MERLINiasp

LinkageAnalysisofAlcoholDependenceSymptomsintheCommunityNarelleK.
Hansell,ArpanaAgrawal,JohnB.
Whiteld,KatherineI.
Morley,ScottD.
Gordon,PenelopeA.
Lind,MicheleL.
Pergadia,GrantW.
Montgomery,PamelaA.
F.
Madden,RichardD.
Todd,AndrewC.
Heath,andNicholasG.
MartinBackground:Wehavepreviouslyidentiedsuggestivelinkageforalcoholconsumptioninacommunity-basedsampleofAustralianadults.
Inthiscompanionpaper,weexplorethestrengthofgeneticlinkagesignalsforalcoholdependencesymptoms.
Methods:Analcoholdependencesymptomscore,basedonDSM-IIIRandDSM-IVcriteria,wasexamined.
Twinsandtheirnontwinsiblings(1,654males,2,518females),aged21to81years,wereinterviewed,with803individualsinterviewedon2occasions,approximately10yearsapart.
Linkageanalyseswereconductedondatasetscompiledtomaximizedatacollectedateithertheyoungerortheolderage.
Inaddition,linkagewascomparedbetweenfullsamplesandtruncatedsamplesthatexcludedthelightestdrinkers(approximately10%ofthesample).
Results:Suggestivepeaksonchromosome5p(LODs>2.
2)werefoundinaregionpreviouslyidentiedinalcohollinkagestudiesusingclinicalpopulations.
Linkagesignalstrengthwasfoundtovarybetweenfullandtruncatedsamplesandwhensamplesdifferedonlyonthecollectionageforasamplesubset.
Conclusions:Theresultssupportthendingthatlargecommunitysamplescanbeinformativeinthestudyofalcohol-relatedtraits.
KeyWords:AlcoholDependenceSymptoms,GeneticLinkageAnalysis,CommunitySample.
ALCOHOLDEPENDENCEISassociatedwithsig-nicanteconomicburden,bothdirectlyandviaitscomorbiditywithothersubstanceusedisordersandpsycho-pathology.
DatacollectedfortheAustralianNationalSurveyofMentalHealthandWellbeingin1997showedthat4.
1%ofthosesurveyedmetthecriteriaforDSM-IValcoholdepen-dence(19%meetingatleast1DSM-IValcoholabuseordependencecriterion)inthepreceding12months(2006).
FindingsaresimilarintheUnitedStates,withprevalencefor12-monthandlifetimeDSM-IValcoholdependencebeing3.
8and12.
5%(Hasinetal.
,2007).
Itisnowknownthatgeneticfactorsinuencevariationinalcoholdependence,withheritabilityestimatesreportedtorange50to70%(AgrawalandLynskey,2008;Heathetal.
,1997;PrescottandKendler,1995,1999).
Overthelast2dec-ades,severallinkagescanshavebeenundertakentolocateandidentifythespecicgenesthatcontributetoalcoholdependence.
AmongtheseeffortsaretheCollaborativeStudyonGeneticsofAlcoholism(COGA)(Begleiteretal.
,1995;Reichetal.
,1998)andtheIrishAffectedSib-PairStudyofAlcoholDependence(IASPSAD)(Prescottetal.
,2005,2006),whichhaveusedlinkagemethodstoidentifylocionseveralchromosomes.
Thesestudieshavefocussedonpatientswithafamilyhistoryofdrinkingproblems.
Inthecurrentstudyweutilizedatacollectedfromacom-munitysampleofover4,000Australianadults.
Inlinewithourpreviousstudy(Hanselletal.
,2009),whichfoundsugges-tivelinkageforalcoholconsumptioninthesamehetereoge-neoussample,theprimaryaimofthepresentstudywastoexaminetheviabilityofusinglinkagemethodsonalcoholdependencedatacollectedfromacommunitysample.
Inaddition,weinvestigatedtheeffectsofexcludingverylightdrinkers(approximately10%ofthedistributionofconsump-tion).
Thisexclusionwasundertakentoprovideafocusongeneticfactorspredisposingtoproblemdrinking.
Lowcon-sumptionmayreectamixtureofbothbiologicalcauses(whichwouldincludeprotectivegenessuchasthealdehydedehydrogenasegeneALDH2(Luczaketal.
