Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

69 Pages·2017·2.42 MB·English

Research
JAMAPsychiatry | OriginalInvestigation
Genome-Wide Association Studies of a Broad Spectrum
of Antisocial Behavior
JorimJ.Tielbeek,MSc;AdaJohansson,PhD;TincaJ.C.Polderman,PhD;Marja-RiittaRautiainen,Msc;
PhilipJansen,MD;MichelleTaylor,PhD;XiaoranTong,MSc;QingLu,PhD;AlexandraS.Burt,PhD;
HenningTiemeier,MD,PhD;EssiViding,PhD;RobertPlomin,PhD;NicholasG.Martin,PhD;
AndrewC.Heath,PhD;PamelaA.F.Madden,PhD;GrantMontgomery,PhD;KevinM.Beaver,PhD;
IrwinWaldman,PhD;JoelGelernter,MD;HenryR.Kranzler,MD;LindsayA.Farrer,PhD;JohnR.B.Perry,PhD;
MarcusMunafò,PhD;DevonLoParo,PhD;TiinaPaunio,PhD;JariTiihonen,MD,PhD;SabineE.Mous,PhD;
IrenePappa,PhD;ChristiaandeLeeuw,MSc;KyokoWatanabe,MSc;AnkeR.Hammerschlag,MSc;
JessicaE.Salvatore,PhD;FazilAliev,PhD;TimB.Bigdeli,PhD;DanielleDick,PhD;StephenV.Faraone,PhD;
ArnePopma,PhD;SarahE.Medland,PhD;DaniellePosthuma,PhD;fortheBroadAntisocialBehavior
Consortiumcollaborators
Supplementalcontent
IMPORTANCEAntisocialbehavior(ASB)placesalargeburdenonperpetrators,survivors,and
society.Twinstudiesindicatethathalfofthevariationinthistraitisgenetic.Specificcausal
geneticvariantshave,however,notbeenidentified.
OBJECTIVES Toestimatethesingle-nucleotidepolymorphism–basedheritabilityofASB;
toidentifynovelgeneticriskvariants,genes,orbiologicalpathways;totestforpleiotropic
associationswithotherpsychiatrictraits;andtoreevaluatethecandidategeneeradata
throughtheBroadAntisocialBehaviorConsortium.
DESIGN,SETTING,ANDPARTICIPANTS Genome-wideassociationdatafrom5large
population-basedcohortsand3targetsampleswithgenome-widegenotypeandASBdata
wereusedformeta-analysisfromMarch1,2014,toMay1,2016.Alldatasetsused
quantitativephenotypes,exceptfortheFinnishCrimeStudy,whichappliedacase-control
design(370patientsand5850controlindividuals).
MAINOUTCOMEANDMEASURES Thisstudyadoptedrelativelybroadinclusioncriteriato
achieveaquantitativemeasureofASBderivedfrommultiplemeasures,maximizingthe
samplesizeoverdifferentageranges.
RESULTS Thediscoverysamplescomprised16400individuals,whereasthetargetsamples
consistedof9381individuals(allindividualswereofEuropeandescent),includingchildand
adultsamples(meanagerange,6.7-56.1years).Threepromisinglociwithsex-discordant
associationswerefound(8535femaleindividuals,chromosome1:rs2764450,
chromosome11:rs11215217;7772maleindividuals,chromosomeX,rs41456347).Polygenic
riskscoreanalysesshowedprognosticationofantisocialphenotypesinanindependent
FinnishCrimeStudy(2536maleindividualsand3684femaleindividuals)andsharedgenetic
originwithconductproblemsinapopulation-basedsample(394maleindividualsand431
femaleindividuals)butnotwithconductdisorderinasubstance-dependentsample(950
maleindividualsand1386femaleindividuals)(R2=0.0017inthemostoptimalmodel, AuthorAffiliations:Author
P=0.03).SignificantinversegeneticcorrelationofASBwitheducationalattainment affiliationsarelistedattheendofthis
article.
(r=–0.52,P=.005)wasdetected.
GroupInformation:TheBroad
AntisocialBehaviorConsortium
CONCLUSIONSANDRELEVANCE TheBroadAntisocialBehaviorConsortiumentailsthelargest collaboratorsarelistedattheendof
collaborationtodateonthegeneticarchitectureofASB,andthefirstresultssuggestthatASB thisarticle.
maybehighlypolygenicandhaspotentialheterogeneousgeneticeffectsacrosssex. CorrespondingAuthor:JorimJ.
Tielbeek,MSc,Departmentof
ComplexTraitGenetics,Centerfor
NeurogenomicsandCognitive
Research,andDepartmentofClinical
Genetics,VUMC,W&NBuilding,
DeBoelelaan1085,1081HV
JAMAPsychiatry.2017;74(12):1242-1250.doi:10.1001/jamapsychiatry.2017.3069 Amsterdam,theNetherlands
PublishedonlineOctober4,2017.CorrectedonJanuary24,2018. ([email protected]).
