全基因组和转录组关联研究鉴定静脉血栓栓塞

SaraLindstr?m,1,2LuWang,3ErinN.Smith,4,5WilliamGordon,1AstridvanHylckamaVlieg,6MarizadeAndrade,7JenniferA.Brody,8JackW.Pattee,9JeffreyHaessler,2BenM.Brumpton,10-12DanielI.Chasman,13,14PierreSuchon,15,16Ming-HueiChen,17,18ConstanceTurman,19MarineGermain,20KerriL.Wiggins,8JamesMacDonald,3SigridK.Braekkan,5,21SebastianM.Armasu,7NathanPankratz,22RebeccaD.Jackson,23JonasB.Nielsen,24FrancoGiulianini,13MarjaK.Puurunen,18ManalIbrahim,15SusanR.Heckbert,1,25ScottM.Damrauer,26,27PradeepNatarajan,28-31DerekKlarin,28,32,33TheMillionVeteranProgram,PaulS.deVries,34MariaSabater-Lleal,35,36JenniferE.Huffman,37TheCHARGEHemostasisWorkingGroup,TheoK.Bammler,3KellyA.Frazer,4,5,38BryanM.McCauley,7KentTaylor,39JamesS.Pankow,40AlexanderP.Reiner,1,2MaikenE.Gabrielsen,10Jean-Fran?oisDeleuze,41,42ChrisJ.O’Donnell,17,18,43JihyeKim,19BarbaraMcKnight,2,44PeterKraft,19John-BjarneHansen,5,21FritsR.Rosendaal,6JohnA.Heit,7BruceM.Psaty,25,45WeihongTang,40CharlesKooperberg,2KristianHveem,10PaulM.Ridker,13,14Pierre-EmmanuelMorange,15,16,46AndrewD.Johnson,17,18ChristopherKabrhel,47-49David-AlexandreTrégou?t,20NicholasL.Smith,1,25,50onbehalfoftheINVENTConsortium1DepartmentofEpidemiology,UniversityofWashington,Seattle,WA;2PublicHealthSciencesDivision,FredHutchinsonCancerResearchCenter,Seattle,WA;3DepartmentofEnvironmentalandOccupationalHealthSciences,UniversityofWashington,Seattle,WA;4DepartmentofPediatricsandRadyChildren’sHospital,UniversityofCaliforniaSanDiego,LaJolla,CA;5K.G.JebsenThrombosisResearchandExpertiseCenter,DepartmentofClinicalMedicine,UiT–TheArcticUniversityofNorway,Troms?,Norway;6DepartmentofClinicalEpidemiology,LeidenUniversityMedicalCenter,Leiden,TheNetherlands;7DepartmentofHealthSciencesResearch,MayoClinic,Rochester,MN;8CardiovascularHealthResearchUnit,DepartmentofMedicine,UniversityofWashington,Seattle,WA;9DivisionofBiostatistics,SchoolofPublicHealth,UniversityofMinnesota,Minneapolis,MN;10K.G.JebsenCenterforGeneticEpidemiology,DepartmentofPublicHealthandNursing,NTNU,NorwegianUniversityofScienceandTechnology,Trondheim,Norway;11MedicalResearchCouncilIntegrativeEpidemiologyUnit,UniversityofBristol,Bristol,UnitedKingdom;12ClinicofThoracicandOccupationalMedicine,St.OlavsHospital,TrondheimUniversityHospital,Trondheim,Norway;13DivisionofPreventiveMedicine,BrighamandWomen’sHospital,Boston,MA;14DepartmentofMedicine,HarvardMedicalSchool,Boston,MA;15LaboratoryofHaematology,LaTimoneHospital,Marseille,France;16CenterforCardioVascularandNutritionresearch(C2VN),UniversiteAix-Marseille,InstitutNationaldelaRechercheAgronomique(INRA),INSERM,Marseille,France;17PopulationSciencesBranch,NationalHeart,Lung,andBloodInstitute,NationalInstitutesofHealth,Framingham,MA;18TheFraminghamHeartStudy,Framingham,MA;19PrograminGeneticEpidemiologyandStatisticalGenetics,HarvardT.H.ChanSchoolofPublicHealth,Boston,MA;20INSERMUMR_S,BordeauxPopulationHealthResearchCenter,UniversityofBordeaux,Bordeaux,France;21DivisionofInternalMedicine,UniversityHospitalofNorthNorway,Troms?,Norway;22DepartmentofLaboratoryMedicineandPathology,SchoolofMedicine,UniversityofMinnesota,Minneapolis,MN;23DivisionofEndocrinology,Diabetes,andMetabolism,TheOhioStateUniversity,ColumbusOH;24DivisionofCardiology,DepartmentofInternalMedicine,UniversityofMichiganMedicalSchool,AnnArbor,MI;25KaiserPermanenteWashingtonHealthResearchInstitute,KaiserPermanenteWashington,Seattle,WA;26DepartmentofSurgery,CorporalMichaelCrescenzVAMedicalCenter,Philadelphia,PA;27DepartmentofSurgery,PerlemanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,PA;28BostonVAHealthcareSystem,Boston,MA;29CardiovascularResearchCenterandCenterforGenomicMedicine,MassachusettsGeneralHospital,Boston,MA;30DepartmentofMedicine,HarvardMedicalSchool,Boston,MA;31PrograminMedicalandPopulationGenetics,BroadInstituteofHarvardandMIT,Cambridge,MA;32CenterforGenomicMedicine,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,MA;33DepartmentofSurgery,MassachusettsGeneralHospital,Boston,MA;34HumanGeneticsCenter,DepartmentofEpidemiology,HumanGenetics,andEnvironmentalSciences,SchoolofPublicHealth,TheUniversityofTexasHealthScienceCenteratHouston,Houston,TX;35UnitofGenomicsofComplexDiseases,InstitutdeRecercadel’HospitaldeSantPau,IIB-SantPau,Barcelona,Spain;36CardiovascularMedicineUnit,DepartmentofMedicine,KarolinskaInstitutet,CenterforMolecularMedicine,KarolinskaUniversityHospital,Stockholm,Sweden;37CenterforPopulationGenomics,MAVERIC,VABostonHealthcareSystem,Boston,MA;38InstituteofGenomicMedicine,UniversityofCaliforniaSanDiego,LaJolla,CA;39LosAngelesBiomedicalResearchInstituteandDepartmentofPediatrics,Harbor–UniversityofCaliforniaLosAngelesMedicalCenter,TorrenceCA;40DivisionofEpidemiologyandCommunityHealth,SchoolofPublicHealth,UniversityofMinnesota,Minneapolis,MN;41CentreNationaldeRechercheenGénomiqueHumaine,DirectiondelaRechercheFondamentale,LeCommissariatàl’énergieatomiqueetauxénergiesalternatives,Evry,France;42TheCentred’EtudeduPolymorphismHumain(CEPH),FondationJeanDausset,Paris,France;43MillionVeteranProgram,Veteran’sAdministration,Boston,MA;44DepartmentofBiostatistics,UniversityofWashington,Seattle,WA;45CardiovascularHealthResearchUnit,DepartmentsofMedicine,Epidemiology,andHealthServices,UniversityofWashington,Seattle,WA;46CentredeRessourcesBiologiquesAssistancePublique–H?pitauxdeMarseille,HemoVasc,Marseille,France;47CenterforVascularEmergencies,DepartmentofEmergencyMedicine,MassachusettsGeneralHospital,Boston,MA;48ChanningDivisionofNetworkMedicine,BrighamandWomen’sHospital,Boston,MA;49DepartmentofEmergencyMedicine,HarvardMedicalSchool,Boston,MA;50SeattleEpidemiologicResearchandInformationCenter,DepartmentofVeteransAffairsOfficeofResearchandDevelopment,Seattle,WA主编：王建祥中国医学科学院血医院翻译：江淼医院江苏省血液研究所审校：季顺东韩悦医院江苏省血液研究所摘要关键点：

