[caspimoffitt]genenvironmentnatneuro

8/9/2019 [CaspiMoffitt]GenEnvironmentNatNeuro

1/8

mammalian nervous system. Curr. Opin. Neurobiol.

14, 617628 (2004).104. Miyawaki, A. Innovations in the imaging of brain

functions using fluorescent proteins. Neuron

48, 189199 (2005).

105. Barco, A., Alarcon, J. M. & Kandel, E. R. Expression

of constitutively active CREB protein facilitates the late

phase of long-term potentiation by enhancing synaptic

capture. Cell108, 689703 (2002).106. Woo, N. H. & Nguyen, P. V. Silent metaplasticity

of the late phase of long-term potentiation requires

protein phosphatases. Learn. Mem.9, 202213(2002).

107. Woo, N. H. & Nguyen, P. V. Protein synthesis is

required for synaptic immunity to depotentiation.

J. Neurosci.23, 11251132 (2003).108. Fiala, J. C. & Harris, K. M. in Dendrites (eds

Stuart, G., Spruston, N. & Husser, M.) 376

(Oxford Univ. Press, New York, 1999).

AcknowledgementsWe thank C. Stevens, M. Wilson and members of the Tonegawa

laboratory for helpful discussions, and critical reading of and

comments on the manuscript. Research was supported by the

RIKEN-MIT Neuroscience Research Center, Howard Hughes

Medical Institute and grants from the National Institutes of

Health (S.T. and R.J.K).

Competing interests statementThe authors declare no competing financial interests.

DATABASESThe following terms in this article are linked online to:

Entrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.cgi?db=gene

4EBP1 | 4EBP2 | BDNF | eEF1 | eIF4E | S6

Access to this links box is available online.

OPINION

Geneenvironment interactions

in psychiatry: joining forces withneuroscience

Avshalom Caspi and Terrie E. Moffitt

Abstract | Geneenvironment interaction research in psychiatry is new, and is a

natural ally o neuroscience. Mental disorders have known environmental causes,

but there is heterogeneity in the response to each causal actor, which gene

environment indings attribute to genetic dierences at the DNA sequence level.

Such indings come rom epidemiology, an ideal branch o science or showing that

geneenvironment interactions exist in nature and aect a signiicant raction o

disease cases. The complementary discipline o epidemiology, experimental

neuroscience, uels geneenvironment hypotheses and investigates underlying

neural mechanisms. This article discusses opportunities and challenges in the

collaboration between psychiatry, epidemiology and neuroscience in studying

geneenvironment interactions.

Geneenvironment interactions occurwhen the effect of exposure to an environ-mental pathogen on a persons health isconditional on his or her genotype. Thefirst evidence that genotype moderatesthe capacity of an environmental risk to

bring about mental disorders was reportedin 2002 (REF. 1). Although mental healthresearch into geneenvironment interac-tions is new, it seems to be gatheringmomentum. We argue that, to fulfill itspotential, geneenvironment interactionresearch must integrate with neuro-science. Moreover, the geneenvironmentinteraction approach brings excitingopportunities for extending the range andpower of neuroscience. Here, we examineopportunities for collaboration betweenexperimental neuroscience and research on

geneenvironment interactions. Successfulcollaboration can solve the biggest mysteryof human psychopathology: how doesan environmental factor, external to theperson, get inside the nervous system andalter its elements to generate the symptoms

of a disordered mind? Concentrating theconsiderable resources of neuroscienceand geneenvironment research on thisquestion will bring discoveries that advancethe understanding of mental disorders,and increase the potential to control andprevent them.

Psychiatric genetic approaches

The recent history of psychiatric researchthat has measured genetic differences atthe DNA sequence level can be dividedinto three approaches, each with its own

logic and assumptions. The first approachassumes direct linear relations betweengenes and behaviour (FIG. 1a). The goal of thisapproach has been to correlate psychiatricdisorders with individual differences inDNA sequence. This has been attemptedusing both linkage analysis and associationanalysis, with regard to many psychiatricconditions such as depression2, schizophre-nia3 and addiction4. Although a few geneshave accumulated replicated evidence ofassociation with disorder, replication failuresare routine and overall progress has beenslow5. Because of inconsistent findings,many scientists have despaired of the searchfor a straightforward association betweengenotype and diagnosis6, that is, for directmain effects.

The second approach has sought tomake more progress by replacing thedisorder outcomes with intermediate phe-

notypes, called endophenotypes (FIG. 1b).Endophenotypes are heritable neurophysio-logical, biochemical, endocrinological,neuroanatomical or neuropsychologicalconstituents of disorders7. Endophenotypesare assumed to have simpler geneticunderpinnings than disorders themselves.Therefore, this research approach pursuesthe hypothesis that it will be easier to iden-tify genes associated with endophenotypesthan genes associated with their correlateddisorders. Although this approach sub-stitutes the psychiatric diagnosis with anintermediate brain measure, it still searchesfor direct main effects.

The third approach to psychiatricgenetics, unlike the first two approaches,seeks to incorporate information about theenvironment (FIG. 1c). This geneenviron-ment interaction approach differs funda-mentally from the main-effect approaches,with regard to the assumptions about thecauses of psychiatric disorders. Main-effect approaches assume that genes causedisorder, an assumption carried forwardfrom early work that identified single-genecauses of rare Mendelian conditions. By

contrast, the geneenvironment interac-tion approach assumes that environmentalpathogens cause disorder, and that genesinfluence susceptibility to pathogens. Incontrast to main-effect studies, there is nonecessary expectation of a direct gene-to-behaviour association in the absence of theenvironmental pathogen. The geneenvi-ronment interaction approach has grownout of two observations: first, that mentaldisorders have environmental causes;second, that people show heterogeneity intheir response to those causes8.

P E R S P E C T I V E S

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Nature and nurture

Like other non-communicable diseases thathave common prevalence in the populationand complex multi-factorial aetiology, mostmental disorders have known non-genetic,environmental risk factors (that is, predictorswhose causal status is unproven) and/orenvironmental pathogens (that is, provencauses)9,10. Environmental pathogens havebeen documented for substance-use disor-ders11, antisocial disorders12, depression13, andeven schizophrenia-spectrum disorders14,15.The pool of environmental factors is currentlymore limited for disorders such as autism,Alzheimers-type dementia, and attention-deficit hyperactivity disorder (ADHD).Nevertheless, the concordance of monozy-gotic twins for even these highly heritabledisorders is less than perfect, indicating theexistence of non-genetic contributing causes.Environmental risk factors for mental disor-ders discovered to date include (but are notlimited to) maternal stress during pregnancy,maternal substance abuse during pregnancy,low birth weight, birth complications, depri-

vation of normal parental care during infancy,

childhood physical maltreatment, childhoodneglect, premature parental loss, exposureto family conflict and violence, stressful lifeevents involving loss or threat, substanceabuse, toxic exposures and head injury.

