Molecular Psychiatry (2009), 1–9& 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00
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PERSPECTIVE

Vulnerability genes or plasticity genes?
J Belsky1, C Jonassaint2, M Pluess1, M Stanton2, B Brummett3 and R Williams3
1
Institute for the Study of Children, Families and Social Issues, Birkbeck University of London, London, UK; 2Departmentof Psychology, Duke University, Durham, NC, USA and 3Department of Psychiatry, Duke University Medical Center, Durham,
NC, USAThe classic diathesis–stress framework, which views some individuals as particularly
vulnerable to adversity, informs virtually all psychiatric research on behavior–gene–environment (G  E) interaction. An alternative framework of ‘differential susceptibility’ is proposed,
one which regards those most susceptible to adversity because of their genetic make up as
simultaneously most likely to benefit from supportive or enriching experiences—or even justthe absence of adversity. Recent G  E findings consistent with this perspective and involving
monoamine oxidase-A, 5-HTTLPR (5-hydroxytryptamine-linked polymorphic region polymorphism) and dopamine receptor D4 (DRD4) are reviewed for illustrative purposes. Results
considered suggest that putative ‘vulnerability genes’ or ‘risk alleles’ might, at times, be more
appropriately conceptualized as ‘plasticity genes’, because they seem to make individuals
more susceptible to environmental influences—for better and for worse.
Molecular Psychiatry advance online publication, 19 May 2009; doi:10.1038/mp.2009.44
Keywords: genetics; environment (G  E); parenting; life events

Introduction
Central to the field of psychiatric genetics is thesearch for ‘vulnerability genes’.1 Particularly important in this search is uncovering the mechanisms
whereby such genes influence disease risk, anddetermining whether they are directly associatedwith more general psychological and behavioral
disturbance (that is, act through ‘main effects’) or
whether they are principally related to dysfunction
only under specific environmental conditions or in
response to particular developmental experiences(that is, act through ‘gene-  -environment (G  E)
interaction’). Findings of studies linking candidate
vulnerability genes (or ‘risk alleles’) directly to
specific psychopathological conditions have provennotoriously difficult to replicate.1
Failure to replicate direct effects of candidate
vulnerability genes on specific psychopathologicalconditions suggests that genes may not influence
behavior directly, leading many investigators to
examine how genes may moderate effects of theenvironment on human G  E interaction. One wellstudied G  E interaction involves monoamine oxidase-A (MAOA), contextual adversity and antisocial
behavior. The interaction of a functional MAOA gene
polymorphism (MAOA-uVNTR) and childhood adversity, first detected by Caspi et al.2 in their research
Correspondence: Professor J Belsky, Institute for the Study ofChildren, Families and Social Issues, Birkbeck University of
London, 7 Bedford Square, London WC1B 3RA, UK.
E-mail: j.belsky@bbk.ac.uk
Received 15 January 2009; revised 10 March 2009; accepted 13
April 2009

on child maltreatment, has now been replicatedenough times that meta-analysis reveals it to bereliable3—despite claims by some to the contrary.4
Thus, there is growing evidence that individuals
possessing the low-MAOA-activity allele are predisposed to become antisocial when they experience avariety of adverse experiences, most notably maltreatment in childhood.
It is not just in the case of the MAOA gene that thenotion of genetic vulnerability takes center stage in
research on G  E interactions. Consider the evidence
showing that the ‘s’ allele of the 5-hydroxytryptamine-linked polymorphic region polymorphism(5-HTTLPR) is associated with increased depression
in a high-stress context, with the ‘l’ allele functioning
protectively.5 Several studies have replicated thisfinding, providing further support for the conclusionthat 5-HTTLPR increases vulnerability to depression
in the context of environmental stress.6
The fundamental premise of this essay, however, isthat viewing relations among genes, behavior and theenvironment from the perspective of the classic
diathesis–stress model of psychopathology, as somuch psychiatric genetic research on G  E interaction does, may distort these relations and thereby
undermine, rather than advance, the understanding of
how genes and environment collectively operate toshape behavior and development, including risk ofmental illness. Central to the diathesis–stress modelis the postulate that some individuals are at heightened risk—because of their genetic make up—of
succumbing to psychological disturbance when theyencounter adversity, whereas others, lacking thegenetic vulnerability, are not so affected even whenVulnerability genes or plasticity genes?
J Belsky et al2

