Family Based Association Analyses between the Serotonin Tran

Abstract We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twi

BehavGenet(2007)37:294–301DOI10.1007/s10519-006-9139-7

ORIGINALPAPER

FamilyBasedAssociationAnalysesbetweentheSerotonin

TransporterGenePolymorphism(5-HTTLPR)andNeuroticism,AnxietyandDepression

ChristelM.MiddeldorpÆEcoJ.C.deGeusÆ

A.LeoBeemÆNicoLakenbergÆJouke-JanHottengaÆP.ElineSlagboomÆDorretI.Boomsma

Received:23June2006/Accepted:26October2006/Publishedonline:10January2007ÓSpringerScience+BusinessMedia,LLC2007

AbstractWestudiedtheassociationbetweentheshort/longpromotor-basedlengthpolymorphismoftheserotonintransportergene(5-HTTLPR)andneuroticism,anxietyanddepression.Subjectsincludedtwins,theirsiblingsandparentsfromtheNetherlandsTwinRegister(559parentsand1,245offspring).Subjectshadparticipatedbetweenoneand vetimesinasurveystudymeasuringneuroticism,anxietyanddepression.OffspringofthesefamilieswerealsoapproachedtoparticipateinapsychiatricinterviewdiagnosingDSM-IVmajordepression.Within-familyandtotalassociationbetween5-HTTLPRandthesetraitsweretested.Onlythreeofthe36testsshowedasigni canteffectof5-HTTLPR(P<0.05).Theseeffectswereinoppositedirections,i.e.bothnegativeandpositiveregressioncoef cientswerefoundforthesallele.Noadditiveeffectofthesallelewasfoundfor

DSM-IVdepression.Ourresultsstronglysuggestthatthereisnostraightforwardassociationbetween5-HTTLPRandneuroticism,anxietyanddepression.Keywords5-HTTLPRÁNeuroticismÁAnxietyÁDepressionÁFamilybasedassociationanalyses

Introduction

In1996,Leschetal.(1996)reportedanassociationbetweenthepromoter-basedlengthpolymorphismoftheserotonintransportergene(5-HTTLPR)andtheanxiety-relatedpersonalitytraitsneuroticismandharmavoidance.The5-HTTLPRisde nedbyalengthvariationofarepetitivesequencewiththeshortandthelongfragmentconsistingofrespectively484and528basepairs.Invitroanalysesshowedthatthebasalactivityofthelongvariantwasaboutthreefoldhigherthanthatoftheshortvariant,indicatingthatthisisafunctionalpolymorphism(Heilsetal.1996).Astheassociationoftheshortvariantwithhigherneuroticismandharmavoidancescoreswasfoundintwoindepen-dentgroupsofsubjectsaswellaswithinfamilies,thisseemedaverypromisingresult(Leschetal.1996).Theassociationbetween5-HTTLPRandanxiety-relatedpersonalitytraitsordepressivepsychopathologyhasbeeninvestigatedinnumerousstudiessincethen,butwithcon ictingresults.Evenmeta-analysesontheassociationbetween5-HTTLPRandpersonalitytraits(Munafoetal.2003;Munafoetal.2005a;Schinkaetal.2004;Senetal.2004)oraffectivedisorders(Lasky-Suetal.2005;LotrichandPollock2004)reachedcon ict-ingconclusions.Thismightbepartlyduetomethod-ologicaldifferencesbetweenthemeta-analyses

EditedbyStaceyCherny

C.M.Middeldorp(&)ÁE.J.C.deGeusÁA.L.BeemÁJ.-J.HottengaÁD.I.Boomsma

DepartmentofBiologicalPsychology,VrijeUniversiteitAmsterdam,VanderBoechorststraat1,Amsterdam1081BT,TheNetherlands

e-mail:cm.middeldorp@psy.vu.nl

C.M.Middeldorp

DepartmentofPsychiatry,VrijeUniversiteitMedicalCenter,Amsterdam,TheNetherlands

E.J.C.deGeusÁA.L.BeemÁJ.-J.Hottenga

CenterforNeurogenomicsandCognitiveResearch(CNCR),Amsterdam,TheNetherlands

http://doc.guandang.netkenbergÁP.E.Slagboom

MolecularEpidemiology,LeidenUniversityMedicalCenter,Leiden,TheNetherlands

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Abstract We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twi

BehavGenet(2007)37:294–301(Munafoetal.2005b;Schinka2005;Senetal.2005).Munafoetal.(2005b),therefore,statedthat‘‘Verylarge,welldesignedprimarystudiesremainthemostreliablewayofobtainingreproducibleresults’’.

SuchastudywasperformedbyWillis-Owenetal.(2005).Anassociationstudywascarriedoutinthreeindependentsamplesincludingrespectively564,1,001and5,000subjectsselectedfromtwogeneralpopula-tionsbasedonextremehighorlowscoresonneuro-ticism.Theirsamplesretainedvirtually100%powertodetectageneticeffectaccountingforjust0.5%ofphenotypicvarianceatanalphalevelof0.05.Theydidnot ndanysigni cantassociationbetween5-HTTLPRandneuroticismmeasuredwiththeEysenckPersonalityQuestionnaire(EysenckandEysenck1975)ormajordepressionasde nedbytheDSM-IV(AmericanPsychiatricAssociation1994).Wecollectedmeasuresofneuroticism,aswellasmeasuresofanxiety,depressionandDSM-IVbaseddiagnosesofdepressioninalargesampleofDutchtwinfamilies.Associationtestswerecarriedoutinasampleof1,800subjectswhoweregenotypedfor5-HTTLPR.Theselfreportmeasuresofneuroticism,anxietyanddepressionwereassessed vetimesinatimeperiodofaroundtenyears.Thismadeitpossibletocarryoutanalysesonthescoresfromthedifferenttimepointstotestwhethereffectsreplicatedacrosstime,aswellasonthemeanscoresovertheoccasions.DSM-IVmajordepressiondata,diagnosedwithastructuredpsychiatricinterview,werealsoinvestigatedforanassociationwith5-HTTLPR.Inadditiontotestingmultiplephenotypesrepeatedlyovertime,thefamilybasedsample,allowedtestingforpopulationstrati cationbydecomposingtheassociationeffectinabetweenandwithinfamilycomponent(Fulkeretal.1999).Asigni cantwithin-familyeffectindicatesgenuineassociationwhereasasigni cantbetweenfamilyeffectmaybeduetopopulationstrati cation.Itisimportanttonotethatpopulationstrati cationcannotonlyresultinspuriousassociations,butcanalsoobscuregenuineassociations(Posthumaetal.2004).

MaterialsandmethodsSubjects

ThisstudyispartofanongoinglongitudinalsurveystudyoftheNetherlandsTwinRegister(NTR)thathasassessedfamilieswithadolescentandadulttwinsroughlyeverytwoyearssince1991(Boomsmaetal.2002).Eachsurveywassenttothetwinsandadditionalfamilymembers,namelyparentsin1991and1 …… 此处隐藏：30984字，全部文档内容请下载后查看。喜欢就下载吧 ……