These environmental causes are con-sidered to be only contributory becauseexposure to them does not always generatedisorder. Both human and animal studiesconsistently reveal variability in individualsbehavioural responses to environmentalpathogens. Heterogeneity of response charac-terizes all known environmental risk factors

for psychopathology, including even the mostoverwhelming of traumas. Such responseheterogeneity is associated with pre-existingindividual differences in temperament,personality, cognition and autonomicphysiology, all of which are known to beunder genetic influence16. The hypothesis ofgenetic moderation implies that differencesbetween individuals, originating in the DNAsequence, bring about differences betweenindividuals in their resilience or vulnerabilityto the environmental causes of many patho-logical conditions of the mind and body. Thispathogenesis hypothesis is under study inrelation not only to mental disorders, but alsoto cancer17, diabetes18, and cardiovascular19,immune/infectious20,21 and respiratory22diseases.

Geneenvironment interaction studiesin psychiatry are new, but some of the initialfindings are intriguing. Our own studies pro-

vided proof of principle of this approach. Inthe first report of geneenvironment interac-tion in relation to behaviour, we tested thehypothesis that a functional polymorphismin the promoter region of the gene encoding

the neurotransmitter-metabolizing enzymemonoamine oxidase A (MAOA) wouldmoderate the effect of child maltreatmentin the cycle of violence. Results showed thatmaltreated children, whose genotype con-ferred low levels of MAOA expression, moreoften developed conduct disorder, antisocialpersonality and adult violent crime thanchildren with a high-activityMAOA geno-type1. In a second study, we proposed that afunctional polymorphism in the promoterregion of the serotonin transporter (5-HTT)gene would moderate the influence

of stressful life events on depression.Individuals with one or two copies of the5-HTT short allele exhibited more depres-sive symptoms, diagnosable depression, andsuicidality following stressful life events thanindividuals with two copies of the longallele23. A third study, by investigating thedifferential effects of cannabis on its users,demonstrated that geneenvironment inter-actions involve environmental pathogensapart from psycho-social risks. We suggestedthat a functional polymorphism in thecatechol-O-methyltransferase (COMT) genewould moderate the link between adolescentcannabis use and risk of developing adultpsychosis. Cannabis users carrying the

COMTvaline allele were likely to exhibitpsychotic symptoms and to develop schizo-phrenia-spectrum disorder, but cannabis usehad no such adverse influence on individualswith two copies of the COMTmethionine

allele24. Additional geneenvironment find-ings are emerging. In two studies of ADHD,polymorphisms in the dopamine systeminteracted with antenatal risk factors (forexample, low birth weight and maternaluse of alcohol) to predict key symptomsassociated with the disorder25,26. In anotherreport, polymorphisms in the glucocorticoidreceptor-regulating gene FKBP5 interactedwith acute injury to predict psychologicaldissociation, a key feature of post-traumaticstress syndrome27.

The study of geneenvironment interac-tions has been the province of epidemiol-ogy, in which genotypes, environmentalpathogen exposures and disorder outcomesare studied as they naturally occur in thehuman population28. Genetic epidemiol-ogy is ideal for achieving three goals. First,epidemiological studies identify the involve-ment of hypothesized geneenvironmentinteractions. Second, to increase confidencein the interaction, epidemiological studiesincorporate control factors necessary forruling out alternative explanations. Third,epidemiological studies attest whetheran interaction accounts for a non-trivial

proportion of the disorder in the humanpopulation. However, genetic epidemiologyis limited for understanding the biologicalmechanisms involved in an interaction, andtherefore its potential will be better realizedwhen it is integrated with experimentalneuroscience. Neuroscience can comple-ment psychiatric genetic epidemiology byspecifying the more proximal role of nervoussystem reactivity in the geneenvironmentinteraction (FIG. 1d). Such information aboutproximal mechanisms will be essential fordeveloping theory and treatments.

Figure 1 | Approaches to psychiatric genetics research. a| The gene-to-disorder approach

assumes direct linear relations between genes and disorder. b| The endophenotype approach replaces

the disorder outcomes with intermediate phenotypes. c | The geneenvironment interaction approach

assumes that genes moderate the eect o environmental pathogens on disorder. d | Neuroscience

complements the latter research by speciying the proximal role o nervous system reactivity in the

geneenvironment interaction.

Gene Disorder

Gene

a

b DisorderEndophenotype

Environmentc Disorder

Genotype

Environmentd Disorder

Genotype

Neural substrate reactivity


584 | JULY 2006 | VOLUME 7 www.nature.com/reviews/neuro


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Bootstrapping with neuroscience

The original impetus for conducting eachof our epidemiological geneenvironmentinteraction studies came from findingsthat had been established by neuroscienceresearch. We have subsequently observedthat, once a novel geneenvironmentinteraction is reported, a wave of new neu-roscience follows. This suggests a mutuallybeneficial relationship of bootstrappingbetween the two fields (FIG. 2).

In the initial phase of research into geneenvironment interactions, neuroscienceprovides building blocks that are needed toconstruct a hypothesis (FIG. 2a). The buildingblocks correspond to the three elements ofthe triad: the disorder, the environmentalpathogen and the genotype. First, evidenceis needed about which neural substrate isinvolved in the disorder. Second, evidence isneeded that an environmental cause of the

disorder has effects on variables indexingthe same neural substrate. Third, evidence isneeded that a candidate gene has functionaleffects on variables indexing that sameneural substrate. It is this convergence ofenvironmental and genotypic effects withinthe same neural substrate that allows for thepossibility of geneenvironment interac-tions. At present, such evidence concerningenvironmental and genotypic effects in rela-tion to neural substrate measures is sparse,and therefore geneenvironment interactionhypotheses are likely to be circumstantialat best, and flimsy at worst. But this situa-tion is steadily improving. When we wereconstructing our hypothesis regarding thegenetic moderation of the depressogeniceffects of stressful life events23, we were aidedby direct evidence linking the 5-HTTcandi-date gene to individual differences in physio-logical responsiveness to stress conditionsin three different experimental paradigms,including knockout mice29, stress-rearedrhesus macaques30 and human functionalbrain imaging31. Such helpful studies areuncommon as yet, but they are emerging.

In the second (epidemiological) phase

of research, the new geneenvironmentinteraction hypothesis is tested against data(FIG. 2b). Elsewhere, we have discussed poten-tial pitfalls of geneenvironment interactionstudies and have outlined strategiesto guide this research8,32. If the initial dataare consistent with the hypothesis, thefinding must be replicated to determinewhether it is sufficiently reliable to warrantfurther neuroscience investigations33. Mostgeneenvironment interaction findingshave emerged too recently to be evaluatedaccording to their replication records.

However, two of these findings are promis-ing. First, several studies have sought toreplicate the interaction between the high-and low-activityMAOA genotypes andmaltreatment3438; a meta-analysis revealeda significant pooled effect36. Second, posi-tive replications of the interaction between

5-HTT*long/5HTT*short genotypes andlife stress have also appeared3947, along withtwo failures to replicate48,49. It is importantto note that useful information can also begleaned from inconsistencies across studyfindings. For example, as more studies accu-mulate it will be possible to evaluate whetherthe moderating effect of the 5-HTTgenotypeon life stress is stronger among females ormales, younger adults or older adults, andfirst-onset or recurrent depression cases.