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Genome-WideAssociationStudiesofBroadAntisocialBehavior OriginalInvestigation Research
A
ntisocialbehavior(ASB)coversarangeofinappropri-
atebehaviorsthatcauseharmtoothers,thecommu- KeyPoints
nity,andtheenvironment.Thesebehaviorsincludeag-
Questions Whichgeneticvariantsareassociatedwithantisocial
gression,hostility,theft,deceitfulness,andviolentfelonies. behavior,aretheysexspecific,anddotheycorrelatewithother
Inadditiontothemonetaryeffects,1violentcriminalbehav- traits?
ioralsohassignificantsocialandemotionalcosts.Communi-
Findings Inthisstudyofgenome-wideassociationdatafrom
tieswithhighratesofcrimeoftenfacehighratesofunem-
5population-basedcohortsand3targetsamples,antisocial
ployment,drugandalcoholabuse,poverty,andothersocial behaviorwasassociatedwithpolygenictraits,demonstrating
pathologicconditions.2Survivorsofcrimeoftenexperience pleiotropicgeneticassociationswitheducationalattainmentand
emotionaltraumaandcandevelopseriousmentalhealthprob- distinctgeneticeffectsacrosssex.
lems,suchasposttraumaticstressdisorder.3Inaddition,ASB
Meaning Largersamples,dividedbysex,areneededtovalidly
hashighcomorbiditywithotherpsychiatrictraitsandmal- identifygeneticvariantsassociatedwithantisocialbehavior.
adaptivebehaviors.4,5Therefore,identificationofthecausal
mechanismsthatunderlieASBisimportanttoidentifypre-
ventionandtreatmentmodalities.Accumulatedevidencefrom
quantitativeandmoleculargeneticstudies6,7revealsthesub- [21246patients])detected1and13genome-widesignificant
stantialinfluenceofgeneticfactorsintheetiologyofASB.Most single-nucleotidepolymorphisms(SNPs),respectively.
evidenceofaroleofgeneticsisderivedfromtwinstudiesand, ToincreasesamplesizesforgenefindingforASB,weini-
toalesserextent,adoptionstudies7,8andindicatesthatap- tiatedtheBroadAntisocialBehaviorConsortium(BroadABC).
proximatelyhalfofthevarianceinASBcanbeexplainedby BroadABCrepresentsacollaborativeresearchinitiativeto
geneticfactors,whereastheremaindercanbeexplainedby conductgeneticanalysesonalargerscaletoidentifybiologi-
uniqueandcommonenvironmentalfactors.6-8Atwinstudy9 calmechanismsthatunderliethecourseofASB.Indesigning
furtherdeterminedthattheassociationbetweenASBandcog- BroadABC’sgene-discoverystrategies,weweighedtheben-
nitiveandpsychiatrictraitsisinpartattributabletocommon efitsandcostsofoutcomemeasureheterogeneityinrelation
geneticfactors,indicatingtheremaybesharedbiological tothetotalsamplesize.Wechosetomaximizesamplesize
mechanismsthatunderliethesebehaviors.Earlycandidate bypoolingtheheterogeneousmeasuresoftheindividual
genestudies9-11identifiedanumberofgeneticpolymor- cohorts,includingdifferentageranges,andjointlyanalyzing
phismsinvolvedinserotonergicandcatecholaminergicfunc- theirdata.Ourrationaleissupportedbyageneticallyinfor-
tion,amongothers,thatmaybeinvolvedinASB.However,a mativelongitudinalstudy24demonstratingevidenceof
systematicreviewandmeta-analysis12ofmostpublishedge- geneticcontinuity(thecontinuityinASBduringchildhood
neticassociationstudiesonaggressionandviolencefailedto andadolescenceisexplainedlargelybygeneticfactors).
revealasignificantoverallassociationbetweenanyofthepre- Moreover,apriorstudy25examiningtheetiologicconnec-
viouslyreportedcandidategenesandaggression.Thelackof tionsbetweentheexternalizingspectrumfoundthatadditive
replicationofcandidategenesforASBisconsistentwithother geneticfactorsaccountfor81%ofthevarianceinexternaliz-
candidategenefindingsinpsychiatry,whichforthemostpart ingbehavior.Lastly,previousmeta-analyticalGWASshave
havefailedtoidentifyreproducibleandclinicallyusefulge- successfullyappliedthisjointanalysisapproachbyidentify-
neticvariants.13Thisisattributableinparttotheaprioriin- ingadditionallociassociatedwithdepressivesymptomsand
ferencesoftheclassiccandidategeneapproach,whichin- neuroticism.26
creasesthechancesoffalse-positivefindingsinthetypically
smallsamplesizesoftheindividualstudies.14
Genome-wideassociationstudies(GWASs)canover-
Methods
cometheselimitations.Todate,relativelyfewGWASshavefo-
cusedonantisocialphenotypes.Onestudy,15performedon BroadABCfocusesonthebroadspectrumofASBandcur-
childhoodconductdisorderinanAmericansample(872pa- rentlyconsistsof5discoverycohorts(acombined16400in-
tientsand3091controlindividuals),detected3genome- dividuals)and3independentpredictionandreplication
widesignificantloci.However,noneoftheotherpublished samples:(1)apopulation-basedsample(n=825),(2)aforen-