,2006)andwhichmaybeevidentinanalysesofthefulldistribution)andsocialfactors(suchaschurchattendance(Strawbridgeetal.
,1997).
Third,asdatawerecollectedon2occasions(10yearsapartonaverage)forapproximately19%ofoursample,weFromtheGeneticEpidemiology,QueenslandInstituteofMedicalResearch(NKH,JBW,KIM,SDG,PAL,GWM,NGM),Brisbane,Australia;DepartmentsofPsychiatry,Psychology,andGenetics,SchoolofMedicine(AA,MLP,PAFM,RDT,ACH),WashingtonUniversity;andCentreforMolecular,Environmental,GeneticandAnalyticEpidemiology,SchoolofPopulationHealthandAppliedGeneticsUnit,ORYGENResearchCentre,DepartmentofPsychiatry(KIM),UniversityofMelbourne,Australia.
ReceivedforpublicationMarch11,2009;acceptedSeptember2,2009.
Reprintrequests:NarelleK.
Hansell,GeneticEpidemiology,QueenslandInstituteofMedicalResearch,PostOfce,RoyalBrisbaneHospital,Queensland4029,Australia;Fax:61-7-33620101;E-mail:Narelle.
Hansell@qimr.
edu.
auRichardTodddiedonAugust22,2008,andthispaperisdedicatedtohismemory.
Copyright2009bytheResearchSocietyonAlcoholism.
DOI:10.
1111/j.
1530-0277.
2009.
01077.
xAlcoholism:ClinicalandExperimentalResearchVol.
34,No.
1January2010158AlcoholClinExpRes,Vol34,No1,2010:pp158–163examinedtheeffectofincludingdatacollectedateithertheyoungerortheolderage.
Lifetimedependencesymptomatol-ogycanvarywithage,eitherduetoincreasingsymptomswithage,orduetoincorrectrecallofsymptomsthatwereapparentattheearlier,butnotthelater,age.
MATERIALSANDMETHODSSampleDatawereobtainedfrom3phasesoftelephoneinterviewscon-ductedbetween1992and2005,asdescribedpreviously(Hanselletal.
,2009).
InterviewswereadaptedfromtheSemi-StructuredAssessmentfortheGeneticsofAlcoholism(SSAGA,Bucholzetal.
,1994).
Lifetimeabstainers(i.
e.
,individualswhohadnevertriedalcohol)2%ofthoseinterviewed)wereexcluded.
For63%ofoursample,self-reportedancestryforallgrandparentswasavailable.
AncestrywaspredominantlyEuropeanwith96%havingfullEuropeanancestry.
Bothalcoholphenotypesandgenotypessuitableforlinkageanaly-siswereavailablefor4,172individuals(1,654males,2,518females)from1,690families.
Thesamplecomprised3,085twins(including1,465completepairs,ofwhich34wereMZ)and1,087nontwinsib-lings.
Thenumberofquasi-independentsiblingpairs(QISPs–i.
e.
,twinpairspluspairingsformedbetweentwinsandtheirnontwinsib-lings)inthedatasetwas3,837.
Genotypingwasavailablefor1,338parents(including483parentalpairs)andthesewereusedtoreneestimatesofIBDprobabilities.
Participantswereaged21to81years(39.
7±10.
5)atthetimeofrstinterview.
Further,803participantswereinterviewedonasec-ondoccasion,withameantimebetweeninterviewsof10.
4±1.
8years(range=2to13years).
Linkageanalyseswererunonthefullsample,rst,usingallrstinterviewdata(Youngerdataset)andsecond,withdatafromthesecondinterviewreplacingrstinterviewdataforthe803individualsinterviewedtwice(Olderdataset).
AdetaileddescriptionofzygositydeterminationandgenotypingforthissamplecanbefoundinHansellandcolleagues(2009).
Forthe4,172participantswithdependencesymptomdata,thenumberofuniqueautosomalmarkersperindividualrangedfrom301to1,359(M=559.
9±234.
1).
AlcoholDependenceSymptomScoreAssessmentwasbasedonlifetimeprevalence.
Analcoholdepen-dencesymptomscorewasobtainedfromnineitemsbasedonthesubstancedependencecriteriafromthethirdrevisedandfourtheditionsoftheDiagnosticandStatisticalManualofMentalDisorders(AmericanPsychiatricAssociation,1987,2000),aslistedinHansellandcolleagues(2008).