In the third phase of research, scientificactivity comes a full circle, back to neuro-science (FIG. 2c). A new wave of studies isstimulated, each aiming to illuminate theblack box of biology between the gene, theenvironmental pathogen, and the disorder50

(as illustrated in the triangle in FIG. 2). Forexample, evidence that variation in thepromoter region of the 5-HTTgene shapesdepressogenic responses to life stress has ledto more focused neuroscience research on agenetic susceptibility mechanism for stress-related depression5154. Similarly, evidence thata polymorphism in the MAOA gene mightcontribute to the cycle of violence in mal-treated children1 a hypothesis stimulatedby behavioural evidence from mouse knock-outs for MAOA55 and functional gene knock-outs in humans56 has, in turn, stimulated

efforts to probe circuits of emotional arousalin the brain by studying this polymorphism inimaging paradigms57 (see also BOX 1).

Enhancing neuroscience

A replicated finding on geneenvironmentinteractions adds new information, produc-ing a stimulating effect on neuroscience.The result of a reliable geneenvironmentinteraction finding is clear evidence for apathway of causal neural process connectingthe three disparate end points that form thetriad of gene, environmental pathogen anddisorder. The pathway might initially behidden from scientific view, but knowingthree endpoints (instead of two) enhancesthe likelihood of finding the neurobiologi-cal paths that unite them. Candidate genescan add information about where in thebody, cell and molecule the environmentalpathogens effect on disorder occurs.

A replicated finding on geneenviron-ment interactions yields at least threeinsights. First, the insight that the result of

exposure to an environmental pathogendepends on the persons genotype offersclues about the root beginnings of a causalpathway. Variation in the DNA sequenceantedates all other variables in the triad.Therefore, covariation between a measuredgenotype and a neural substrate variableis useful for making deductions about theposition of the neural substrate variable inthe causal chain. For example, if a studyshowed that amygdala activation in responseto emotional stimuli was abnormal indepressed subjects, this could indicate either

Figure 2 | Integrating neuroscience and geneenvironment interaction research. Neuroscience

provides the building blocks or constructing hypotheses about geneenvironment interaction (a) that

are tested against data (b), subsequently stimulating new studies to illuminate the black box o biology(c) between the gene (G), the environmental pathogen (E) and the disorder (D).

a Neuroscienceevidence base

b Epidemiological geneenvironmentinteraction research

c Experimentalneuroscience

Neuroscience NeuroscienceGeneenvionment interaction

Building blocks Hypothesis Finding New studies

Genetic variation

in neurosystemresponses toenvironments

1 Disorder linksto neural substrate N

D

EG

N2 Environmentafectsneural substrate N

3 Genotypeafects

neural substrate N

G ED




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a causal role for the amygdala in depres-sion, or a consequence of depression onthe amygdala. However, if such amygdalaactivation depends on the subjects genotype,this suggests that amygdala activation hasprecedence. Such precedence is not sufficientfor causation, but it is necessary.

Second, awareness of geneenvironmentinteractions can help to reveal stronger effects

in neuroscience data. Neuroscience variablesare generally responsive to environmentalinput. If responsiveness is under the influenceof hidden genetic variation within a researchsample, this unmeasured heterogeneitywill dilute findings. Returning to the priorexample, amygdala activation to an emotionalstimulus can appear positive but weak acrossall subjects in an experiment, as the result

of unwittingly averaging data from twogenotype groups, one of strong respondersand another of non-responders. If genetically

vulnerable subgroups can be identified foranalysis, modest associations may be revealedas stronger than previously thought.

Third, geneenvironment interactionsmight help to solve the perennial riddleof disorder-specific pathophysiology.Most environmental pathogens constitutea nonspecific risk for many disorders.For example, smoking influences cancer,osteoporosis, lung disease, heart diseaseand fetal growth; child maltreatment influ-ences both aggression and depression; birthcomplications influence both ADHD andschizophrenia. A potential explanation forwhy there are different outcomes from oneenvironmental pathogen is that the patho-gen is connected to each disorder through adifferent pathophysiological pathway; there

is little research into this, although genes ofknown functionality may offer clues.

Furthering geneenvironment research

Psychiatric genetics has earned an ignoblereputation for its methodological problems,but this reputation should not discourageneuroscientists from bringing genetics intotheir laboratories to study the genetic mod-eration of environmental pathogens effectson neural substrates. Many initial reports ofgene-to-disorder associations proved to befalse positives5, prompting the publicationof methodological warnings5860. However,most of the methodological problemsarise from the fact that genetic epidemiol-ogy is an observational discipline thatmeasures genotypes, environmental riskconditions and disorder outcomes as theynaturally occur. This observational methodinvolves several compromises to validity,but the same problems do not afflict theexperimental method. Therefore, experi-mental neuroscience paradigms will benefitgeneenvironment interaction researchby addressing some of the methodologicalconcerns that are now plaguing genetic

epidemiology, as explained below.First, there is concern about the need for

very large samples in genetics research61.In case-control studies, large samples areneeded because genetic effects are expectedto be very small. In cohort studies, smalleffects are also a concern, and there is theadded need for large samples due to the factthat the environmental exposure and/orthe disorder might have a low prevalence incohorts33. By contrast, experimental studieshave more control over the group sizes andintensity of environmental stimulus needed

Box 1 | How does genotype moderate the psychological effects of cannabis use?

Evidence from studies around the world shows that cannabis use is a statistical risk factor for the

emergence of psychosis, ranging from psychotic symptoms (such as hallucinations and delusions) to

clinically significant disorders (such as schizophrenia)93. However, most people who use cannabis do

not develop psychosis, which suggests that some individuals may be genetically vulnerable to its

effects. This hypothesis received initial support from research showing that the association between

cannabis use and psychosis outcome is most marked in subjects with an established vulnerability to

psychosis94

. However, the genetic risk involved was not specified. Subsequent research focused onrisk measured by individual differences on the catechol-O-methyltransferase (COMT) gene; in

particular, a valine allele at codon 158 producing more enzymatic activity and faster breakdown of

dopamine than the methionine allele. Both the COMTvaline allele77 and cannabis use95 have been

independently associated with brain endophenotypes for schizophrenia96,97. An epidemiological

study (see panel a) that traced a longitudinal cohort from prior to the onset of cannabis use (age 11

years), through to the peak risk period of psychosis onset (age 26 years), revealed that individuals

with one or more high-activity valine alleles (VAL/METor VAL/VAL) showed subsequent increased risk

of psychotic symptoms and psychosis-spectrum disorder if they used cannabis24. Cannabis use had

no such adverse influence on individuals with two copies of the methionine allele (MET/MET). But is

the quantification of drug exposure information using the self-reports of adolescent subjects

sufficiently accurate? Is it possible that valine-allele carriers who use cannabis are unusual in some

unmeasured way? And how does the valine allele influence sensitivity to cannabis? These questions

have been addressed by researchers in the Netherlands, who used an experimental design to extend

the epidemiological finding98. In their studies, subjects were tested on two occasions, separated by

1 week, as part of a double-blind, placebo controlled cross-over design. In randomized order, theyreceived either 0g or 300g -9-tetrahydrocannabinol (the principal component of cannabis) per

kilogram bodyweight. Cannabis affected cognition and state psychosis, but this was conditional on

COMTgenotype. As illustrated in panel b, individuals carrying two copies of the valine allele

exhibited more cannabis-induced memory and attention impairments than carriers of the

methionine allele, and were the most sensitive to cannabis-induced psychotic experiences. Further

research including the use of both animal and imaging paradigms is needed to provide a fuller

understanding of genetically moderated responses to cannabis99.