GWASs16-19reportedevidenceofagenome-wideassociation sicsample(n=6220),and(3)andasubstance-dependent
withanygeneticvariants. sample(n=2336).Intotal,BroadABChasgenotypicandphe-
ThislackofpositiveresultsfromGWASsismostlikelyat- notypicdatafrom25781individualsacross8uniquesamples
tributabletolowstatisticalpowertodetectsmalleffects.20For and,toourknowledge,isthelargestcollectivesampleavail-
example,recentworkoftheSchizophreniaWorkingGroupof abletoestimatetheeffectsofgenome-widegeneticvariants
thePsychiatricGenomicsConsortiumrevealedthedirectas- forASBandtestingforgeneticoverlapwithothertraits.Allpar-
sociationbetweensamplesizeandsuccessindetectingge- ticipantsprovidedwritteninformedconsent.Alldatawerede-
neticvariants.TheirlatestGWASs,including36989patients identified.Becauseoftheextraperceivedvulnerabilityofthe
and113075controls,identified108genome-widesignificant FinnishCrimeStudyparticipants,multiplecommittees,in-
independentgenomicloci,providingnewinsightsinthepa- cludingtheEthicsCommitteeforPediatrics,AdolescentMedi-
thologyofschizophrenia,21whereasearlierstudiesbyPurcell cine,andPsychiatry,HospitalDistrictofHelsinkiandUusimaa,
etal22(N=6909[3322patients])andRipkeetal23(N=59318 andCriminalSanctionsAgency,approvedthisstudy.27
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Research OriginalInvestigation Genome-WideAssociationStudiesofBroadAntisocialBehavior
Table1.StudyDesign,SampleSizes,andPhenotypesforGenome-WideAssociationStudyCohorts
TotalSampleSize Age,Mean
Sample StudyDesign AntisocialMeasure (M/F),No. (SD),y
Discoverysamples
ALSPAC Prospectivepregnancy DevelopmentandWell-being 4336(2065/2271) 13.1(0.1)
cohort(familydesign) Assessment,conductdisorderscale
COGA Alcoholdependence Countofthenumberofantisocial 1379(739/640) 43.8(11.7)
case-controlsample personalitydisordercriteria
(familydesign)
GENR Populationbased Rule-breakingbehavior, 1420(718/702) 6.7(4.2)
(familydesign) TeacherReportForm
TEDS Populationbased AntisocialProcessScreeningDevice 2734(1257/1477) 12.5(.2)
(familydesign)
QIMR Populationbased Retrospectiveconductdisorder 6531(2993/3538) 33.8(2.4)
Abbreviations:ALSPAC,Avon
(twin-familydesign)
LongitudinalStudyofParentsand
Targetsamples
Children;COGA,Collaborative
FinnishCrime Case-control(prisoners StructuredClinicalInterview 6220(2536/3684) 56.1(12.8) StudiesonGeneticsofAlcoholism;
Study sample) forDSM-IVdisorders GENR,GenerationRotterdam;
MSUTR Populationbased ChildBehavioralChecklist: 825(394/431) 8.2(1.5) MSUTR,MichiganStateUniversity
(familydesign) conductproblems TwinRegistry;QIMR,Queensland
(reportedbymother)
InstituteofMedicalResearch;
Yale-Penn Substance-dependent DSM-IVconductdisordercriteria 2336(950/1386) 41.0(8.2) TEDS,TwinsEarlyDevelopment
sample
Study.
CohortsandPhenotypes analysisoftheGWASsummaryresultswereperformedby2
ExceptfortheFinnishCrimeStudy,whichusedadichoto- ofus(J.J.T.andA.J.)followingastrictanalysisprotocol.Ad-
mizedoutcomemeasure,allstudiesusedacontinuousscale ditionaldetailsonthestandardoperatingprocedureanalysis
toincreasestatisticalpower.28Tomaximizesamplesize,we planandqualitycontrolareprovidedineAppendix2inthe
includedstudieswithabroadrangeofantisocialmeasures,in- SupplementandontheBroadABCwebsite(http://broadabc
cludingaggressiveandnonaggressivedomainsofASBand .ctglab.nl/).
usingstudy-specificscalesindifferentagegroups(Table1and
eAppendix1intheSupplement).Fivelargepopulation-based Meta-analysisofDiscoveryCohorts
discoverycohortsand3targetsamples(allparticipantswere Themeta-analysisacrossdiscoverycohortswasrunforthe
ofEuropeandescent)wereincludedinthisstudyfromMarch pooledmale-femaleGWASresults(N=16400),aswellassepa-
1,2014,toMay1,2016(seeTable1forcohort-specificdetails). ratelyforthesexes(8535femaleindividualsand7772malein-
Thediscoverysamplescomprised16400individuals,whereas dividuals),usingafixed-effectsmodelwithzscoresweighted
thetargetsamplesconsistedof9381individuals.Allpartici- bysamplesizeasimplementedinthesoftwareMETAL.31We
pantswererecruitedfromdifferentregions;thus,sampleover- onlyreportedandinterpretedtheresultsofpolymorphisms
lapwashighlyunlikely. withatotalsamplesizegreaterthan10000(acrossallsamples)
and5000(sexspecific).Thegenome-widesignificancethresh-
Genotyping oldwassetat1.67×10−8becauseweperformed3meta-
Genome-widegenotypingwasperformedindependentlyinthe analyses;polymorphismswithP<10−6wereconsideredtobe
cohortsusingcommerciallyavailablegenotypingarrays.Allco- promisingfindings.
