Role of Genotype in the Cycle of Violence in Maltreated Children. Fears of the Future in Children and Young People

Caspi, Avshalom; u.a.

Role of genotype in the cycle of violence in maltreated children. Fears of the future in children und young people

ZSE : Zeitschrift für Soziologie der Erziehung und Sozialisation 25 (2005) 2, S. 133-145 urn:nbn:de:0111-opus-56685

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of Education and Socialization

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Schwerpunkt/Main Topic

Anlage ^{und Umwelt - neue} Perspektiven ^{einer alten}

Debatte

Nature und Nurture^-NewPerspectives ^{on an Old Debate}

Franz. J. Neyer,^{Jens B.}Asendorpf

ZurEinführung^{in den}Themenschwerpunkt

Introductiontothe MainTopic ¹¹⁵

JensB.Asendorpf

Umwelteinflüsse auf die Entwicklung ^aus entwicklungsgenetischer

Sicht

Environmental Influences ^on Development from ^a Developmental

GeneticsPerspective ¹¹⁸

AvshalomCaspi, JosephMcClay,^TerrieE.MofFitt,^JonathanMill, Judy Martin,^{Ian W.} Craig,^AlanTaylor,Richie Poulton

RoleofGenotype^intheCyle^ofViolence in Maltreated Children ^.... 133 FrankM. Spinath,^HeikeWolf,AloisAngleitner, ^PeterBorkenau,^Rai¬

nerRiemann

Multimodale Untersuchung ^von Persönlichkeiten und kognitiven Fähigkeiten. Ergebnisse der deutschenZwillingsstudien ^BiLSATund

GOSAT

MultimodalInvestigationofPersonality^andCognitiveAbility. ^Results from^{twoGerman Twin}Studies BiLSATund GOSAT 146

FriederR. Lang,^{Franz J.}Neyer

Soziale Beziehungen ^alsAnlage^und Umwelt. Einevolutionspsycho¬

logischesRahmenmodell derBeziehungsregulation

SocialRelationships^{asNature and}Nurture. AnEvolutionary-Psycho- logical^Frameworkof^SocialRelationship Regulation ¹⁶² Beiträge

WernerGeorg

DieReproduktion ^sozialerUngleichheit^imLebenslauf

TheReproductionof^SocialInequality^intheLife^{Course 178}

MariaFölling-Albers

Chancenungleichheitin der Schule^-(k)ein^Thema?Überlegungen^zu pädagogischenund schulstrukturellenHintergründen

Unequal Opportunities^inSchool-(not)^anIssue?Reflections^onPeda-

gogicaland StructuralReasons 198

Rezension/Book Reviews

Einzelbesprechungen

D.Geulen überM.Grundmannu. R. Beer„Subjekttheorieninterdiszi¬

plinär" ²¹⁴

Lehrbücher

W.Gehresbesprichtzwei Lehrbücher für soziale Berufe:Soziologie^{und ^ 15} Psychologie

Aus der Profession/Inside the Profession

Porträt

W. Reschka über FlorianZnaniecki 217

Nachruf

FrauProf. Dr. Steffani Engler^istgestorben ²²²

Veranstaltungskalender

Pierre Bordieu alsProvokateurderErziehungswissenschaft, Fachtagung

inFrankfurt/Main ₂₂₃

Vorschau/Forthcoming^{Issue 224}

AvshalomCaspi, JosephMcClay,^{TerrieE.Moffitt,JonathanMill,} Judy Martin, ^{Ian W.} Craig,^AlanTaylor, Riechie Poulton

Role of Genotype ^{in the} Cycle of Violence in Maltreated Children1

Fears ofthe Future in Children undYoung People

Westudieda largesampleofmale^childrenfrom ^{birthto adulthoodto determine} why^{some children who are maltreated}grow up^to develop ^{antisocial behavior,}

whereas others donot.Afunctionalpolymorphism^inthegeneencoding^theneuro- transmitter-metabolizingenzyme monoamineoxidaseA(MAOA)^wasfound^tomode¬

ratetheeffectofmaltreatment. Maltreated children withagenotypeconferringhigh levelsof^MAOA expression^wereless likely^todevelop ^antisocialproblems. ^These findingsmaypartlyexplainwhy^{notallvictims}ofmaltreatment_{grow up}tovictimi- zeothers, andtheyprovideepidemiologicalevidence that genotypes^canmoderate children 'ssensitivity^toenvironmental Insults.