COMTgenotype

VAL/METMET/MET VAL/VAL MET/MET VAL/MET VAL/VAL

COMTgenotype

0

5

10

15

20

Schizophreniformd

isorderina

dulthood(%)

a

No adolescent cannabis useAdolescent cannabis use

(151

)(48)n

=n=

(311

)(91)

(148)

(54)

9

10

11

12

b

Memoryperformance:delayed

recognition

scoresonavisualmemorytask

Placebo conditionCannabis treatment condition

(19)

(19)

(35)

(35)

(20)

(20)




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to obtain a detectable effect62. Moreover,unlike mental disorders, neural substrateoutcome measures (such as emotionalarousal or adrenocorticotropic hormoneresponses) tend to be quantitatively distrib-uted such that low prevalence is not at issue.

Second, there is concern about geneenvironment correlation63,64. When genesinfluence the probability of subjects expo-sure to an environmental pathogen, thisresults in the contamination of measures ofenvironmental exposure with genetic varia-tion, thereby clouding interpretation ofthe findings. For example, the probabilityof experiencing certain stressful life eventsis known to be under partial genetic influ-ence, as is the tendency to expose oneself toenvironmental pathogens such as cannabisor tobacco. By contrast, experimental ran-dom assignment of subjects to the environ-mental risk condition rules out this type of

self-selection. For example, epidemiologistsstudy self-initiated cigarette smoking, whileneuroscientists can study participants thatare randomly assigned to nicotine exposure.

Third, there is concern about the dif-ficulty of achieving precise and reliable mea-sures of environmental exposure, particularlyif the exposure typically occurs over extendedperiods of the life course8,65. For example, itis very difficult to ascertain the frequency,timing and extent of the trauma that isentailed in stressful life events. Likewise, it isnotoriously difficult, using survey methods,to measure the amount of active drug thatis ingested during recreational cannabis useover many years. Experimental administra-tion of the environmental pathogen or stimu-lus with standardized dosage and timingrules out this concern.

Fourth, there is concern about the lowprior probability of a true association betweena disorder and any one among many thous-ands of genetic polymorphisms66. If little ornothing is known prior to a statistical test ofassociation between a gene and behaviour,then this results in a low prior probabilityof the hoped-for association, and any asso-

ciation uncovered could easily be a chancefalse positive result. Neuroscience researchenhances the prior probability of a candidategene being associated with disorder byconnecting that genotype with brain respon-siveness to a known environmental cause ofthe disorder. Thus, a key contribution fromexperimental neuroscience is evidence andtheory that supports the biological plausibilityof genetic hypotheses, which helps to preventfalse positives. Consider research in cognatemedical fields, where caffeine consumptionhas been linked to the risk of myocardial

infarction. Caffeine is metabolized by anenzyme (CYP1A2) in the liver, knowledgethat allowed researchers to test (and confirm)the hypothesis that carriers of the slowmetabolizer variant of theCYP1A2 gene are ata heightened risk of myocardial infarction67.As researchers learn more about genes, thebrain and environmental pathogens, the priorprobability of hypotheses will become stron-ger, and false positive gene findings fewer.

One caveat must be mentioned.Experiments that randomly assign subjectsto environmental pathogens will inevitablybe limited to using substitutes analogoustothe environmental pathogens that causemental disorders. Real environmentalpathogens are not amenable to experimentaladministration for three reasons: first, ethicsprohibit exposing humans to risk; second,

animal-model exposures cannot be equatedwith human exposures; and third, harmfrom naturally occurring environmentalpathogens often accumulates for months oryears longer than a laboratory experiment.These shortcomings of experimental geneenvironment interaction studies must beacknowledged. However, the shortcomingsare diminished where a chain of inferencecan link experimental findings involvingan analogue pathogen to epidemiologicalfindings involving its counterpart naturalenvironmental pathogen.

Towards a nomological network

A nomological network refers to theinterlocking system of laws the predictedpattern of theoretical relationships whichdefine a construct68. A chain of inferences isrequired to validate the claim that specificgeneenvironment interactions are sur-rounded by a nomological network of indi-

vidual supporting findings. In mental healthresearch, such an emerging nomologicalnetwork is illustrated by many approachesthat are used to understand the role of5-HTTgene variation in emotion regulationand emotional disorders69,70. We hope thatthe present article will encourage furthercollaboration between genetic epidemiologyand experimental neuroscience in a jointeffort to unravel the complex mechanismsthat underlie geneenvironment interac-

tions. We envisage six ways forward.First, animal models of environmental

pathogen exposure are needed (FIG. 3). Innon-human animals, both genotype andexposure to a pathogen can be manipulatedunder experimental control71,72. Studyingnon-human subjects is an advantagebecause they can be assigned to detrimentalconditions that are not permitted in humanstudies (for example, deprivation of maternalrearing). These experiments use differentstrains, genetically modified animals oranimals that have known human-relevant

Figure 3 | Exposure to adverse rearing, genotype and adrenocorticotropin hormone (ACTH)

levels. Inluence o exposure to early stress (peer rearing) on subsequent exaggerated responses o

the limbic-hypothalamic-pituitary-adrenal axis (LHPA) responses to stress is conditioned by serotonin

transporter gene promoter variation (rh-5HTTLPR) in rhesus macaques. When exposed to stress later

in lie, peer-reared animals with the short/long genotype had higher ACTH levels than animals with

the long/long genotype. There were no dierences between genotypes among animals reared with

their mothers (data rom REF. 105).

Mother-rearedPre-stressor

Short/long

Long/long

Post-stressor

0 100 200 300 400 500

ACTH

Pre-stressor

Post-stressor

0 100 200 300 400 500

ACTH

Peer-rearedPre-stressor

Short/long

Long/long

Post-stressor

0 100 200 300 400 500

ACTH

Pre-stressor

Post-stressor

0 100 200 300 400 500

ACTH

Genotyperh-5HTTLPR

Exposure to environmentalpathogenInant rearing condition orhesus macaques

Neural substrate reactivity measureACTH release under stress




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polymorphisms. The experiments measureresponsiveness through various physio-logical and behavioural phenotypes. Weemphasize the value of animal models ofenvironmental pathogen reactivity, ratherthan animal models of mental disorders.Animal models of mental disorders havebeen criticized because they cannotrepresent core cognitive symptoms of human

mental disorders73. By contrast, animalmodels of genetic susceptibility to environ-mental pathogens offer a valuable windowfor understanding the effects of pathogenexposure on disease processes7476.