hortsimputedtheirgenotypedatatothe1000Genomesphase
1version3(build37,hg19)referencepanelusingthestandard PolygenicRiskScores
softwarepackageMACH29orIMPUTE230exceptfortheFinn- Weperformedapolygenicriskscore(PRS)analysisintheFinn-
ishCrimeStudyandMichiganStateUniversityTwinRegistry ishCrimeStudytotestwhetherageneticriskforASBcould
(MSUTR),whichwerenotimputed.Additionaldetailsandco- significantlydiscriminatebetweenprisonersandmatchedcon-
hort-specificproceduresconcerningthegenotypingprocess, trols.WeusedthesoftwarepackagePRSicetoestimatethebest-
imputation,andqualitycontrolareprovidedineTable1and fitPRSatabroadrangeofPvaluethresholds.Forclumping,
eTable2intheSupplement. thelinkagedisequilibrium(LD)thresholdwassettoanR2of
0.25anda500-kbdistance.ThePRSanalyseswerecon-
StatisticalAnalysis ductedbasedonthesex-combinedsamplesandthemale-
GWASsattheCohortLevel specificsamples(giventheoverrepresentationofmalepris-
AnalysesoftheGWASswereperformedatthecohortlevelac- oners),andsex,age,and4principalcomponentswereincluded
cordingtoaprespecifiedanalysisplan(standardoperatingpro- ascovariates.Inaddition,toevaluateevidenceforsharedge-
cedures).Eachcohortuploadedsex-specificandcombined neticorigin,weusedthesummary-summarystatistic–based
GWASresultstotheBroadABCserverasinputforthemeta- analysisasimplementedinPRSice,usingthesex-combined,
analyses.AllanalyseswererestrictedtosamplesofEuropean male-specific,andfemale-specificsamplesinMSUTRandYale-
ancestry.Forsex-pooledanalysisoftheXchromosome,males Pennsamplesafterapplyingmorestringentclumpingthresh-
weretreatedashomozygousfemales.Qualitycontrolandmeta- olds(R2=0.05,300-kbdistance).
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Genome-WideAssociationStudiesofBroadAntisocialBehavior OriginalInvestigation Research
Figure1.MiamiPlotShowingPValuesoftheSingle-NucleotidePolymorphismAssociations
WithAntisocialBehaviorinMalesandFemales
12
Males
10
rrss4411445566334477
88
66
444
ue 22
Val
P 00
10g
o 22
-l
444
66
88
rrss22776644445500 rrss1111221155221177
Thethresholdforgenome-wide
10 Females significance(P<1.67×10−8)is
12 indicatedbythereddottedline,and
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 thethresholdforpromisingfindings
Chromosomes (P<1.0×10−5)isindicatedbythe
bluedottedline.
LDRegressionScoreHeritabilityandCorrelationAnalyses (N<10000),resultingin7392849SNPsavailableforanaly-
TocalculatetheSNPheritabilityandestimatethegeneticcor- ses.Therewerenodiscrepanciesbetweentheresultsfilesof
relationbetweenASBandarangeofcognitive,psychiatric,and the2analystsatthecohortormeta-analysislevel.Thege-
reproductivetraits,weusedthe(cross-trait)LDscoreregres- nomicinflationfactorswere1.015forthecombinedanalysis,
sionmethod.TheLDscoremethoddisentanglesthecontri- 1.012forthemaleanalysis,and1.001forthefemaleanalysis,
butionoftruepolygenicsignalandbiascausedbypopulation whichareasexpectedunderapolygenicmodelgiventhe
stratificationtotheinflatedteststatisticsinGWASsandop- samplesize,prevalence,andheritabilityofASB(eFigure3in
tionallycalculatesageneticcorrelation(r )amongdifferent theSupplement).
g
traits.32Thismethodisparticularlyusefulbecauseitonlyre-
quiresGWASsummarystatisticsandisnotbiasedbysample Meta-analysisofGWAS
overlap.33GeneticcorrelationsofASBwerecalculatedwith Thecombineddiscoverymeta-analysisincorporatingboth
cognitiveandpsychiatrictraitspreviouslyreportedtobe sexesdidnotidentifygeneticvariantsofgenome-widesig-
comorbidwithASBusingsummaryresultsfromattention- nificance(n=16400,lowestP=6.1×10−7).Thestrongestas-
deficit/hyperactivitydisorder(ADHD),schizophrenia,and sociationswerelocatedonchromosome20,followedbychro-
bipolardisorder21,34,35thatarepubliclyavailableonthePsy- mosomes1,19,22,and6(eFigure4intheSupplement).The
chiatricGenomicsConsortiumwebpage(https://www.med.unc SNPsyieldingPvaluessmallerthan1.0×10−6wereconsid-
.edu/pgc/results-and-downloads).Thesummarystatisticsof eredpromising(eTables11,12,and13intheSupplement).