exposed to the very same adversity. Thus, whereas anindividual with a particular genetic vulnerability will
be prone to develop a genetically specific disorder if
he or she experiences what could be some particular or
any of a variety of environmental stressors (for example, child abuse, negative life events, death of parent),
the same environmental exposure will not engender
psychopathology in an individual possessing a different version of the candidate gene in question.7
An alternative to the diathesis–stress framework at
the heart of genetic vulnerability thinking is the one
which presupposes that it is not so much that
individuals vary only in their susceptibility toadversity vis-à-vis psychopathology, but rather thatthese putatively ‘vulnerable’ individuals are actuallymore susceptible and, thus, responsive to both
positive and negative environmental conditions, thatis, in a ‘for better and for worse’ manner. Thisdifferential-susceptibility perspective does not justcontend, as many have, that genes are neither
inherently good or bad, or even that their developmental and behavioral effects depend on person–
environment fit,8,9 but rather—and distinctively—that
individuals vary in their plasticity or susceptibility toenvironmental influences. Thus, the very genes that
seem—in so much psychiatric genetic research—to
make individuals disproportionately vulnerable toadversity vis-à-vis psychopathology may, simultaneously, confer on them an advantage when it comesto benefiting from exposure to environmental support
or enrichment (for example, nurturance), including
just the absence of adversity. Were this the case, itwould seem more appropriate to speak of ‘plasticity
genes’ rather than ‘vulnerability genes’ and of highly
plastic or malleable individuals rather than the socalled vulnerable ones. Boyce and Ellis,10 although
not directly concerned with G  E effects, which is thefocus of this paper, also have argued that individuals
vary in their susceptibility to environmental influences, what they refer to as ‘biological sensitivity tocontext.’ However, there is no presumption in theirwork that such malleability is a function of genotype,as they intriguingly entertain the prospect thatexperience can shape plasticity.
Ultimately, the purpose of this paper is not so muchto challenge the view that diathesis–stress phenomena exist or that processes related to them operate.
That seems indisputable. However, it is to contend—
and illustrate empirically—that in many cases,
wherein this may seem to be so, something different
may be occurring, yet go virtually unnoticed as aresult of expectations derived from the prevailingconceptual perspective, which guides both inquiry
and interpretation of findings. Indeed, a central claimof this paper is that the disproportionate attention
paid to the negative effects of contextual adversity,
broadly defined and varied in its operationalization,on the problematic functioning and on disturbances
in development and mental health, may actually leadscholars to mischaracterize environmental influences,
as well as human development processes and phe-