Second, studies that compare humangenotype groups on their responses toexperimentally administered environmentalstimuli are needed. In the vanguard ofsuch research is imaging genomics, whichcompares the responses of genotype groupsusing functional neuroimaging measures7780.There is untapped potential in other

experimental psychopathology paradigms.We look towards a new wave of investiga-tions asking whether genotype influenceshumans responsiveness to emotion-elicitingstimuli, laboratory stress paradigms or otheranalogue environmental pathogens. Thesehuman geneenvironment experiments willuse neurophysiological, biochemical, endo-crinological, neuroanatomical, cognitive,

emotional or neuropsychological measuresas phenotypes. Likely examples mightinclude peripheral psychophysiologicalmeasures such as the electroencephalogram,electrodermal or heart rate reactivity8183 andadreno-cortical reactivity84 (see also BOX 2).

Third, more epidemiological cohortstudies should collect neurosciencemeasurements. Many ongoing cohortstudies are now adding DNA to their datacollection protocols. These longstandingcohort studies already have prospective lon-gitudinal histories of participants environ-

mental exposures and mental disorders thatmake them ideal for geneenvironmentinteraction research, if their participantsgenotypes are characterized8. New cohortstudies of geneenvironment interactionsare also being planned85,86. To the extentthat these studies incorporate neurosciencemeasures of individual differences (forexample, neuropsychological tests, heartrate reactivity and immune-system mark-ers), they will create opportunities tointegrate experimental and epidemiologicalfindings. Taking neuroscience measure-ments in large cohorts can be costly and, forfunctional imaging paradigms, prohibitive.However, with more measures in common,epidemiological findings about geneticallymoderated environment-to-disorder asso-ciations can be integrated with experimen-tal findings about genetically moderatedenvironment-to-brain associations (FIG. 1d).

Fourth, the characterization of subjectsgenetic vulnerability as opposed to theirresilience needs to move beyond singlegenetic polymorphisms. New approaches willuse information about biological pathwaysto identify gene systems and study sets ofgenetic polymorphisms that are active in thepathophysiology of a disorder87. For example,in relation to depression, information aboutthe biology of psycho-social stress8890 canbe used as a first step to characterize a set ofgenes that define a genotype that is vulnerableas opposed to resilient to stressful life events.Incorporating information about geneticpathways into geneenvironment interactionstudies will enhance explanatory power, but itwill also present unique statistical challengesrelated to the use of data-mining tools and thepooling of data across different studies33.

Fifth, although we have largely focusedon testing hypotheses about geneenviron-ment interactions using candidate genes,the geneenvironment interactionapproach might also aid the identif icationof new genes that are responsible for vul-nerability to a particular disease. Genome-wide scans for new disease genes, like most

designs in psychiatric genetics, aim to dis-cover genes that have direct main effects ondisease susceptibility91. However, this main-effects approach is inefficient for detectingnew genes whose effects are conditional onenvironmental risk. As a result, genes thatshow no direct connection to disordersin genome-wide scans may neverthelessbe connected to disorder through hiddengeneenvironment interactions. Genome-wide scans might be more powerful if genehunters recruit samples selected for knownexposure to an environmental pathogen for

Box 2 | Bringing genetics into experimental psychopathology

The use of experimental models in behavioural genomics is exemplified by research on substance-

use disorders. Rather than search for direct main-effect associations between candidate genes and

addiction, this research uses experimental paradigms to identify how genotype moderates

subjects reactions to environmental stimuli (such as to priming doses or drug cues) that are

associated with addictive substances. In one experiment, the researchers investigated whether a

functional variable number of tandem repeats (VNTR) polymorphism in the D4 dopamine receptor

gene (DRD4) affected craving after priming doses and drug cues. Participants were tested on twooccasions, randomly assigned to receive three alcoholic drinks on the first session and three control

drinks on the second session, or the reverse. Individuals carrying the DRD4 long (L) allele reported a

stronger urge to drink in the alcohol condition than in the placebo condition. By contrast,

individuals with two short DRD4 alleles (S) reported no differences in the urge to drink between the

two conditions100. Next, the investigators manipulated the putative pharmacological mechanism

that mediates the effect of DRD4 on craving. It was suggested that alcohol increases craving

through activation at the D4 receptor and that carriers of the DRD4*L allele are especially

vulnerable to this effect. Subjects classified as DRD4*L or DRD4*S were administered olanzapine (a

D4 antagonist that was proposed to block the ability of alcohol to trigger craving) or

cyprohyptadine (a control medication) prior to the alcohol-challenge study. Olanzapine was more

effective for DRD4*L subjects, helping to narrow the mediating mechanism involved in genetic

control of sensitivity to the environment101,102. These findings suggest that the DRD4 polymorphism

moderates craving after alcohol consumption, and indicate that DRD4*L individuals may be more

susceptible to losing control over drinking. But the DRD4 polymorphism is not simply a genetic risk

for alcohol abuse. Individuals carrying the L allele also experience more craving and arousal afterexposure to tobacco smoking cues, whereas DRD4*S individuals do not (data for the panelare fromREF. 103). This suggests that DRD4 may influence the incentive salience of appetitive stimuli more

generally, and offers a clue as to why different addictive disorders tend to co-occur in the same

individuals104.

DRD4 short Baseline

Post-exposure

DRD4 long

50 60 70 80 90 100

Baseline

Post-exposure

50 60 70 80 90 100

Craving

Craving

GenotypeDRD4 VNTR

in tobacco smokers

Exposure to environmentalstimulusa lit cigarette

Neural substrate reactivity measuresel-reported craving




7/8

the disorder they wish to study, and thenscan for genetic variants in subjects whohave, versus those who have not, developedthe disorder8. Known environmentalpathogens might be profitably exploited asresearch tools for gene hunting.

Sixth, any serious initiative to under-stand aetiology and inform prevention,including genetics, must be able to explainfundamental demographic patterns ofdisorder. The most solid facts we have aboutmost mental disorders are that prevalenceand incidence vary according to age andsex. There are two leading contenders forexplaining these differences92. First, thedemographic groups (such as males andfemales) could be equally vulnerable tocausal factors, but differentially exposedto them. Alternatively, the demographicgroups could be equally exposed to causalfactors, but differentially vulnerable to

them. To date, lacking a good empiricalhandle on biological vulnerability, researchhas made little progress towards under-standing age and sex differences in mentaldisorders. Geneenvironment interactionresearch, with its focus on hypotheses ofenvironmental exposure and biological

vulnerability, is ideally suited to investigateage and sex differences.