Childhood maltreatmentisauniversalriskfactor for antisocial behavior.Boys

whoexperience^{abuse-and,more}generally,^thoseexposed^toerratic, coercive, andpunitive parenting^{-areatrisk of}developing ^{conductdisorder,antisocial} personalitySymptoms, ^{and of}becomingviolent offenders (1, 2).^Theearlier childrenexperience maltreatment,^themorelikely they^aretodevelop^theseprob¬

lems (3).^Buttherearelargedifferences between children in theirresponse^to maltreatment.Althoughmaltreatmentincreasesthe risk oflatercriminalityby

about50%,^mostmaltreated childrendonotbecomedelinquents^{oradultcrimi-}

nals(4).^{Thereasonfor this}variabilityin response islargely unknown,^{but it}

may be that vulnerability^toadversities is conditional, depending^on genetic susceptibility^factors(5, 6).^Inthisstudy,individual differencesatafunctional polymorphism^inthepromoterofthe monoamineoxidase A(MAOA)gene^were usedtocharacterizegenetic susceptibility^tomaltreatment andto testwhether the_{MAOA gene}modifies the influence of maltreatmentonchildren'sdevelop¬

mentof antisocial behavior.

The MAOA _gene is located onthe Xchromosome(Xpl 1.23-11.4) (7). ^Iten- codesthe MAOA enzyme, which metabolizes neurotransmitterssuchas nore-

pinephrine (NE),^Serotonin(5-HT),^anddopamine(DA), rendering^theminac- tive(8). ^Geneticdeficiencies inMAOA activity^havebeen linkedwith_aggres¬

sioninmiceand humans(9).^Increasedaggression^{andincreasedlevelsofbrain} NE, 5-HT,^andDAwereobserved inatransgenic^{mouselinein which}the gene

1 Wir danken AvshalomCaspi^undseinenKolleginnen^undKollegenfür die freund¬

liche ErlaubniszumAbdruck des Artikels und desSupplements.^DerAbdruck der in SCIENCE (297,^S. 851-854)publiziertenOrignialarbeiterfolgtaußerdem mit

Genehmigungder AmericanAssociation for the Advancement of Science. Copy¬

right^{2002 AAAS.}

encoding^{MAOA wasdeleted}(10), ^andaggression^{wasnormalized}by^restor- ing^MAOA expression (II). ^In humans, ^a null allele attheMAOA locuswas

linked withmale antisocial behavior in^aDutchkindred(12). Because MAOA isanX-linked_gene,affected males withasinglecopyproduced^noMAOAen¬

zyme ^-effectively, ^ahuman knockout. However, this mutation is extremely

rare. Evidence foran association between MAOA andaggressive^behaviorin

thehumangeneral populationremains inconclusive(13-16).

Circumstantial evidencesuggests^thehypothesis^thatchildhood maltreatment predisposes^moststrongly ^{toadultviolence}among children whoseMAOA is insufficienttoconstrain maltreatment-inducedchanges^toneurotransmitter_Sys¬

tems..Animal studies document that maltreatmentstress(e.g.,^maternaldepri¬

vation, peerrearing) ⁱⁿ early life alters NE, 5-HT, and DA neurotransmitter Systemsⁱⁿways that ^canpersistinto adulthood andcaninfluenceaggressive

behaviors(17-21).^Inhumans,^alteredNE and 5-HTactivity^{is linkedto}aggres¬

sive behavior(22).Maltreatment haslastingneurochemical correlatesinhuman children(23,24),^andalthough^nostudyhas ascertained whether MAOAplays

arole,^{itexertsaneffectonall}aforementioned neurotransmitterSystems.^Defi- cientMAOA activitymaydispose^theorganism^towardneuralhyperreactivity

tothreat(25).^Asevidence, phenelzineinjections,which inhibit theaction of monoamineoxidase,prevented^ratsfromhabituating^{tochronicstress}(26).^Low

MAOA activitymaybeparticularly problematic earlyⁱⁿlife,^becausethereis insufficient MAOB (a homolog ^{ofMAOA with broad} specificity ^{to neuro¬}

transmitteramines)^tocompensate^foranMAOAdeficiency (8).

Basedon thehypothesis^{that MAOA} genotype^{canmoderate the}influence of childhood maltreatment onneural Systemsimplicatedin antisocialbehavior,

wetestedwhetherantisocial behavior would bepredicted by^aninteractionbe¬

tweenagene(MAOA)^andanenvironment(maltreatment).^Awell-characterized variable number tandemrepeat (VNTR)polymorphism^existsatthepromoter ofthe MAOA gene, which is knownto affectexpression. ^Wegenotyped^this polymorphism^inmembersofthe DunedinMultidisciplinary^{HealthandDevel¬}

opmentStudy,^asample^withoutpopulationstratification confounds(27).^This birth cohort of1,037^children(52% male)has been assessedatages3, 5,7,9,

11, 13, 15, 18,^{and 21} andwasvirtually^intact(96%)^atage 26years.