neuroticismandeducationalattainment(definedasnumberof TheGWASmeta-analysisforfemalesonly(n=8535)
yearsintheeducationalsystem)wereprovidedbytheSocial (eTable12intheSupplement)revealed2promisinglocion
ScienceGeneticAssociationConsortium.26,36Thegenetic chromosome1(rs2764450,R2=0.35%,P=4.8×10−8)and
correlationsofASBwithreproductivetraitswerecomputedfrom chromosome11(rs11215217,R2=0.37%,P=2.1×10−8),whereas
acentralizeddatabaseofsummary-levelGWASs.37 themeta-analysisformales(n=7772)(eTable13intheSupple-
Themethodsandresultsregardingthefunctionalannota- ment)identifiedaneargenome-widesignalonchromosome
tion,geneanalysis,gene-setanalyses,replicationanalysis,and X(rs41456347,R2=0.41%,P=2.0×10−8).Wefoundnoevi-
testsforenrichmentinlocipreviouslyrelatedtoantisocialphe- denceofheterogeneity(I2=0)acrossdiscoverysamplesinthe
notypesarereportedineAppendixes3through6,eTables3 associationofrs2764450(χ2 =2.62,P=.45),rs11215217
3
through10,andeFigure1andeFigure2intheSupplement). (χ2=3.01,P=.54),andrs41456347(χ2=2.72,P=.60)with
4 4
ASB(eFigure5intheSupplement).Functionalannotationwas
performedforthetop3locitogaininsightintopossiblecausal
genes(eAppendix6andeAppendix7andeFigure1inthe
Results
Supplement).Topsignalswerelocateddifferentlyacrosssex
Thediscoverysamplescomprised16400individuals,whereas (Figure1andeTable14intheSupplement).Wetestedwhether
thetargetsamplesconsistedof9381individuals(allindivi- thesignsoftheregressioncoefficientswereconsistentlyin
dualswereofEuropeandescent),includingchildandadult thesamedirectionbetweentheSNPsformalesandfemales.
samples (mean age range, 6.7-56.1 years). We removed Thesigntestsshowednoconsistentdirectionsofeffect
2134049SNPsbecauseofinsufficienttotalsamplesize (proportionswere0.51,0.50,and0.50)forSNPsselectedfor
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Research OriginalInvestigation Genome-WideAssociationStudiesofBroadAntisocialBehavior
different P value thresholds (0.05, 0.001, and 0.0001,
respectively).Moreover,Fisherexacttestsfoundnoevi- Discussion
denceforenrichmentofSNPswithlowPvaluesacrosssex
regardlessofsign(oddsratio[OR],0.9;P=.05formales; Toourknowledge,thisstudyrepresentsthelargestinvesti-
OR,1.1;P=.001forfemales)(eTable15intheSupplement). gationonthegeneticarchitectureofASBtodate.Ourmeta-
Thesex-specificsignalsweresupportedbyalargenum- analysesofdiversecontinuousmeasuresofASBfoundthatASB
berofpromisingSNPs,whichwereinincompleteLDwiththe isheritableandhighlypolygenicandsuggeststhatpartofthe
leadSNP(eFigure4).ImputationqualityfortheleadSNPswas geneticarchitectureissexspecific.Thisfindingisnotsurpris-
highforrs41456347(meanR2=99.7),rs2764450(mean inginviewofthesex-influencedphenotypicexpression.We
R2=93.8),andrs11215217(meanR2= 86.8).Gene-basedand alsofoundastronginversecorrelationofASBwithgeneticvari-
gene-setanalysesyieldednosignificantgenes(topgenewas antsforeducationalattainmentandsomereproductivetraits
centromericproteinI[OMIM300065],P=3.2×10−5)(eTables andapositivegeneticcorrelationwithneuroticismbutnotwith
3-9,and14andeFigure1intheSupplement)orgenesets(top schizophrenia,bipolardisorder,orADHD.
gene-setwasReactomecellcommunication,P=3.6×10−4) TheSNPheritabilityanalysesfoundthatthecollectiveef-
(eTable6intheSupplement).Noneofthetraditionalcandi- fectofthemeasuredSNPsaccountedfor5%ofthevariance
dategenesonASBweresignificantlyassociatedwithASB(top or10%oftheheritabilityofapproximately50%,asestimated
genewastyrosinehydroxylase[OMIM191290],P=0.08for fromfamily-basedstudies.RecentGWASsonothercomplex
correlation)(eTables7,8,and9intheSupplement). traits,suchasheight,bodymassindex,andschizophrenia,
demonstratedthatwithgreatersamplesizes,theSNPh2in-
PolygenicRiskScores creases.TherelativelysmalltotalGWASdiscoverysamplesize
TheBroadABCantisocialgeneticriskscoreswereassociated yieldedlimitedpowertodetectsmallgeneticeffects,which
withcase-controlstatusofantisocialpersonalitydisorderin couldexplaininpartthehighmissingheritabilityinourstudy,
theFinnishCrimeStudy(sexcombined,R2=0.0017,P=.03; althoughwecannotruleoutthatmostofthegeneticvari-
male-specificR2=0.0018,P=.05)(Figure2AandB).Never- anceinASBisattributabletorarealleles.Takentogether,we
theless,theanalysesrevealedlowNagelkerkeR2estimates suspectthatwithgreatersamplesizesandbetterimputation
(R2=0.0019inthemostoptimalmodel)notexceedingthe andcoverageofthecommonandrareallelespectrum,over
Bonferroni-correctedthresholdforsignificance.Usingsum- time,SNPheritabilityinASBcouldapproachthefamily-
marystatisticsinPRSicesoftware,wefoundthatthegenetic basedestimates.