Mental disorders have well-documentedenvironmental causes. But why do somepeople who are exposed to an environmen-tal pathogen develop mental disorders,while others do not? Why do some disor-ders excessively afflict one sex or one agegroup? How can two people experiencingthe same environmental pathogen laterdevelop very different disorders? How doesan environmental pathogen, especiallyone that is psycho-social in its nature, getunder the skin to alter the nervous systemand generate mental disorders? All of theseimportant questions are questions aboutthe interaction between diathesis andstress, between host and pathogen and, inessence, between genotype and environ-ment. Neuroscience and geneenvironment

interaction research are joining forces tolook for answers.

Avshalom Caspi and Terrie Moffitt are at the Medical

Research Council Social, Genetic and Developmental

Psychiatry Centre, Institute of Psychiatry, Kings

College London, P0 Box 80 De Crespigny Park, London

SE5 8AF, UK.

They are also at the Department of Psychology,

University of Wisconsin, 1202 West Johnson Street,

Madison, Wisconsin 53706, USA.

Correspondence to A.C. or T.E.M.

e-mails: [email protected]; [email protected].

doi:10.1038/nrn1925

1. Caspi, A. et al. Role of genotype in the cycle of

violence in maltreated children. Science297,

851854 (2002).

2. Levinson, D. F. The genetics of depression. Biol.

Psychiatry 18 Nov 2005 (doi: 10.1016/

j.biopsych.2005.08.024).

3. Owen, M. J., Williams, N. H. & ODonovan, M. C. The

molecular genetics of schizophrenia: new findings

promise new insights. Mol. Psychiatry9, 1427

(2004).

4. Goldman, D., Orozsi, G. & Ducci, F. The genetics of

addictions: uncovering the genes. Nature Rev. Genet.6, 521532 (2005).

5. Insel, T. & Collins, F. S. Psychiatry in the genomics era.

Am. J. Psychiatry160, 616620 (2003).

6. Hamer, D. Rethinking behavior genetics. Science298,

7172 (2002).

7. Gottesman, I. I. & Gould, T. D. The endophenotype

concept in psychiatry: etymology and strategic

intentions.Am. J. Psychiatry160, 636645

(2003).

8. Moffitt, T. E., Caspi, A. & Rutter, M. Strategy for

investigating interactions between measured genes

and measured environments.Arch. Gen. Psychiatry

62, 473481 (2005).

9. Moffitt, T. E. The new look of behavioral genetics in

developmental psychopathology. Psychol. Bull.131,

533554 (2005).

10. Rutter, M. Environmentally mediated risks for

psychopathology: research strategies and findings.

J. Am. Acad. Child. Adolesc. Psychiatry44, 318

(2005).

11. Heath, A. C. & Nelson, E. C. Effects of the interaction

between genotype and environment: research into the

genetic epidemiology of alcohol dependence.Alcohol

Res. Health26, 193201 (2002).

12. Loeber, R. & Farrington, D. P. Serious and Violent

Juvenile Offenders: Risk Factors and Successful

Interventions (Sage, Thousand Oaks, California, 1998).

13. Kendler, K. S., Gardner, C. O. & Prescott, C. A. Toward

a comprehensive developmental model for major

depression in women.Am. J. Psychiatry159,

11331145 (2002).

14. Tsuang, M. T., Stone, W. S. & Faraone, S. V. Genes,

environment and schizophrenia. Br. J. Psychiatry178,

S18S24 (2001).

15. van Os, J., Krabbendam, L., Myin-Gerneys, L. &

Delespaul, P. The schizophrenia environment. Curr.

Opin. Psychiatry18, 141145 (2005).

16. Plomin, R., DeFries, J. C., McClearn, G. E. & McGuffin, P.

Behavioral Genetics (W. H. Freeman, New York, 2001).

17. King, M.-C., Marks, J. H. & Mandell, J. B. Breast and

ovarian cancer risks due to inherited mutations inBRCA1 and BRCA2. Science302, 643646 (2003).

18. ORahilly, S., Barroso, I. & Wareham, N. J. Genetic

factors in type 2 diabetes: the end of the beginning?

Science307, 370373 (2005).19. Corella, D. & Ordovas, J. M. Single nucleotide

polymorphisms that influence lipid metabolism:

interaction with dietry factors.Annu. Rev. Nutr.25,

341390 (2005).

20. Smith, M. W. et al. Contrasting genetic influence of

CCR2 and CCR5 variants on HIV-1 infection and

disease progression. Science277, 959965 (1997).21. Kotb, M. et al.An immunogenetic and molecular basis

for differences in outcomes of invasive group A

streptococcal infections. Nature Med.8, 13981404

(2002).

22. Kleeberger, S. R. & Peden, D. Gene-environment

interactions in asthma and other respiratory diseases.

Annu. Rev. Med.56, 383400 (2005).

23. Caspi, A. et al. Influence of life stress on depression:

moderation by a polymorphism in the 5-HTT gene.Science301, 386899 (2003).

24. Caspi, A. et al. Moderation of the effect of adolescent-

onset cannabis use on adult psychosis by a functional

polymorphism in the COMT gene: longitudinal

evidence of a gene X environment interaction.

Biol. Psychiatry57, 11171127 (2005).

25. Brookes, K.-J. et al.A common haplotype of the

dopamine transporter gene associated with attention-

deficit/hyperactivity disorder and interacting with

maternal use of alcohol during pregnancy.Arch. Gen.

Psychiatry63, 7481 (2005).

26. Thapar, A. et al. Catechol-O-methyltransferase gene

variant and birth weight predict early-onset antisocial

behavior in children with attention-deficit/hyperactivity

disorder.Arch. Gen. Psychiatry.62, 12751278

(2005).

27. Koenen, K. C. et al. Polymorphisms in FKBP5 are

associated with peri-traumatic dissociation in

medically injured children. Mol. Psychiatry10,

10581059 (2005).28. Khouri, M. J., Millikan, R., Little, J. & Gwinn, M. The

emergence of epidemiology in the genomics age.

Int. J. Epidemiol.33, 936944 (2004).

29. Murphy, D. L. et al. Genetic perspectives on the

serotonin transporter. Brain. Res. Bull.56, 487494

(2001).

30. Bennett, A. J. et al. Early experience and serotonin

transporter gene variation interact to influence primate

CNS function. Mol. Psychiatry7, 188122 (2002).

31. Hariri, A. R. et al. Serotonin transporter geneticvariation and the response of the human amygdala.

Science297, 400404 (2002).

32. Moffitt, T. E., Caspi, A. & Rutter, M. Measured gene-

environment interactions in psychopathology:

concepts, research strategies and implications for

research, intervention and public understanding of

genetics. Persp. Psychol. Sci.1, 527 (2006).

33. Hunter, D. J. Gene-environment interactions in

human diseases. Nature Rev. Genet.6, 287298

(2005).

34. Foley, D. L. et al. Childhood adversity, monoamine

oxidase A genotype, and risk for conduct disorder.

Arch. Gen. Psychiatry61, 738744 (2004).

35. Haberstick, B. C. et al. Monoamine oxidase A (MAOA)

and antisocial behaviors in the presence of childhood

and adolescent maltreatment.Am. J. Med. Genet

135B, 5964 (2005).