Molecular Psychiatry

nomena. And this is because, as stipulated by thedifferential-susceptibility hypothesis,11–14 ‘the verysame individuals who may be most adversely affectedby many kinds of stressors, may simultaneously reap
the most benefit from environmental support andenrichment (including the absence of adversity)’.
In the primary body of this paper, we provide
extensive but still illustrative G  E evidence to thiseffect, most of it very recent and much of which hasgone unnoticed, even at times by the investigators
generating it. What follows should not be regarded as
an exhaustive review of the literature; however, norshould it be seen to imply, much less demonstrate,that evidence of differential susceptibility outweighs
evidence of diathesis–stress, either in the literature asa whole or even in each and every study cited forillustrative purposes. To make the case, as we
exclusively seek to, that differential susceptibility
seems operative in human development and functioning, but that individual differences in plasticity
have been largely overlooked—in favor of prevailingviews that some individuals are simply more vulnerable to adversity than others—it is our contention thatan admittedly selective compilation of illustrativeG  E findings is exactly what is appropriate at thepresent time. This would seem especially so in lightof the fact that almost all the available human G  E
research focuses on both a restricted range ofenvironments, typically emphasizing the negative
end of the spectrum and failing to measure at all the
positive (except for the absence of adversity), and a
restricted range of psychological and behavioral outcomes, also typically emphasizing the negative,
thereby failing to assess competent functioning (except for the absence of dysfunction). As a result of
these design characteristics of so many G  E investigations, it remains unknown whether extensive
evidence consistent with a diathesis–stress modeland seemingly inconsistent with a differential-susceptibility framework is an accurate reflection ofG  E processes or an artefact of study designs. Quite
conceivably, simply treating the absence of adversity
as the ‘good’ end of the environmental-exposure
continuum and/or absence of a disorder as the ‘good’
end of the psychological functioning continuum maylead to the under-detection of differential-susceptibility findings and an over representation of vulnerability ones. It is for these reasons that it is consideredappropriate at the present time to provide illustrative
evidence of apparent differential-susceptibility effects
rather than undertake a formal meta-analysis of G  Efindings in hopes of determining which model fits thedata better.

Illustrative evidence: MAOA, 5-HTTLPR, dopamine
receptor D4 (DRD4)
Belsky et al.13 recently delineated a series of empiricalrequirements, or steps, for convincingly establishingevidence of differential susceptibility to environmental influence, that is, individual differences inVulnerability genes or plasticity genes?
J Belsky et alplasticity. The first concerns the application of conventional statistical criteria for evaluating genuine
moderation of a putative environmental influence byan organismic plasticity or susceptibility factor,15
including genotype, with some emphasis on excluding interactions with regression lines that do not cross(sometimes referred to as removable interactions).
The next steps distinguish differential susceptibility
from person–environment correlations, includingGene–Environment ones, which may reflect evocative
effects of person characteristics on environmental
experiences and from diathesis–stress models. If the(genetic) susceptibility factor and the (problematic)
outcome are related, diathesis–stress is suggested. The
specificity of the differential-susceptibility effect isdemonstrated if the model is not replicated when other(genetic) susceptibility factors (that is, moderators) andoutcomes are used.16,17 Differential susceptibility isthus demonstrated when the moderation reflects acrossover interaction that covers both the positive andthe negative aspects of the environment, with the positive typically (and unfortunately) represented by themere absence of adversity. The slope for the susceptible
subgroup should be significantly different from zeroand at the same time significantly steeper than theslope for the non-(or less-) susceptible subgroup.
In the remainder of this section, we present
illustrative G  E evidence of differential susceptibility to environmental influence that are consistent
with the view that individuals differ in theirplasticity, with some being more affected than others
by experiential influences in a for-better-and-forworse manner. Perhaps, because so much of the work
to be cited is new—and often conducted with adiathesis–stress frame of reference in mind—it isactually rare for investigations to address all or evenmost of the statistical criteria highlighted by Belsky
et al.13 for providing convincing evidence of differential susceptibility to environmental influence. Indeed, even when investigators detect statistical interactions of a crossover nature, as is the case in all the
researches to be cited, different strategies of following
up such interactions are adopted to illuminate theirnature. Whereas some investigations adopt a grouping
approach for dealing with the interacting predictor
variables, plotting or tabling sub-group means, others
calculate and contrast slopes reflecting the differential predictive relation between the continuously
measured environmental predictor and outcome forgroups that differ on the moderating susceptibility
factor. Only rarely is it reported whether such slopes
differ significantly from each other, as would be preferable when the moderator does not have a natural
break point, but is a continuous dimension (but as
is not be required when the moderator is naturally
categorical with only two categories). Perhaps analogously, it is not always reported when the subclassmeans are plotted and exactly which mean differs
significantly from which others.
In the service of illustrating what seems to be
individual differences in plasticity, and thus, differ-ential susceptibility in existing G  E research, we
adopt a liberal standard of evidence once a significant
crossover interaction has been detected when it
comes to regarding the results as evidence ofdifferential susceptibility to environmental influences. Specifically, and with regard to subgroupmeans, if one subgroup shows both the highest andthe lowest mean of all susceptibility-factor-defined
subgroups (for example, short vs long 5-HTTLPR
allele) on an outcome with regard to the environmental effect in question, this is interpreted as in linewith the for-better-and-for-worse differential-susceptibility patterning of results. Similarly, but with regard
to slopes, whenever they indicate that one subgroupdefined on the basis of the susceptibility factor inquestion would score highest and lowest given theenvironmental influence under investigation (that is,
steepest slope), this too is interpreted as evidence ofdifferential susceptibility. All the findings to bepresented meet these criteria, with some pertaining
to MAOA, some to 5-HTTPLR and some to DRD4.

