基于慢性脑灌注不足的蛋白质组孟德尔随机化研究揭示白质高信号的血浆靶点

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【中图分类号】R743 【文献标志码】A

Proteome-wide Mendelian randomization identifies plasma targets for white-matterhyperintensities in chronic cerebral hypoperfusion

Xiaoyan'，Yu Zhuoyuan²，Yang Meil （1.Neuroscience Research Center，School Basic Sciences， ; 2.Department Afliated ）

【AbstractlObjective：Chroniccerebralhypoperfusion（CCH）isanupstreamdrivercerebralsmallveseldisease，yetwithalack drugablepathwaysandtargets.Withwhitematerhyperintensities（WMH）astheprimarybiomarkeratthepopulationlevel，tisar ticleaimstoidentifyrelatedplasmaproteinsbasedonhumangeneticevidence.Methods：Thefullsetplasmaproteiquantitative traitlociwasidenifiedintheEuropeancohort，andtwosample Mendelianrandomization（MR）wasperforedforeveryprotein.WMH was the primary outcome measure （ n =37 355）.In addition，directional validation was performed in perivascular spaces（PVS） （ n= 38598）and lacunar stroke（LS）（ n =232596）.Bayesian colocalization was used to assess locus sharing，and the false discovery rate wascontrolldatO.O5.Cell-typeannotationdatawerecoectedfroma34-celltyphumanbrainsgle-nucleus transriptoeatlas. CausalinferencewasonlyperformedforWMH，andPVSandLSwereonlyusedfordirectionalvalidation.Results：Therewere13pro teinsasociatedwithWMHaftermultipletests.In-depthanalysis wasperformedfor4proteins withcisactinggeneticevidene，i， ACOX1，ART4，MGP，andthelaminnassygroupanchoredatLAMC1.DirectionalityanalysisshowedthatART4increasedtheiskWMH，whereasACOX1，MGP，andlamininhadaprotectiveeffectThe Bayesian colocalization analysis further supported a shared causalvariantbetween ART4/MGPand WMH，therebystrengtheningthe confidence for the association between ART4 and MGP，conversely，ACOX1 appeared to have an independent genetic signal， while laminin showed weaker evidence for sharing. The remaining9 trans-signal-drivenproteiswereretaiedashypothsisgeneratiandidates.InPVSandLS，tedectioalefectstepoteis alignedwithtosebservedinWH，beitwithtenuatedmagnitudes.Conclusion：Proteome-wideMRscreening，ombinedwithco localizationanalysis，cross-endpointchecks，andcel-type mappngdentifiesART4andMGPashigh-onfidence targetsfr WMH undertheCCHframework.AlthoughACOX1andlamininshowprotectiveMRasociations，theiriconsistentorweakcolocalizatinre sults require further fine mapping and functional validation.

【Keywordscerebralsmallveeldisease;leukoaraiosis;Mendelianrandomizationanalysis;proteomics;quantitativetraitloci

慢性脑灌注不足（chronic cerebral hypoperfusin，CCH）是老年脑损伤和血管性认知障碍的关键上游病理状态，但目前缺少明确、可操作的药物靶点脑白质高信号（whitematter hyperintensities，WMH）是CCH相关白质损伤的一种可量化影像学标志，并且与卒中、痴呆及死亡风险的升高密切相关，这凸显了其重要的临床与流行病学意义[2。（剩余15511字）