AllitemswerescoredYesNo(10),withtheexceptionofItems2and7,whichwerecodedas3levelordinalmea-sures[Item2:no=0,1unsuccessfulattempttocutdown=1,morethan1unsuccessfulattempttocutdown=3,andItem7:no=0,amarked(butlessthan50%)increaseintheamountrequiredtoachievethedesiredeffect=1,atleasta50%increaseintheamountrequired=2].
Itemsweresummedtoobtainasinglescore.
DistributionsofalcoholdependencesymptomscoresareshowninFig.
1.
Approximately,34%ofthesamplehadpositiveresponsesfor3ormorecriteria,consistentwithbeingclassiedasalcoholdependent.
StatisticalAnalysesPedigree-wideanalyseswereconductedforthe22autosomalchro-mosomesusingMERLIN-REGRESSandtheXchromosomeusingMINX(Abecasisetal.
,2002).
MultipointlinkageanalyseswereexaminedfortheYoungerandOlderdatasets.
Dataforbothco-twinsfromMZpairsweremodeledinanalyses(withzygosityidentied),althoughtheMZrelationshippersedoesnotcontributetolinkage.
Posthoclinkageanalysesexaminedtheeffectsofexcludingindividualswiththeleastalcoholexposurebydroppingapproxi-mately10%ofthesample(8.
3%fortheYoungerdatasetand7.
6%fortheOlder)fromthelowerendofthesexandage-adjusteddistributionofconsumption.
Essentially,thissubsetwerenon-drinkersduringtheprevious12-monthperiod(0.
90,andconsequently,agewasagoodsurrogatecovar-iatetoaccountfortheeffectsofpossibleseculartrends.
Normalizedresiduals(mean0,variance1)wereusedforallvari-ablestofacilitateanalysesinMERLIN-REGRESS(Shametal.
,2002).
Therewerenounivariateoutliers.
Bivariateoutliers,asdenedinBenyaminandcolleagues(2008),accountedforlessthan0.
4%ofthesampleandwereexcludedfromlinkageanalyses.
RESULTSMultipointlinkageresultsareshowninFig.
2.
LODscoresexceeding1.
5werenotedonchromosome3(D3S1292,140.
7cM),chromosome4(GATA70E01,37.
1cM),andchromosome5(ATAG078,35.
1cM;GATA134B03,42.
6cM;andGATA7C06,53.
8cM).
ThehighestmultipointLODof2.
7(p=0.
0002)wasfoundonchromosome5usingthedatasetmaximizingdatacollectedatayoungerage,andwithlightestdrinkersdropped.
AsimilarLOD(2.
6)wasfoundwhenmaximizingdatacol-lectedatanolderage.
However,includinglightdrinkersFig.
1.
Distributionsofalcoholdependencesymptomscores(derivedfrom9symptomswithamaximumscoreof11)areshownforfull(100%)andtruncatedsamplesandfordatasetsthatdifferforasubsetof803indi-vidualsforwhomdatawerecollectedon2occasions[rstoccasiondata(M=1.
8±2.
2)wereincludedintheYoungerdatasetandsecondoccasiondata(M=2.
2±2.
6)intheOlderdataset].
ANALYSISOFALCOHOLDEPENDENCESYMPTOMS159reducedmaximumLODscoresintheregionto1.
2and1.
0respectivelyfortheyoungerandoldersamples.
Whilenoneofthesendingsaresignicantbystandardcriteriaforlinkagestudies,thoseLODscores2.
2couldbeconsideredsuggestivebasedonanexpectationofstatisticalevidenceoccurringonetimeatrandominagenomescan(apointwisesignicancelevelof7·10)4forsib-pairstudies),asproposedbyLanderandKruglyak(1995).
DISCUSSIONWesoughttoidentifylinkageregionsforanalcoholdepen-dencesymptomscoreinalargecommunitysampleofAustralianadults.
Althoughnoneofourndingsachievegenomewidelevelsofsignicance,ourLODscoresgreaterthan2.
0areinaregiononchromosome5previouslylinkedtoalcohol-relatedtraits(e.
g.
Schuckitetal.
,2001).
Thecurrentndingssuggestthatgenesinthisregionmayinuencealcohol-relatedproblemsrangingfrommildthroughtothesevereproblemstypicallyfoundinaclinicalsample.