3

Monoamine oxidase-A
Often unnoticed in Caspi et al.’s2 groundbreaking
G  E research showing that males with the less active
version of the MAOA gene proved most antisocial inyoung adulthood when they experienced maltreatment in childhood, is that individuals with the same
MAOA allele scored lowest in anti-social behavior
when not exposed to child maltreatment, even if notby much. A re-interpretation of this study’s results interms of plasticity and differential susceptibility
rather than vulnerability and diathesis stress would
seem viable given results of a significant number ofefforts to replicate the findings. For example,
Kim-Cohen et al.3 studied 975 boys to determine
whether the MAOA polymorphism moderated effects
of mother-reported physical abuse in early childhoodon later mental health problems. At age 7 years, boys
with the low-MAOA-activity variant were rated bymothers and teachers as having more mental healthproblems—and specifically attention-deficit hyperactivity disorder (ADHD) symptoms—if they had been
victims of abuse, but fewer problems if they had not,compared with boys with the high-MAOA-activity
genotype. In another longitudinal study, this one of
514 adolescent twin boys aged 8–17 years, Foley etal.18 found that childhood adversity—based on parent
and child report—predicted a 3-month history of
conduct disorder (DSM-III, Diagnostic and Statistical
Manual (of mental disorders)) differently for children
with and without the low-activity-MAOA allele.
Once again, boys with the low-MAOA-activity allele
were more likely to be diagnosed with conductdisorder if exposed to higher levels of childhood
adversity and less likely if exposed to lower levels ofadversity, compared with boys with the high-MAOAactivity allele. Similar results emerged in Nilsson
et al.’s19 cross-sectional investigation of 81 adolescentboys when the predictor was psychosocial risk,
operationalized in terms of maltreatment experience
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Vulnerability genes or plasticity genes?
J Belsky et al