effectfromthefemales-onlyASBanalysissignificantlyover- Polygenicriskscoreanalysis,basedonabroadconceptu-
lappedwithgeneticeffectsintheexpecteddirectiononcon- alizationofASB,couldreliablydeterminesomeofthevaria-
ductproblemsinMSUTR(R2=0.021forthemostoptimal tioninantisocialpersonalitydisorderinaforensiccohort,dem-
model,P=.004)butnotwiththesex-combinedandmales- onstratingthatpopulation-basedgeneticassociationstudiescan
onlyanalyses(Figure2C-E).Nosignificantgeneticoverlapwas alsobeinformativeforsamplesthatareatrisk.Nevertheless,
foundwithconductdisorderinYale-Pennsample,althougha effectsizesweresmall,indicatinglimitedprognosticationac-
nominalsignificanteffect(R2=0.0022,P=.04)intheex- curacyandclinicalutilityforthecurrentGWASoutcomes.
pected direction was found in the males-only analysis Despitethesmallbutsignificantcollectivegeneticeffect
(Figure2E-H). onASB,noneoftheindividualgeneticvariantsexceededthe
significancethresholdinouroverallmeta-analysis.Thesex-
SNPHeritabilityandGeneticCorrelationofASB specificmeta-analyses,however,revealed3promisingloci.
WithOtherTraits Moreover,strongerpolygenicriskeffectswerefoundforthe
TheestimatedproportionofthephenotypicvarianceinASB sex-specificanalyses.Giventhesubstantialdifferencesin
explainedbyallSNPswas5.2%,withanSEof2.7%(P=.03). prevalence,ageatonset,andseverityofASBbetweenmales
Sample sizes were too small in the sex-specific meta- andfemales,39whichmightinpartreflectsexdifferencesin
analysestobeusedtoestimateSNPheritability(h2)forthemale geneticarchitecture,itisimportanttoaccountforthoseef-
andfemalesamplesseparately.Wefoundasignificant(cor- fectsingeneticresearchdesigns.40Ourcurrentresultssug-
rectedα=.006)andmoderatenegativegeneticcorrelationbe- gestthepresenceofatleastsomesex-specificgeneticeffects.
tweenASBandeducationalattainment(r=−0.52,P=.005). Eventhoughsamplesizesweresmaller,thesex-specificanaly-
Follow-upanalysesusingtheFisherexacttestrevealedevi- sesyieldedincreasedspecificitybecausepotentialnoiseat-
denceofenrichmentoflowP(P<.001)inthesameSNPsfor tributabletodifferentgeneticlocidrivingthegeneticcompo-
ASBandeducationalattainment(OR=3.26,P=.001).More- nentofASBinmaleandfemaleindividualswasremoved.
over,wefoundapromisingpositivegeneticcorrelationwith Ourgeneticcorrelationanalysesrevealedapromisingposi-
neuroticism(r=0.29,P=.02)andsupportforanegativege- tivegeneticcorrelationofASBwithneuroticism,afindingthat
netic correlation between ASB and age at menopause isconcordantwithprevioustwinresearchdemonstratinga
(r=−0.49,P=.01),ageoffirstbirth(r=−0.43,P=.008),and sharedgeneticoriginofexternalizingbehaviorandnegative
apositivegeneticcorrelationwithnumberofchildreneverborn emotionality.41Moreover,wefoundsignificantgeneticover-
(r=0.42,P=.03)38(Table2).Therewasnoevidenceforge- lapbetweenASBandeducationalattainment,indicatingacom-
neticoverlapbetweenASBandschizophrenia,bipolardisor- monunderlyinggeneticarchitecturethatinfluencedbothphe-
der,ADHD,orageatmenarche. notypes.Thenegativegeneticcorrelationwitheducational
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Genome-WideAssociationStudiesofBroadAntisocialBehavior OriginalInvestigation Research
Figure2.PolygenicRiskScores(PRSs)intheFinnishCrimeStudy,MichiganStateUniversityTwinRegistry
(MSUTR),andYale-PennSamples
A Finnish Crime Study sex-combined sample B Finnish Crime Study male-only sample
0.0020 0.0020
a
2nce R 0.0015 a a 2nce R 0.0015
a a
Vari Vari
d 0.0010 d 0.0010
e e
n n
ai ai
pl pl
x x
S E 0.0005 S E 0.0005
R R
P P
a
0 0
0.01 0.05 0.1 0.2 0.3 0.4 0.5 0.01 0.05 0.1 0.2 0.3 0.4 0.5
Polygenic Score Polygenic Score
No. of SNPs 2608 11 15120 60737 68353 03065 27365 877 No. of SNPs 2606 11 15720 61037 69053 02965 88265 882
C MSUTR sex-combined sample D MSUTR male-only sample
0.0020 0.0020
2R 2R
nce 0.0015 nce 0.0015
a a
Vari Vari
d 0.0010 d 0.0010
e e
n n
ai ai
pl pl
x x
S E 0.0005 a S E 0.0005
R R
P P
a
0 0
0.01 0.05 0.1 0.2 0.3 0.4 0.5 0.01 0.05 0.1 0.2 0.3 0.4 0.5
Polygenic Score Polygenic Score
No. of SNPs 1553 6956 13 12624 42634 95044 84554 117 No. of SNPs 1685 7154 13 50025 29536 25546 31555 743
E MSUTR female-only sample F Yale-Penn sex-combined sample
0.0025 0.0030
b
2R 0.0020 2R 0.0025
e a e
anc a anc 0.0020
Vari 0.0015 a Vari
ed ed 0.0015 ThePRSsforantisocialpersonality
ain 0.0010 ain disorder(ASPD)amongpatientswith
xpl xpl 0.0010 antisocialbehavior(ASB)inthe
E E
PRS 0.0005 PRS 0.0005 Fseinxn-cisohmCbriinmeedS(tAu)daynudsminagle-only(B)
0 0 samples.Summary-summary
0.01 0.05 0.1 0.2 0.3 0.4 0.5 0.01 0.05 0.1 0.2 0.3 0.4 0.5 statistic–basedresultsplottingthe
Polygenic Score Polygenic Score explainedvarianceinASBwithinthe
No. of SNPs 1564 6994 13 24824 63235 36745 35654 365 No. of SNPs 2078 7520 12 29719 11624 21228 18431 421 MSUTR(sexcombined[C],males
only[D],andfemalesonly[E])and
Yale-Penn(sexcombined[F],males
G Yale-Penn male-only sample H Yale-Penn female-only sample
only[G],andfemalesonly[H])
0.0030 0.0030 samples.Theproportionofvariance
explained(NagelkerkeR2)was
2d Variance R 000...000000221505 a 2d Variance R 000...000000221055 cmwooniotmlyhd)pea.ulSr(teecedvodeuvbnacyredidaciftomfemesorpepdnaleurtlissP(cPovonRavSolau)fresiaactfoeurslel
ne ne thresholdsforselectingriskalleles
plai 0.0010 plai 0.0010 a aredenotedbythecolorofeachbar.