Thestudyoffers threeadvantages ^fortesting gene-environment(GXE)^inter¬

actions.First,ⁱⁿcontrast tostudies ofadjudicated^orclinicalsamples,^thisstu¬

dy^ofarepresentative general population sample^avoidspotential distortions inassociation between variables (28, 29). Second, ^the sample has well-cha¬

racterizedenvironmentaladversity^{histories.Betweenthe}agesof3and_{11 years,} 8% ofthestudy ^childrenexperienced "severe"maltreatment,^28% experien-

ced"probable"maltreatment,^{and 64%}experienced^nomaltreatment(27).(Mal¬

treatmentgroupsdidnotdifferonMAOAactivity,%2(2)⁼0.38,^P=0.82,sug-

gesting^thatgenotype^{didnotinfluence}exposure^tomaltreatment.) Third,^the studyhas ascertained antisocial outcomesrigorously.Antisocial behavior isa

complicated phenotype, and each method and data sourceusedtomeasureit

(e.g.,^clinicaldiagnoses,personality checklists,official convictionrecords) ^is characterized by^different strengths and limitations. Using informationfrom

independent ^sources appropriate ^{to different} stages ^of development, ^we

examinedfouroutcomemeasures(27).

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1 1 1

None Probable Severe

Childhood maltreatment

Fig. ^{1. Meansonthe}compositeindex of antisocial behavioras afunction of MAOA activity ^{anda childhood} historyof maltreatment (27). ^MAOA activity ^{is the}gene

expression level associated with allelic variants of the functional promoter poly¬

morphism, groupedinto low andhigh activity;childhood maltreatment is grouped into 3 categories^ofincreasing severity.The antisocial behaviorcomposite ^isstan- dardized(z score)^toaM=0 and SD= 1;_groupdifferencesareinterpretable^{in SD unit} differences (d).

Adolescentconduct disorderwasassessedaccording^{tocriteriaofthe}Diagnostic andStatistical Manual of MentalDisorders(DSM-IV);convictionsfor violent crimeswere identifiedvia the Australian and New Zealandpolice;^apersona¬

litydispositiontoward violencewasmeasuredaspart^ofapsychological^assess¬

ment atage26;Symptoms ^ofantisocial personality^disorderwereascertained atage 26bycollecting informationabout thestudymembers frompeople they

nominatedas"someone whoknowsyou well." A common-factor model fit the fourmeasures ofantisocial behavior well (27), ^{with factor} loadings ranging from0.64to0.74, showing^{thatall fourmeasuresindex} liability^toantisocial behavior.

Using^moderatedregressionanalysis,^wepredictedscores on acomposite^anti¬

social indexcomprising^{the fourmeasuresofantisocialbehavior}(27) (Fig. 1).

Themain effect ofMAOA activity^onthe composite^{index ofantisocialbeha¬}

vior^wasnot significant (b⁼0.01, ^SE=0.09,^t=0.13,^P=0.89),^whereasthe main effect ofmaltreatmentwas significant (b ⁼ 0.35, ^{SE =} 0.07, ^{/ =} 4.82, P^<0.001).^Atestofthe interactionbetweenMAOAactivity^andmaltreatment revealeda significant^GXEinteraction(b ⁼-0.36,^SE=0.14, ^/= 2.53, ^{P =} 0.01). This interactionwithin each genotype group showedthatthe effect of childhood maltreatment on antisocial behavior was significantly ^weaker

among males with high ^MAOA activity (b ⁼ 0.24, ^SE= 0.11, ^{t =} 2.15, P ⁼

180 79 20

High^MAOA activity 12^- c

09-

06

03 ,

0 r1]

-03 r1\ ^p-03

iao 79

High^MAOA adtvity

[~1No maltreatment ?Probable maltreatment

Ad

activity activity I Severemaltreatment

Fig.2. The association between childhood maltreatment andsubsequent^antisocial behavioras a function of MAOA activity. (A) Percentage ^{of males}(and ^Standard errors)meeting diagnosticcriteria for Conduct Disorder between ages ¹⁰and18. In

ahierarchical logistic regression^model,the interaction between maltreatment and MAOAactivity^{was in the}predicteddirection,^{b =}-0.63, ^SE=0.33,^z= 1.87,P⁼ 0.06. Probingthe interaction within eachgenotypegroup showed that the effect of maltreatmentwashighly significantin the \ow-MAOAactivitygroup(b⁼0.96,^SE

