，中介作为结局进行双样本MR分析时，出现了异质性显著的情况（中介为中等大小的HDL中的TC时，P（IVW）=0.010 9，P（MR-Egger）=0.011 1；中介为Obg样ATP酶1时，P（IVW）=0.020 0，P（MR-Egger）=0.012 7），故使用MR-PRESSO剔除PRESSO检验显著的SNPs（数据库met-c-898中的rs1800961和prot-a-2143中的rs2161037）之后，异质性消失（中介为中等大小的HDL中的TC时，P（IVW）=0.452，P（MR-Egger）=0.352；中介为Obg样ATP酶1时，P（IVW）=0.504，P（MR-Egger）=0.416）且IVW结果仍然显著。中介每一步分析的结果见表5。
3　讨论
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本研究发现，遗传预测的ICP易感性可能与子代ADHD和TS及其他抽动障碍的风险升高存在因果关联。此外，本研究探讨了ICP和子代ADHD和TS相关的潜在病理机制，且发现中等大小的HDL中的TC和Obg样ATP酶1 2个中介分子，这些为子代多动和抽动障碍性疾病的发病机制提供了新的理论依据。
3.1　ICP和子代多动抽动障碍性疾病之间的因果关联
多动和抽动障碍性疾病作为常见的儿童神经发育障碍性疾病，遗传因素是其发病机制中的重要环节，然而由于其异质性强，现有的研究无法解释其家族聚集性［22］，且遗传因素导致的神经发育障碍的病理机制至今不完全明确［23］。ICP的病因亦不清楚，但同样有较强的遗传倾向，它与多种基因突变密切相关，比如ABCB4、FIC1、ABCB11等［24］。既往的报道显示ICP会增加氧化应激反应，影响胎儿发育［25］，但是其如何影响胎儿的脑发育尚不明确。迄今为止，仅一项队列研究表明了ICP与ADHD之间存在联系，但由于其仅为观察性研究，潜在偏倚仍然无法消除［8］。本研究首次从遗传流行病学角度探讨ICP与子代多动和抽动障碍疾病之间的关联，并揭示其因果关系，大大降低了偏倚。强调了ICP对胎儿神经系统造成了持久的不良影响，从遗传角度强有力地支持了上述队列研究。并且本研究采用了MR研究方法，通过等位基因的随机分配，避免了非差异测量误差和环境中的混杂因素的影响，具有较强的因果推断能力，异质性分析和多效性分析也支持了这一点。虽然结果仅有IVW方法是显著的，但是除了简单模式之外的方法方向均与IVW相同，也表明了较好的稳健性。然而ICP孕妇与后代ADHD发生的OR值为1.003，意味着患有ICP的孕妇比不患ICP的子代发生ADHD概率仅大0.3%。尽管风险效应非常微弱，但ADHD是一类不能完全治愈的神经发育障碍性疾病，只能通过临床的尽早发现与干预尽可能地缓解病情，减轻社会负担，因此其仍具有临床意义。
3.2　HDL中的TC可能穿过胎儿不完整的血脑屏障起到保护作用
在探索ICP与多动抽动障碍疾病之间的潜在中介时，本研究发现中等大小的HDL中的TC含量是其中之一，并且是起保护作用的中介因子，表明ICP会导致HDL水平下降，并且孕期HDL的下降会增加子代ADHD的发生率。这条路径的2步结果的方向分别与ZHAN等［25］的meta分析和XU等［26］的研究是一致的。JI等［27］的波士顿出生队列研究表明，孕期的HDL和TC降低会增加子代罹患多动症的风险。上述研究都是该中介在ICP和多动抽动之间作为起保护作用的中介因子的有力证据。从机制的角度，脂蛋白在妊娠期间可以透过胎盘屏障进入胎儿的血液循环［28］，而胎儿期血脑屏障尚未发育完全，且HDL 颗粒可以通过胞吞作用或选择性摄取进入大脑［29］，这些表明孕期的HDL下降可能会导致转运至胎儿的HDL减少，干扰胎儿的脂蛋白代谢进而导致子代ADHD的发生。该中介的效应占比为30.217%，表明该类物质在减少ICP导致的多动抽动患儿中起到了一定的作用。虽然本研究通过大样本的GWAS 数据降低了时间和混杂因素的影响，但是ADHD患儿的HDL来源于母体还是子代自身、HDL如何导致儿童的ADHD发病率增高、自然状态下TS患儿的胆固醇水平等一系列问题，需要更多的基础和临床研究证实。综上所述，该结果为多动和抽动障碍的发病机制指明了新的研究方向。
3.3　Obg样ATP酶1可能保护ICP孕妇胚胎免受氧化应激的损伤
与此同时，本研究发现Obg样ATP酶1也是ICP和多动抽动之间的起保护作用的中介因子之一。Obg样ATP酶1在人体多种器官中表达，通过调节P53和P21的表达调控细胞增殖。该基因的缺失会导致严重的肺发育不良和不完全致死［30］。因此，Obg样ATP酶1在胚胎发育中具有至关重要的作用。虽然并没有研究证实Obg样ATP酶1与ICP或ADHD、TS之间的关系，但有文献指出Obg样ATP酶1可以整合秀丽隐杆线虫的感觉神经元的温度和饥饿信号［31］，并且在人类和动物之间该基因高度保守，因此该分子作为保护性中介是符合逻辑的。ICP与炎症细胞因子和氧化应激密切相关［32］。虽然现阶段缺乏ICP母亲体内Obg样ATP酶1的表达情况，但是现有研究认为Obg样ATP酶1能够稳定热休克蛋白70使细胞稳定，而热休克蛋白70同时可以参与发育过程［33］。因此，结合本研究的两步MR研究，本研究推测Obg样ATP酶1可能在胎儿期因ICP引起的氧化应激反应而降低，干扰热休克蛋白70介导的发育过程，进而导致多动和抽动障碍，这表明Obg样ATP酶1在神经发育中可能具有潜在的正向调控作用。但是这一假设亟需后续实验研究，如动物模型、细胞实验进行验证。
3.4　本研究的局限性
然而，本研究仍然存在一些局限性：①ICP数据集病例组人数很低（1 249人），导致识别出来的工具变量的效果欠佳。OR值与观察性研究不完全符合，需要从多个角度谨慎解读该结果；②选择SNPs的标准部分低于常规全基因组显著阈值（P<5×10-8），虽然在多效性不显著的情况下，只要SNPs的选择标准不低于1E-04，弱工具变量效应影响较小［11］，但是由于选择标准在所有分析中不完全一致，仍然可能导致假阳性的发生；③结局的2个数据库是混合数据库，不能完全区分ICP导致的是ADHD和TS中的一种还是二种；④中介效应的占比的95%CI偏大，不论是从生物学遗传学还是临床上均需要谨慎解读该结果。因此，仍需大量的基础研究来验证本研究的发现。

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doi: 10.16016/j.2097-0927.202506083
  • 接收时间：2025-06-29
  • 首发时间：2026-10-30
  • 出版时间：2025-11-30
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  • 收稿日期：2025-06-29
  • 修回日期：2025-11-07
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    1陆军军医大学大坪医院儿科，重庆

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彭文杰，Email：
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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