确定导致VET风险的新型遗传基因位点。

提供血液因素参与VTE发生的潜在生物机制证据。摘要静脉血栓栓塞症（venousthromboembolism,VTE）是致死致残的重要原因。为了加深对VTE生物机制的理解，我们进行了VTE的全基因组关联研究（genome-wideassociationstudy,GWAS）以及基于全血和肝脏推定基因表达的转录组关联研究（transcriptomewideassociationstudy,TWAS）。我们对来自18项研究中30,例VTE病例和,例对照的GWAS数据进行了荟萃分析，评估了12,,处基因变异与VTE之间的相关性。我们计算了全血和肝脏组织基因表达的变异预测分数，评估其与VTE之间的相关性。对新发现的VTE基因位点相关的遗传性状进行了孟德尔随机分析。通过GWAS荟萃分析鉴定了34个独立的VTE风险的遗传信号，其中14个是新报道的关联位点：11个新的关联遗传位点（C1orf，PLEK，OSMR-AS1，NUGGC/SCARA5，GRK5，MPHOSPH9，ARID4A，PLCG2，SMG6，EIF5A和STX10），其中有6个是重复的；以及存在于3个已知VTE相关基因中3个单独的信号。此外，通过TWAS研究还鉴定出5个额外的位点，其在全血（SH2B3，SPSB1，RP11-H7.3，RP4-E23.2）和肝脏（ERAP1）中存在病例和对照之间的推定基因表达水平差异。对于部分GWAS位点，我们发现了支持性证据表明新的和先前已知区域中VTE相关的信号与定量性状表达的基因位点共定位。孟德尔随机分析表明，血液因素可能是导致VTE的潜在风险。总之，我们鉴定出16种新的VTE易感基因位点，其中的部分位点可能是通过邻近基因表达介导关联信号。(Blood.;(19):-)表1.全基因组中与VTE相关的独立重要基因位点的跨人种荟萃分析结果加粗字体表示新发现位点。CI，可信区间；OR，比值比；EA，欧洲人群；AA，非裔美国人群。*变异位点rs，欧洲人群荟萃分析P值为5.3E-09(OR0.94)，在VWF基因中与VTE的关联仅次于rs。?变异位点rs，欧洲人群中P值为2.5E-08(OR1.06)，达到全基因组显著性。?变异位点rs，仅在欧洲人群中使用样本大小加权模型进行荟萃分析，缺少非裔美国人群的OR值和等位基因频率。

DOI10./blood.000435

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