=0.27,^z=3.55,^P<0.001),^andmarginally significant^inthehigh-MAOAgroup(b

=0.34, ^SE=0.20,^z= 1.72,^P=0.09).(B)Percentageof males convicted ofa vio¬

lent crime by age ^26. The GX Einteraction was in the predicted direction, ^{b =}

-0.83,^SE=0.42,^z= 1.95,^P=0.05.Probing^theinteraction,^theeffect of maltreat¬

mentwassignificantin the \ow-MAOAactivitygroup(b⁼1.20,^SE=0.33,^z=3.65, P^<0.001),^butwasnotsignificant ^{in the}high MAOA group(b⁼0.37, ^SE=0.27,

z⁼1.38,^P=0.17). (C)^Meanzscores(M⁼0,SD⁼ 1)^ontheDisposition^Toward

Violence Scaleatage26. Inahierarchicalordinary^leastSquares(OLS) regression model,^{the GX E}interaction wasin thepredicted^direction(b^=-0.24,^SE=0.15,

t⁼1.62,P⁼0.10);the effect of maltreatmentwassignificantin the \ow-MAOA acti¬

vitygroup(b⁼0.35,^SE=0.11,^t=3.09,^P=0.002)^{butnotin the}high^MAOAgroup

(b⁼0.12, ^SE=0.07,^t=1.34,P^-0.17). (D)^Meanzscores(M⁼0,^SD= 1)^onthe AntisocialPersonality^Disordersymptom^scaleatage26. The GXE interactionwas

in thepredicted ^direction(b^=-0.31, ^SE=0.15, ^t=2.02,^P=0.04); the effect of maltreatmentwassignificant in the low-MAOAactivitygroup(b⁼0.45, ^SE=.12,

t=3.83,^P<0.001)^{butnotin the}high^MAOA group(b⁼0.14, ^SE=0.09,^t= 1.57, aD=0.12).

0.03)than among males withlowMAOAactivity(b⁼0.68,^SE=0.12,^t=5.54, P<0.001).

We conducted furtheranalyses^{to testif the GXE}interactionwasrobustacross

each ofthe four measuresofantisocial behaviorthat made up the composite

index. Forall four antisocial outcomes, ^thepattern^offindings ^{wasconsistent}

136 ZSE,25. H. 2

withthe hypothesis^{that the}association between maltreatmentandantisocial behavior isconditional, depending^onthechild's MAOAgenotype(GXE^inter¬

action P⁼ 0.06, 0.05, 0.10, ^and 0.04, respectively). ^For adolescent conduct disorder(Fig. 2A),maltreated males(includingprobable^{andseverecases)with}

the low-MAOA activitygenotype^weremorelikelythan nonmaltreatedmales withthisgenotype^todevelopconduct disorderby^asignificant^{odds ratio}(OR) of 2.8 [95%^{confidenceinterval}(Cl): ^1.42to5.74].^Incontrast,amongmales withhigh^MAOAactivity,maltreatmentdidnotconfersignificant^{risk forcon¬}

ductdisorder(OR⁼ 1.54,95% Cl: 0.89to2.68).^Foradult violent conviction

(Fig. 2B),^{maltreatedmales with}the low-MAOAactivitygenotype^{were more} likelythan nonmaltreatedmales with thisgenotype^tobe convicted ofavio¬

lent crimeby^asignificantodds ratio of9.8 (95%^{Cl: 3.10to}31.15). ^Incon¬

trast,among maleswithhigh^MAOAactivity,maltreatmentdidnotconfersig¬

nificant risk for violent conviction (OR ⁼ 1.63, ^{95% Cl=0.72to} 3.68). ^For self-reported disposition^{towardviolence} (Fig. 2C)^and informant-reports ^of antisocialpersonality^disorderSymptoms(Fig. 2D),^{males withthe\ow-MAOA} activity genotype^{who weremaltreatedin}childhood had significantly ^eleva¬

ted antisocial scores relative to their \ow-MAOA counterparts ^{who were not} maltreated. In contrast, males withhigh^MAOA activity^didnothave elevated antisocial _scores,evenwhenthey^hadexperienced^childhoodmaltreatment.