Further,ourresultsindicate,aspreviouslyfoundforalcoholconsumption(Hanselletal.
,2009),thatthelinkagemethodissensitivetorelativelysmalldifferencesininclusioncriteria.
Inthiscase,variationsinparticipantageanddrinkingstatusledtopeakvariation.
Givenexpectederrorinlocationestimates(AtwoodandHeard-Costa,2003),oursuggestivendingsconvergewithnumerouspreviousreports.
Linkagepeaksonchromosome5,whicharemaximalfortheyoungersample(LOD2.
7)andenhancedthroughexclusionofthelowestalcoholusers,areapproximately10to15cMfromthatreportedforresponsetoalcohol(Schuckitetal.
,2001)andageofonsetharmavoidancenoveltyseeking(Dicketal.
,2002)andapproxi-mately35cMfromaregionimplicatedinalcoholism(Hilletal.
,2004).
GenesofinterestinthisregionincludeSLC1A3andCDH12.
SLC1A3[solutecarrierfamily1(glialhighafnityglutamatetransporter),member3;genemaplocus5p13]isaglutamatergicneurotransmissiongenewithexpressionlevelsfoundtobesignicantlyelevatedinpostmortemprefrontalcortexofalcoholicindividualscomparedwithnonalcoholiccontrols(Flatscher-BaderandWilce,2006;Flatscher-Baderetal.
,2005).
CDH12(cadherin12,genemaplocus5p14-p13)showsincreasedexpressioninpostmortemtemporalcortexofindividualswithahistoryofalcoholabuseordependencecomparedwithcontrols(Sokolovetal.
,2003)andsimilarly,intheorbitofrontalcortexinviolentsuicidevictimscomparedwithnonpsychiatriccontrols(Thalmeieretal.
,2008).
Celladhesion-relatedgenessuchasCDH12haverolesinbuildingandmaintainingsynapticstructures(Bensonetal.
,2000),pointingtopossibledisturbancesofsynapticneuroplasticityinindividualswithalcoholdependence(Sokolovetal.
,2003).
Minorlinkageonchromosome2(LOD1.
5)isapproxi-mately15to30cMfromthatreportedforalcoholism(HillFig.
2.
MultipointLODscoresforalcoholdependencesymptomscoreareshownforYoungerandOldersamples(identicalexceptforasubsetof822individualsforwhomdatawerecollectedon2occasionswithrstoccasiondataincludedintheYoungerdatasetandsecondoccasiondataintheOlderdataset)andforfull(100%)andtruncated(90%)samples.
GenelocationsareshownfortheGABAAandADHgeneclustersandCHRM2,allofwhichhavebeenassociatedwithalcoholphenotypesinmultiplestudies(EdenbergandForoud,2006)andGAD1,SLC1A3,andCDH12,whicharecandidateaddictiongenesfoundundercurrentlinkagepeaks.
ResultswithmappositionsandmarkernamesareshowninTableS1.
160HANSELLETAL.
etal.
,2004),rank-transformedalcoholdependencesymptomcountintheIASPSADsample(Kendleretal.
,2006),heavyalcoholuseintheHeartStudy(Wyszynskietal.
,2003),sever-ityofalcoholuseinMissionIndians(Ehlersetal.
,2004),andmaximumdrinksinCOGA(Sacconeetal.
,2005).
Further,itisabout40to50cMfromregionsimplicatedinalcoholdependence(Reich,1996),conductdisorder(Dicketal.
,2004),andmorerecently,analcoholdependencesymptomscore(Agrawaletal.
,2008),intheCOGAsample.
Inthecur-rentanalyses,linkagewasmaximalintheoldersampleandsampletruncationdidnotaltertheresult.
Thisregionofchromosome2ishometoGAD1(glutamatedecarboxylase1,genemaplocus2q31),whichcatalyzestheconversionofglutamicacidtogamma-aminobutyricacid(GABA),themajorinhibitoryneurotransmitterintheverte-bralcentralnervoussystem.
Ithasbeenassociatedwithalco-holdependenceinHanTaiwanesemales(Lohetal.
,2006).
IntheIASPSADsample,noassociationwasfoundwithdepen-dence,butsignicantassociationswerefoundwithinitialsen-sitivitytoalcoholandtoageatonsetofdependence(Kuoetal.
,2008).