4

and living arrangement. Only boys with the lowMAOA-activity allele were affected by such risk, suchthat those with a history of adversity engaged in morecriminal behavior (composite of vandalism, violence,stealing) and those lacking this history engaged in less.
Three additional studies extend the Caspi et al.2
findings: one was a prospective investigation of 631
male and female, and white and black victims of(court-substantiated) child abuse and neglect, alongwith a comparison group matched on age, sex, race/
ethnicity and social class background;20 the second
one a retrospective study of 235 adult psychiatricoutpatients and healthy controls who reported ontrauma experienced in childhood and physicalaggression in adulthood;21 and the last one a crosssectional retrospective study with an American
Indian sample of 291 adult women, 50% of whom
had a history of childhood sexual abuse.22 White (butnot black) males and females with the low-MAOAactivity allele in the longitudinal study manifested
the most lifetime violent and antisocial behavior
during adolescence, as well as around age 40, if they
had been maltreated, but the least (at both times ofmeasurement) if they had not been victims of abuse.
In the second study, men (only) with the low-MAOAactivity variant reported more physical aggression if
they experienced one or more (retrospectively reported) objective traumatic events while growing up(for example, death of mother, severe physical handicap of sibling) and less physical aggression if there
was no history of trauma, compared with highMAOA-activity men (for whom trauma proved unrelated to aggression). In the third study, womenhomozygous for the low-MAOA-activity variant had
the highest count of antisocial personality disorder
symptoms when reporting childhood sexual abuse
and the lowest count when having no history of
sexual abuse, compared with women homozygous forthe high-activity allele. In all inquiries except for theone by Kim Cohen et al.,3 the MAOA polymorphism
proved unrelated to the environmental predictor andto the outcome investigated, consistent with adifferential-susceptibility interpretation.
The 5-hydroxytryptamine-linked polymorphic region
polymorphism
Again breaking the empirical ground in G  E
research, Caspi et al.5 were the first to show that the
5-HTTLPR moderates effects of stressful life events
during early adulthood on depressive symptoms aswell as on probability of suicide ideation/attempts,
and of major depression episode at age 26 years.
Individuals with two ‘s’ alleles proved most adversely
affected, whereas effects on l/l genotypes were weakeror entirely absent. Of special significance, given our
focus on differential susceptibility, is that carriers of
the s/s genotype scored best on the outcomes justmentioned when stressful life events were absent,
though this was just as true among low-MAOA
activity individuals in Caspi et al.,2 although not byvery much.

Molecular Psychiatry

Several research groups have attempted to replicate
Caspi et al.’s5 findings of increased vulnerability todepression in response to stressful life events forindividuals with one or more copies of the ‘s’ allele,with most succeeding (see below), even if not all (forexample, Surtees et al.23). Going unnoticed in most,even if not all, of this work to be summarized below,
however, is the fact that those carrying short alleles (s/s, s/l) did not just function most poorly when exposed
to many stressors, but best—showing least problems—when encountering few or none of thestressors. Consider, for example, Taylor et al.’s24
findings (appreciated by the investigators) showingthat young adults homozygous for short alleles (s/s)
manifested greater depressive symptomatology than
individuals with other allelic variants when exposed
to early adversity (that is, problematic childrearing
history) as well as many recent negative life events,
consistent with a diathesis–stress framework, yet the
fewest symptoms when they experienced a supportive early environment or recent positive experiences,that is—and importantly—not just the absence ofadversity. A similar for-better-and-for-worse pattern ofenvironmental effects emerged in still other investigations of stressful life events and depression,
including one targeting depressed patients, healthy
controls and experiences during the 6 months before
study enrollment,25 and another of a sizeable community sample (n = 567) and life events up to 2 years
before the assessment of depression.26
The same for-better-and-for-worse pattern of results
are evident—and noted—in Brummett et al.’s27 investigation of more than 200 adults (mean age 58
years) who differed in whether or not they served as
caregiver of a relative with Alzheimer’s disease (seeFigure 1) and in Eley et al.’s28 research on adolescent
girls who were and were not exposed to riskyfamily environments. Indeed, careful considerationof Figure 1 in Eley et al.’s28 report reveals a beneficial

Figure 1 Center for Epidemiological Studies-Depression(CESD) scores for female caregivers and non-caregivercontrols by 5-HTTLPR genotype (Brummett et al.27).