x x
S E S E Thenumberofsingle-nucleotide
PR 0.0005 PR 0.0005 polymorphisms(SNPs)perthreshold
a isdisplayedbeloweachbar.
0 0
0.01 0.05 0.1 0.2 0.3 0.4 0.5 0.01 0.05 0.1 0.2 0.3 0.4 0.5 aStatisticalsignificanceatP<.05.
Polygenic Score Polygenic Score bStatisticalsignificanceafter
No. of SNPs 2540 9460 16 25326 99135 52642 81248 941 No. of SNPs 5169 17 56128 30644 52256 74966 56474 633 correctingformultipletestingat
P<.006.
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Research OriginalInvestigation Genome-WideAssociationStudiesofBroadAntisocialBehavior
Table2.GeneticCorrelationEstimatesfor9TraitsWithBroadAntisocialBehavior
Phenotype SampleSize SNPh2a r (SE)b PValue
g
Educationalattainment 293723 0.099 -0.52(0.18) .005
Abbreviations:SNPh2,
Neuroticism 170911 0.094 0.29(0.13) .02 single-nucleotidepolymorphism
Schizophrenia 150064 0.576 0.07(0.15) .64 heritability.
Bipolardisorder 17091 0.516 0.17(0.20) .41 aSNPh2istheestimationof
narrow-senseheritability.
Attention-deficit/hyperactivitydisorder 9152 0.156 0.002(0.29) .99
br isthegeneticcorrelationandis
Ageatmenarche 87802 0.207 −0.04(0.09) .68 g
calculatedwiththelinkage
Ageatmenopause 69360 0.134 −0.49(0.19) .01 disequilibriumscoreregression
Ageatfirstbirth 251151 0.061 −0.43(0.16) .008 softwarepackageusing
precalculatedlinkagedisequilibrium
No.ofchildreneverborn 343072 0.025 0.42(0.19) .03
scoresfromFinucaneetal.38
attainmentisconsistentwithapreviousepidemiologicstudy42 over,despitethebroadconceptualizationofASBinthecur-
thatreportedanegativeassociationbetweenacademicper- rentstudy,thesamplesizeisrelativelysmallforgene-finding
formanceanddelinquency.Thisfindingisimportantbe- purposes.Still,wefoundapolygenicsignal,andourcorrela-
causeitmayprovideinsightintothedevelopmentalpath- tionanalysesfurtherreflectthevalidityandusefulnessofour
waysthatunderlietheassociationbetweenacademicfailure approach.ToidentifyindividualSNPsorgenesassociatedwith
andASB.43Ofinterest,ASBalsocorrelatedwithreproductive ASB,wefoundthatevenlargersamplesareneeded.
traits,thusfittingtotheunifiedevolutionarytheorythat
Boutwellandcolleaguesproposed.44Theirtheorysuggeststhat
increasedcriminalityrepresentsafasterlifehistoryapproach—
Conclusions
onethatwouldbesignificantlycalibratedbygenes.