Kuoandcolleagues(2008)proposedthattheunderlyingpathophysiologyregulatedbyGAD1maybemoredirectlyrelatedtothecomponentprocessesofdependence,thantothedisorderitself.
Asmalllinkagepeak(LOD1.
6)onchromosome3waslocatedinthesameregionaslinkagefoundpreviouslyinthesamesampleforalcoholconsumption(LOD2.
7)(Hanselletal.
,2009).
Inaddition,aminorpeak(LOD1.
0)wasobservedintheregionencompassingthegamma-aminobutyricacidreceptorAsubunit2(GABRA2)gene.
Thisgeneandothersinitsclusteronchromosome4(GABRA4,GABRB1,GABRAG1)havebeenfoundtobeassociatedwithalcoholdependence(aswellasothersubstanceusedisordersandpsychopathology)acrossseveralindependentstudies(Covaultetal.
,2004;Edenbergetal.
,2004;Fehretal.
,2006;Lappalainenetal.
,2005;Lindetal.
,2008;Matthewsetal.
,2007;Soykaetal.
,2008).
Somelimitationsneedtobeconsidered.
First,theseresultswerenotgenomewidesignicant.
However,thelikeli-hoodthatthesearefalsepositivesissomewhatdiminishedastheresultsreplicatelinkagefoundintheseregionsbypre-viousstudies.
Further,quantitativetraitlociofsmalleffectaretobeexpectedgiventhatanalcoholdependencesymp-tomscoreislikelytobeinuencedbymanygenesofsmalleffect,ashasbeenfoundfornumeroustraitsingenomewideassociationstudies(Wrayetal.
,2007).
Largerlinkagesig-nals,ashavebeenreportedpreviously,maysimplyreectthehighvarianceofeffectsizeestimatesfoundwithsmallersamples.
Linkagedifferencesrelatedtosamplevariationwerefoundinthecurrentstudy,butarenotsufcientlylargeformeaningfulinterpretation.
Afurtherlimitationisthatthecomponentsampleswerecollectedforheteroge-neouspurposesandmaynotbeentirelyrepresentativeoftheadultAustralianpopulation.
Notwithstandingtheselimi-tations,ouranalysesdemonstratetheutilityofacommunitysample,resultsofwhichareeasilygeneralizable,forlinkageanalyses.
Thechromosomalregionsidentiedprovideafocusforfuturegene-mappingefforts.
ACKNOWLEDGMENTSWethankallparticipatingfamilies,theprojectcoordina-torsandinterviewersunderthesupervisionofDixieStatham,thedatamanagersunderthesupervisionofJohnPearsonandDavidSmyth,andlaboratorypersonnelunderthesupervisionofMeganCampbellandAnjaliHenders.
Forgenomescansoftwinsandsiblings,weacknowledgeandthanktheMam-malianGenotypingService,MarsheldWI(Director:Dr.
JamesWeber)forgenotypingunderagranttoDr.
DanielO'Connor;Drs.
ElineSlagboomandDorretBoomsmafortheLeidengenomescan;Dr.
PeterReedfortheGeminigen-omescan;andDr.
JeffHallfortheSequanagenomescan.
NationalInstituteofHealthgrantshavesupportedthiswork,includinggrantstoDrs.
AndrewHeath(AA07728,AA10248,AA11998,AA13321),PamelaMadden(DA12854),NickMartin(AA13326),MichelePergardia(DA019951),RichardTodd(AA13320),andJohnWhiteld(AA014041).
Dr.
ArpanaAgrawalreceivessupportfromDA023668andABMRFTheFoundationforAlcoholResearchandDr.
KatherineMorleyfromaNationalHealthandMedicalResearchCouncilPublicHealthFellowship(520452).
WiththeexceptionofABMRF,allfundingisgovernmentsourced.
Fundingbodiesplayednoroleinthecollectionoranalysisofdatanorinthewritingofthispaper.
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SUPPORTINGINFORMATIONAdditionalSupportingInformationmaybefoundintheonlineversionofthisarticle:TableS1.
MarkerannotationsindicategenotypingsourcePleasenote:Wiley-Blackwellisnotresponsibleforthecon-tentorfunctionalityofanysupportinginformationsuppliedbytheauthors.
Anyqueries(otherthanmissingmaterial)shouldbedirectedtothecorrespondingauthorforthearticle.
ANALYSISOFALCOHOLDEPENDENCESYMPTOMS163