36. Kim-Cohen, J. et al. MAOA, early adversity and gene-

environment interaction predicting childrens mental

health: new evidence and a meta-analysis.

Mol. Psychiatry (in the press).37. Nilsson, K. W. et al. Role of monoamine oxidase A

genotype and psychosocial factors in male adolescent

criminal activity. Biol. Psychiatry59, 121127 (2005).

38. Young, S. E. et al. Interaction between MAO-A

genotype and maltreatment in the risk for conduct

disorder: failure to confirm in adolescent patients.

Am. J. Psychiatry163,10191025 (2006).39. Eley, T. C. et al. Gene-environment interaction analysis

of serotonin system markers with adolescent

depression. Mol. Psychiatry9, 908915 (2004).

40. Grabe, H. J. et al. Mental and physical distress is

modulated by a polymorphism in the 5-HT transporter

gene interacting with social stressors and chronic

disease burden. Mol. Psychiatry10, 220224

(2005).

41. Jacobs, N. et al. Stress-related negative affectivity and

genetically reduced 5-HTT function: evidence for

synergism in shaping risk for depression.Arch. Gen.

Psychiatry (in the press).

42. Kaufman, J. et al. Social support and serotonintransporter gene moderate depression in maltreated

children. Proc. Natl Acad. Sci.101, 1731617321

(2004).

43. Kaufman, J. et al. BDNF-5HTTLPR gene interactions

and environmental modifiers of depression in children.

Biol. Psychiatry59, 673680 (2006).

44. Kendler, K. S., Kuhn, J. W., Vittum, J., Prescott, C. A. &

Riley, B. The interaction of stressful life events and a

serotonin transporter polymorphism in the prediction

of episodes of major depression: a replication.Arch.

Gen. Psychiatry62, 529535 (2005).45. Wilhelm, K. A. et al. Life events, first depression onset

and the serotonin transporter gene. Br. J. Psychiatry

188, 210215 (2006).

46. Zalsman, G. et al.A triallelic serotonin transporter

gene promoter polymorphism.Am. J. Psychiatry (in

the press).

47. Mandelli, L. et al. Interaction between serotonin

transporter gene, catechol-O-methyltransferase gene

and stressful like events in mood disorders.Int. J. Neuropsychopharmacol. 7 Jun 2006 (doi :10.10

17/51461145706006882).

48. Gillespie, N. A., Whitfield, J. B., Williams, B., Heath, A.

C. & Martin, N. G. The relationship between stressful

life events, the serotonin transporter (5-HTTLPR)

genotype and major depression. Psychol. Med.35,

101111 (2005).

49. Surtees, P. G. et al. Social adversity, the serotonin

transporter (5HTTLPR) polymorphism and major

depressive disorder. Biol. Psychiatry59, 224229

(2006).

50. Merikangas, K. & Risch, N. Will the genomics

revolution revolutionise psychiatry?Am. J. Psychiatry

160, 625635 (2003).

51. Ansorge, M. S., Zhou, M., Lira, A., Hen, R. & Gingrich,

J. A. Early-life blockade of the 5-HT transporter alters

emotional behavior in adult mice. Science306,

879881 (2004).




8/8

52. Fox, N. et al. Evidence for a gene-environment

interaction in predicting behavioral inhibition in

middle childhood. Psychol. Sci.16, 921926 (2005).

53. Hariri, A. R. et al.A susceptibility gene for affective

disorders and the response of the human amygdala.

Arch. Gen. Psychiatry62, 146152 (2005).

54. Pezawas, L. et al. 5-HTTLPR polymorphism impacts

human cingulate-amydala interactions: A genetic

susceptibility mechanism for depression. Nature

Neurosci.8, 828834 (2005).

55. Cases, O. et al.Aggressive behavior and altered

amounts of brain serotonin and norepinephrine inmice lacking MAOA. Science268, 17631766

(1995).

56. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers,

H. H. & Vanoost, B. A. Abnormal-behavior associated

with a point mutation in the structural gene for

monoamine oxidase-A. Science262, 578580 (1993).

57. Meyer-Lindenberg, A. et al. Neural mechanisms of

genetic risk for impulsivity and violence in humans.

Proc. Natl Acad. Sci.103, 62696274 (2006).

58. Bearden, C., Reus, V. I. & Freimer, N. B. Why genetic

investigation of psychiatric disorders is so difficult.

Curr. Opin. Genet. Dev.14, 280286 (2004).

59. Colhoun, H. M., McKeigue, P. M. & Smith, G. D.

Problems of reporting genetic associations with

complex outcomes. Lancet361, 865872 (2003).

60. Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S.

& Hirschhorn, J. N. Meta-analysis of genetic

association studies supports a contribution of

common variants to susceptibility to common disease.

Nature Genet.33, 177182 (2003).

61. Plomin, R. & Crabbe, J. DNA. Psychol. Bull.126,

806828 (2000).

62. McClelland, G. H. & Judd, C. M. Statistical difficulties

of detecting interactions and moderator effects.

Psychol. Bull.114, 376390 (1993).

63. Plomin, R. & Bergeman, C. S. The nature of nurture:

genetic influence on environmental measures. Behav.

Brain. Sci.14, 373386 (1991).64. Rutter, M., Moffitt, T. E. & Caspi, A. Gene-environment

interplay and psychopathology: multiple varieties but

real effects.J. Child. Psychol. Psychiatry47,

226261 (2006).

65. Wong, M. Y., Day, N. E. , Luan, J. A., Chan, K. P. &

Wareham, N. J. The detection of gene-environment

interaction for continuous traits: should we deal with

measurment error by bigger studies or better

measurement? Int. J. Epidemiol.32, 5157 (2003).

66. Sullivan, P. F., Eaves, L. J., Kendler, K. S. &

Neale, M. C. Genetic case-control association studies

in neuropsychiatry.Arch. Gen. Psychiatry.58,

10151024 (2001).67. Cornelis, M. C., El -Sohemy, A., Kabagambe, E. K. &

Campos, H. Coffee, CYP1A2 genotype, and risk of

myocardial infarction.JAMA10, 11351141 (2006).

68. Cronbach, L. J. & Meehl, P. E. Construct validity in

psychological tests. Psychol. Bull.52, 281302

(1955).

69. Hariri, A. R. & Holmes, A. Genetics of emotional

regulation: the role of the serotonin transporter in

neural function. Trends Cogn. Sci.10, 182191

(2006).

70. Leonardo, E. D. & Hen, R. Genetics of affective and

anxiety disorders.Annu. Rev. Psychol.57, 117137

(2006).

71. Crabbe, J. C. in Behavioral Genetics in the

Postgenomic Era (eds Plomin, R., DeFries, J. C., Craig,

I. W. & McGuffin, P.) 291308 (American

Psychological Association, Washington, 2003).

72. Flint, J. in Behavioral Genetics in the Postgenomic Era

(eds Plomin, R., DeFries, J. C., Craig, I. W. &

McGuffin, P.) 425442 (American PsychologicalAssociation, Washington DC, 2003).