OurstudysuggeststhatASBmaybehighlypolygenicandhas
Limitations potentialheterogeneousgeneticassociationsacrosssex.As
GiventhenatureofASBwithnoacceptedgoldstandardformea- large-scaleinitiatives,suchastheBroadABC,continuetoin-
suringthetrait,ourattempttobringtogetherlargehistoriccol- crease,thesecollaborativeeffortswillalsofacilitatethecon-
lectionsispossiblyburdenedbymeasurementdiversity.The ductofepidemiologicstudiesthatincorporategenome-wide
consortiumincludesadultandchildsamples,andwithinthe dataandenvironmentalfactorsinajointanalysis.48Discov-
adultsamples,somefocusonlifetimeantisocialbehaviorand eriesobtainedfromsuchgene-environment–wideinterac-
othersfocusonretrospectivereportsofchildbehavior.Nev- tionstudiesmaycontributetomoreadvancedexplanatory
ertheless,previousstudies45-47havedemonstratedstableand modelsofthecomplexoriginofASB,therebyultimatelyaid-
uniquegeneticinfluencesonASBduringthelifespan.More- ingpreventionandinterventionstrategies.49
ARTICLEINFORMATION Hospital,UniversityofEasternFinland,Kuopio PsychologyandtheVirginiaInstituteforPsychiatric
AcceptedforPublication:August3,2017. (Rautiainen,Paunio);DepartmentofPsychiatry, andBehaviouralGenetics,VirginiaCommonwealth
UniversityofHelsinkiandHelsinkiUniversity University,Richmond(Salvatore);Departmentof
PublishedOnline:October4,2017. Hospital,Helsinki,Finland(Rautiainen,Paunio); AfricanAmericanStudies,VirginiaCommonwealth
doi:10.1001/jamapsychiatry.2017.3069 DepartmentofEpidemiology,ErasmusMedical University,Richmond(Aliev);FacultyofBusiness,
Correction:ThisarticlewascorrectedonJanuary Center,Rotterdam,theNetherlands(Jansen, KarabukUniversity,Karabuk,Turkey(Aliev);Virginia
24,2018,tofixanincorrectdegreeinthebyline. Tiemeier,Hammerschlag);MedicalResearch InstituteforPsychiatricandBehavioralGenetics,
AuthorAffiliations:DepartmentofComplexTrait Council(MRC)IntegrativeEpidemiologyUnit, VirginiaCommonwealthUniversity,Richmond
Genetics,CenterforNeurogenomicsandCognitive UniversityofBristol,Bristol,England(Taylor, (Bigdeli);DepartmentofPsychology,African
Research,NeuroscienceCampusAmsterdam,Vrije Munafò);DepartmentofEpidemiologyand AmericanStudies,andHuman&Molecular
UniversiteitAmsterdam,Amsterdam,the Biostatistics,MichiganStateUniversity,East Genetics,VirginiaCommonwealthUniversity,
Netherlands(Tielbeek,Polderman,Jansen, Lansing(Tong,Lu);DepartmentofPsychology, Richmond(Dick);DepartmentofPsychiatryand
deLeeuw,Watanabe,Hammerschlag,Posthuma); MichiganStateUniversity,EastLansing(Burt); BehavioralSciences,PsychiatricGenetic
DepartmentofChildandAdolescentPsychiatry, DepartmentofChildandAdolescentPsychiatry/ EpidemiologyandNeurobiologyLaboratory,SUNY
VUUniversityMedicalCenter,Amsterdam,the Psychology,ErasmusMedicalCenter–Sophia UpstateMedicalUniversity,Syracuse,NewYork
Netherlands(Tielbeek,Popma);QIMRBerghofer Children’sHospital,Rotterdam,theNetherlands (Faraone);DepartmentofNeuroscienceand
MedicalResearchInstitute,Herston,Queensland, (Tiemeier,Mous,Pappa);DepartmentofPsychiatry, Physiology,PsychiatricGeneticEpidemiologyand
Australia(Tielbeek,Martin,Montgomery,Medland); ErasmusMedicalCenter,Rotterdam,the NeurobiologyLaboratory,SUNYUpstateMedical
DepartmentofPsychologyandSpeech-Language Netherlands(Tiemeier);DivisionofPsychologyand University,Syracuse,NewYork(Faraone);
Pathology,UniversityofTurku,Turku,Finland LanguageSciences,UniversityCollegeLondon, DepartmentofClinicalGenetics,Neuroscience
(Johansson);DepartmentofPharmacology, London,England(Viding,Plomin);Departmentof CampusAmsterdam,VrijeUniversiteitMedical
InstituteofNeuroscienceandPhysiology, Psychiatry,WashingtonUniversitySchoolof Center,Amsterdam,theNetherlands(Posthuma);
SahlgrenskaAcademy,UniversityofGothenburg, Medicine,StLouis,Missouri(Heath,Madden); DivisionofHumanGenetics,Departmentof
Gothenburg,Sweden(Johansson);Departmentof CollegeofCriminologyandCriminalJustice,Florida Psychiatry,YaleUniversitySchoolofMedicine,New
Psychology,FacultyofArts,Psychology,and StateUniversity,Tallahassee(Beaver);Centerfor Haven,Connecticut(Gelernter);VeteransAffairs
Theology,ÅboAkademiUniversity,Turku,Finland SocialandHumanitiesResearch,KingAbdulaziz (VA)ConnecticutHealthcareCenter,NewHaven
(Johansson);NationalInstituteforHealthand University,Jeddah,SaudiArabia(Beaver); (Gelernter);DepartmentofPsychiatry,Universityof
Welfare,Helsinki,Finland(Rautiainen,Paunio); PsychologyDepartment,EmoryUniversity,Atlanta, PennsylvaniaPerelmanSchoolofMedicine,
DepartmentofForensicPsychiatry,Niuvanniemi Georgia(Waldman,LoParo);Departmentof Philadelphia(Kranzler);CorporalMichaelJ.
1248 JAMAPsychiatry December2017 Volume74,Number12 (Reprinted) jamapsychiatry.com
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Genome-WideAssociationStudiesofBroadAntisocialBehavior OriginalInvestigation Research
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Neuroscience,KarolinskaInstitutet,Stockholm, approvalofthemanuscript;andthedecisionto psychopathy:areviewoftherecentliterature.
Sweden(Tiihonen);DepartmentofForensic submitthemanuscriptforpublication. BehavSciLaw.2010;28(2):148-173.
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