ORIGINAL ARTICLEEnvironmental Adversity and IncreasingGenetic Risk for Externalizing DisordersBrian M. Hicks, PhD; Susan C. South, PhD; Ana C. DiRago, MA; William G. Iacono, PhD; Matt McGue, PhDContext: Studies of gene-environment interplay in thedevelopment of psychiatric and substance use disordersare rapidly accumulating. However, few attempts havebeen made to integrate findings and to articulate gen-eral mechanisms of gene-environment influence in theemergence of psychopathology.Objective: To identify patterns of gene-environment in-terplay between externalizing disorders (antisocial be-havior and substance use) and several environmental riskfactors.Design: We used quantitative genetic models to exam-ine how genetic and environmental risk for externalizingdisorders changes as a function of environmental context.Setting: Participants were recruited from the commu-nity and took part in a daylong assessment at a univer-sity laboratory.Participants: The sample consisted of 1315 male andfemale twin pairs participating in the assessment of theMinnesota Twin Family Study at age 17 years.Main Outcome Measures: Multiple measures and in-formants were used to construct a composite of exter-nalizing disorders and composite measures of 6 environ-mental risk factors, including academic achievement andengagement, antisocial and prosocial peer affiliations,mother-child and father-child relationship problems, andstressful life events.Results: A significant gene ⫻ environment interactionwas detected between each environmental risk factorand externalizing such that greater environmentaladversity was associated with increased genetic risk forexternalizing.Conclusions: In the context of environmental adver-sity, genetic factors become more important in the eti-ology of externalizing disorders. The consistency of theresults further suggests a general mechanism of environ-mental influence on externalizing disorders regardless ofthe specific form of the environmental risk.Arch Gen Psychiatry. 2009;66(6):640-648VARIOUS LINES OF EVIDENCEtestify that genetic and en-vironmental factors con-tribute to psychiatric andsubstance use disorders.1Recently, psychiatric genetic research hasevolved beyond simple estimates of heri-table and nonheritable influences to in-vestigations that begin to delineate themechanisms of gene-environment inter-play. This includes studies using the spe-cific gene ⫻ measured environment de-sign,2with the most well-known examplebeing that variants of the 5-HTT gene in-crease risk for major depression in the con-text of stressful life events.3,4In addition,there is an accumulating literature of quan-titative genetic studies5-9that use twin,adoption, and family designs to delineateprocesses of gene-environment inter-play, such as how the relative contribu-tion of genetic and environmental risk fac-tors changes as a function of theenvironmental context. Although there hasbeen a veritable explosion in studies ofgene-environment interplay in psychopa-thology in recent years, there have beenfew attempts to integrate findings in an ef-fort to articulate more general principlesof gene-environment influence across dif-ferent environmental variables and psy-chiatric disorders.10-12Key questions thatremain unanswered include the follow-ing: Is the mechanism of environmentalinfluence the same regardless of the en-vironmental variable such as parenting,peers, or stressful life events? Or, do dif-ferent environmental variables exhibitvarying mechanisms of influence? Also, arethe mechanisms of gene-environment in-fluence the same for all types of psychi-atric disorders? For example, are pro-cesses of gene-environment interplay thesame or different for internalizing (majorAuthor Affiliations:Department of Psychology,University of Minnesota,Minneapolis.(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 6), JUNE 2009 WWW.ARCHGENPSYCHIATRY.COM640©2009 American Medical Association. All rights reserved. at University of Colorado - Denver HSL, on August 26, 2011 www.archgenpsychiatry.comDownloaded fromdepression and anxiety disorders) vs externalizing (an-tisocial behavior and substance use) disorders?We begin to answer these questions by examining gene-environment interplay processes between externalizingdisorders and 6 environmental risk factors in a large ado-lescent twin sample. By late adolescence, genetic risk forexternalizing disorders is largely nonspecific and is pri-marily attributable to a highly heritable general vulner-ability dimension (h2=0.80).13-15However, externaliz-ing disorders also exhibit strong associations withenvironmental variables (such as poor performance andlack of engagement in school,16,17deviant peer affilia-tion,18harsh discipline,19,20and poor parental monitor-ing21,22) and with various stressful life events (eg, pov-erty, parental discord, residential instability, and familialpsychopathology).23However, the mechanisms under-lying these associations are less well delineated.24For ex-ample, do these environmental risk factors cause exter-nalizing symptoms, or does genetic risk for externalizinginstigate selection processes that result in greater expo-sure to these environmental risk factors?Two gene-environment processes are essential to un-derstanding the etiology of psychiatric disorders. Gene-environment correlations are the first process and refer tothe fact that environmental risk is not distributed ran-domly but rather is, to some extent, a result of an indi-vidual’s decisions and actions (specifically, active and evoca-tive gene-environment correlations).24-27For example, thebehavior of preadolescents who exhibit childhood disrup-tive disorders or of adolescents who precociously use sub-stances can initiate a cascade of experiences, including weak-ened attachment to and increased conflict with parents,28,29poor performance and lack of engagement in school,16,17,30and stronger affiliation with deviant peers,31which in-creases risk of developing psychiatric and substance usedisorders in adulthood. Gene-environment correlations alsohelp account for the finding that almost every putatively“environmental” measure exhibits heritable variance.32,33That is, an individual’s genetically influenced characteris-tics, such as personality and intelligence, help to shape hisor her environment, including exposure to environmen-tal risk factors, which then increases risk for psychiatricdisorders.24,25Gene ⫻ environment interactions are the second pro-cess and refer to