Thesefindings provideinitial evidencethatafunctionalpolymorphism^{in the}

MAOA gene moderatestheimpact^ofearlychildhood maltreatmentonthe de¬

velopment ^ofantisocial behavior in males. Replications^{ofthis GXE inter¬}

actionare nowneeded.Replicationstudies shouldusevalidand reliableascer-

tainments ofmaltreatmenthistoryand should obtainmultiple^{measuresof anti¬}

social outcomes,ⁱⁿlargesamples^{of malesandfemales}(30).^Ifreplicated,^the findings^have implications ^forresearch and clinical practice. ^With regard ^to research in Psychiatric genetics, knowledge ^about environmental context

might help gene-huntersrefine theirphenotypes.^Geneticeffects in the popu¬

lation_{may be} dilutedacross all individuals inagivensample, ^{if theeffect is} apparentonlyamongindividualsexposed^tospecificenvironmental risks. With regard^{toresearchonchild}health, knowledge^aboutspecific genetic^risksmay

help^toclarify^riskprocesses. Numerousbiological^andpsychologicalproces¬

ses have beenput ^forwardto explain why^{and how} experiences ^ofmaltreat¬

mentareconverted into antisocialbehaviortowardothers(17,24, 31-34),^but there isnoconclusive evidencethat_anyof these_processescanaccountforthe

progression^fromchildhood maltreatmenttolater criminalviolence.Moreover,

someyoungsters^maketheprogression,^{but othersdo}not,^andresearchershave

sought^tounderstandwhy (35).The search has focusedonsocialexperiences that_mayprotect^somechildren,overlooking^apotentialprotective^roleofgenes.

Genesareassumedtocreatevulnerability^{todisease,butfroman}evolutionary perspectivethey^areequallylikely^toprotectagainstenvironmental insult(36).

Maltreatmentstudies maybenefitfromascertaininggenotypesassociated with

sensitivity ^tostress, and^the known functionalproperties of MAOA maypoint

towardhypotheses,^basedonneurotransmittersystemdevelopment,^abouthow

stressfulexperiences^{areconvertedintoantisocialbehaviortowardothersinsome,}

butnotall,victims of maltreatment.

Until this study's findings ^are replicated, speculation ^{aboutclinical} implica¬

tions ispremature.Nonetheless, althoughindividualshaving^thecombination

oflow-activity^MAOA genotypeand maltreatmentwereonly ^{12%ofthe male}

birthcohort,they^{accountedfor 44%}ofthe cohort's violentconvictions,yield- ing ^an attnbutable risk fraction (11%) comparable^to that of the major^risk

factors associated with cardiovascular disease(3 7).Moreover, ^{85%of cohort} maleshaving^alow-activity^MAOAgenotype^whowereseverely^{maltreateddevel¬}

oped ^{some form}of antisocial behavior. Both attributable riskandpredictive sensitivityindicate that thesefindingscould inform thedevelopment^{of future} pharmacologicaltreatments.

References and Notes

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Maser,^Eds.(Wiley,^NewYork, 1997).

5. K. S. Kendler, ^{Arch. Gen.} Psychiatry 58, ¹⁰⁰⁵ (2001). ^{6. M.} Rutter, ^J. Silberg, Annu. Rev.Psychol.53,⁴⁶³(2002).

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13.A.F. Jormetal,Psychiatr. ^{Genet. 10,87}(2000).

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19.G. W. Kraemer, ^{M. H.} Ebert, ^{D. E.} Schmidt, ^{W. T.} McKinney, Neuropsycho- pharmacologyl,¹⁷⁵(1989).^{20.A.J.Bennettet}al,^Mol.Psychiatry!, ¹⁸⁸(2002).

21. S. J.Suomi,in HandbookofDevelopmentalPsychopathology,^A.J.Sameroff, M.Lewis,^S.Miller,Eds. (Plenum,^NewYork, ⁱⁿpress).

22. M.E.Berman,^R.J.Kavoussi,^{E. F.}Coccaro,in Handbookof^AntisocialBehavior, D. M.Stoff,^J.Breiling,^J.D.Maser,^Eds.(Wiley,^NewYork, 1997).

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29. A.F.Jorm,^S.Easteal,^Soc.Psychiatry Psychiatr. Epidemiol 35, ¹ (2000).

30.Thisstudy^{focusedonmales}because theirsingle^Xchromosomeyields^twostraight- forwardlycharacterized MAOAgenotypes:highactivity (63%^inthissample)^and

lowactivity(37%).Females,having^twocopies^oftheXchromosome,^{fall intotwo} homozygousgroups,high-high(42%^{in this}sample),^low-low(12%),^andathird heterozygousgroup, low-high(46%),^thatcannotbe characterized withcertainty

because it isnotpossible^todetermine which of thetwoalleles is inactivated for eachfemaleparticipant.^{Given the}rarityⁱⁿfemales of both the low-lowgenotype