73. Cryan, J. & Holmes, A. The ascent of mouse: advances

in modelling human depression and anxiety. Nature

Rev. Drug Discov.4, 775790 (2005).

74. Carola, V., Frazzetto, G. & Gross, C. Identifying

interactions between genes and early environment in

the mouse. Genes Brain Behav.5, 189199 (2006).

75. Holmes, A., Murphy, D. L. & Crawley, J. N. Abnormal

behavioral phenotypes of serotonin transporter

knockout mice: parallels with human anxiety and

depression. Biol. Psychiatry54, 953959 (2003).

76. Lipoldova, M. & Demant, P. Genetic susceptibility to

infectious disease: lessons from mouse models of

leishmaniasis. Nature Rev. Genet.7, 294305

(2006).77. Egan, M. F. et al. Effect of COMT Val108/158Met genotype

on frontal lobe function and risk for schizophrenia.Proc.

Natl Acad. Sci.98, 69176922 (2001).

78. Egan, M. F. et al. The BDNF val66met polymorphism

affects activity-dependent secretion of BDNF and

human memory and hippocampal function. Cell112,

257269 (2003).

79. Hariri, A. R., Drabant, E. M. & Weinberger, D. R.

Imaging genetics: perspectives from studies of

genetically driven variation in serotonin function and

corticolimbic affective processing. Biol. Psychiatry59,

888897 (2006).80. Heinz, A. et al.Amygdala-prefrontal coupling depends

on a genetic variation of the serotonin transporter.

Nature Neurosci.8, 2021 (2005).81. Fallgatter, A. J. et al.Allelic variation of serotonin

transporter function modulates the brain electrical

response for error processing.

Neuropsychopharmacology 29, 15061511 (2004).82. Battaglia, M. et al. Influence of the serotonin

transporter promoter gene and shyness on childrens

cerebral responses to facial expressions.Arch. Gen.

Psychiatry62, 8594 (2005).

83. Finley, J. C. et al.A genetic polymorphisn of the -2-

adrenergic receptor increases autonomic responses to

stress.J. Appl. Physiol.96, 22312239 (2004).

84. Wust, A. F. et al. Common polymorphisms in the

glucocorticoid receptor gene are associated with the

adrenocorticol responses to psychosocial stress.

J. Clin. Endocrinol. Metab.89, 565573 (2004).

85. Collins, F. S. The case for a US prospective cohort

study of genes and environment. Nature429,

475477 (2004).

86. Wright, A. F., Carothers, A. D. & Campbell, H. Gene-

environment interactions the Biobank UK study.

J. Pharmacogenomics2, 7582 (2002).87. Hattori, E., Liu, C., Zhu, H. & Gershon, E. S. Genetic

tests of biological systems in affective disorders. Mol.

Psychiatry10, 719740 (2005).

88. Charney, D. S. Psychobiological mechanisms of

resilience and vulnerability: implications for successful

adaptation to extreme stress.Am. J. Psychiatry161,

195216 (2004).89. de Kloet, E. R., Jols, M. & Holsboer, F. Stress and the

brain: from adaptation to disease. Nature Rev.

Neurosci.6, 463475 (2005).

90. Heim, C., Plotsky, P. M. & Nemeroff, C. B. Importance

of studying the contributions of early adverse

experience to neurobiological findings in depression.

Neuropsychopharmacology 29, 641648 (2004).

91. Hirschhorn, J. N. & Daly, M. J. Genome-wide

association studies for common diseases and complex

traits. Nature Rev. Genet.6, 95108 (2005).92. Rutter, M., Caspi, A. & Moffitt, T. E. Using sex

differences in psychopathology to study causal

mechanisms: unifying issues and research strategies.J. Child. Psychol. Psychiatry44, 10921115

(2003).

93. Arseneault, L., Cannon, M., Witton, J. & Murray, R. M.

Causal association between cannabis and psychosis:

examination of the evidence. Br. J. Psychiatry184,

110117 (2004).

94. Henquet, C. et al. Prospective cohort study of

cannabis use, predisposition for psychosis and

psychotic symptoms in young people. Br. Med. J.330,

1115 (2005).

95. Solowij, N. S. et al. Cognitive functioning of long-term

heavy cannabis users seeking treatment.JAMA287,

11231131 (2002).

96. Bunney, W. W. & Bunney, B. G. Evidence for a

compromised dorsolateral prefrontal cortical parallel

circuit in schizophrenia. Brain Res. Rev.31, 138146

(2000).

97. Weinberger, D. R. et al. Prefontal neurons and the

genetics of schizophrenia. Biol. Psychiatry50,

825844 (2001).

98. Henquet, C. et al.An experimental study of COMT Val-

158-Met moderation of cannabis-induced effects on

psychosis and cognition (manuscript in preparation).

99. Castle, D. & Murray, R. Marijuana and Madness

(Cambridge University Press, Cambridge, 2004).100. Hutchison, K. E., McGeary, J., Smolen, A., Brayn, A. &

Swift, R. M. The DRD4 VNTR polymorphism

moderates craving after alcohol consumption. Health

Psychol.21, 139149 (2002).101. Hutchison, K. E. et al. Olanzapine reduces craving for

alcohol: a DRD4 VNTR polymorphism by

pharmacotherapy interaction.

Neuropsychopharmacology 28, 18821888 (2003).

102. Hutchison, K. E. et al. The effect of olanzapine on

craving and alcohol consumption.

Neuropsychopharmacology 31,13101317 (2006).

103. Hutchison, K. E., La Chance, H., Naiura, R., Bryan, A.

& Smolen, A. The DRD4 VNTR polymorphism

influences reactivity to smoking cues.J. Abnorm.

Psychol.111, 134143 (2002).

104. Slutske, W. S., Caspi, A., Moffitt, T. E. & Poulton, R.

Personality and problem gambling: a prospective

study of a birth cohort of young adults.Arch. Gen.

Psychiatry.69, 769775 (2005).

105. Barr, C. S. et al. Rearing condition and rh5-HTTLPR

interact to influence limbic-hypothalamic-pituitary-

adrenal axis response to stress in infant macaques.

Biol. Psychiatry55, 733738 (2004).

AcknowledgementsSupported by the UK Medical Research Council, the National

Institute of Mental Health, National Institutes of Health, the

William T. Grant Foundation, and Royal Society Wolfson Merit

Awards to T.E.M. and A.C. We thank the reviewers for their

helpful comments.

Competing interests statementThe authors declare no competing financial interests.

DATABASESThe following terms in this article are linked online to:

Entrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.cgi?db=gene

5-HTT|COMT|DRD4 |MAOA

OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.cgi?db=OMIM

ADHD

FURTHER INFORMATIONCenter for Disease Control, Office of Genomics and

Disease Prevention: http://www.cdc.gov/genomics

Kyoto Encyclopedia of Genes and Genomes (KEGG):

http://www.genome.ad.jp/kegg/

UK Biobank: http://www.ukbiobank.ac.uk/

US National Institute of Environmental Health Sciences

Environmental Genome Project:

http://egp.gs.washington.edu

Access to this links box is available online.

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