Vulnerability genes or plasticity genes?
J Belsky et al

Proportion of Depressed Subjects

effect of the s/s genotype in low-stress environments,
with females homozygous for short alleles being 25%
less likely to be in the high depression group than l/lparticipants. This positive effect is actually greaterthan the negative one described by the authors in thecase of the s/s genotype in a high stress environment(that is, 20% more likely to be in high depression
group than l/l). Re-graphing Eley et al.’s28 Figure 1
using the format adopted originally by Caspi et al.5
brings this fact to the fore (see Figure 2 below).
Comparison of the two figures highlights graphicallythe point being made repeatedly: the s/s genotype isassociated with elevated depressive symptoms or risk
among women in high-stress environments, yet
among those in low-stress environments the s/s
genotype is associated with reduced depressive
symptom levels or risk relative to women with thel/l genotype. Wilhelm et al.’s29 longitudinal data
document the same pattern in an investigation ofprobability of life-time major depression and exposure to adverse events across a 5-year study period.
The effect of 5-HTTLPR in moderating environmental influences in a manner consistent withdifferential susceptibility is not restricted to depression and its symptoms, but also—and perhaps
unsurprisingly—to anxiety and ADHD. Gunthert
et al.30 documented the former result in a longitudinal
study of 350 college students. At study entry and ayear later, participants reported anxiety and negative
events daily for 30 days. Genotyping distinguishedthree alleles, but the LG allele was grouped with ‘s’alleles owing to its functional equivalence vis-à-vis
promoter activity. Individuals judged homozygous for
short alleles (including s/LG and LG/LG) reported moreanxiety in the evening when daily-event stress washigh compared with individuals with different genotypes, but also less anxiety than other genotypes
when experiencing little daily-event stress, a patternconsistent across measurement occasions. Once again
the fact that the susceptibility factor did not predict
the environmental measure or the outcome is considered important.

90

s/s
l/l

80
70
60
50
40
Lo Envir Risk

Hi Envir Risk

Figure 2 Proportion of female participants with a highlevel of depression by environmental risk group and 5HTTLPR genotype (Eley et al.28).

In a second study focused on undergraduate
students (n = 247) and anxiety,31 but this time concerned with (retrospectively reported) emotional
abuse in childhood, a G  E interaction once more
emerged, with genotype importantly proving unrelated to the environmental predictor and the outcome,anxiety sensitivity. The significantly steeper abuse–anxiety slope in the case of students homozygous for
short alleles relative to those with one or more longalleles indicated that s/s individuals scored highest inanxiety sensitivity when exposed to abuse and lowest
when not exposed.
Moving on to consider ADHD (in childhood andadulthood), Retz et al.32 focused on the moderated
effects of an adverse childhood environment in theirstudy of 184 male delinquents who averaged 34 yearsof age. Using a retrospective assessment of childhood
ADHD as well as of early adversity, but a clinicalinterview to assess functioning in adulthood, theseinvestigators detected a crossover interaction withrespect to the persistence of ADHD over time.
Compared with l/l genotypes, individuals with ‘s’alleles had more and less persistent ADHD, depending on whether or not, respectively, they experienced
an adverse early environment.
One observation that makes the findings underconsideration particularly interesting is that shortalleles on the serotonin transporter gene have also
been found, in at least some molecular-genetic
research,33 to be associated with negative emotionality in young infants. What makes this gene–
behavior linkage particularly important is that, eventhough negative emotionality or difficult temperament in infants has long been conceptualized as a risk
or vulnerability factor for the development of behavior problems in childhood,34 a growing literature on
differential susceptibility reveals negatively emotional or difficult infants to be more plastic or
malleable than other infants—in a for-better-and-forworse manner.35 That is, they do worse than others
under poor rearing conditions, but better than others
under good ones. Consider in this regard the evidence
that infants rated by mothers as highly negatively
emotional at 6 months of age not only manifest,
relative to other children, more behavior problems inearly childhood when experiencing low-quality parenting36 or low-quality child care,37,38 but also fewer
problems and more social skills than other children
when exposed to high-quality parenting or child care.
Relatedly, Kochanska et al.39 observed that highly
fearful 15-month-olds experiencing high levels of
power-assertive paternal discipline were most likely
to cheat in a game at 38 months, yet when cared for ina supportive manner, such negatively emotional,
fearful and putatively vulnerable toddlers manifested
the most rule-compatible conduct. Even more noteworthy than such longitudinal/correlational evidence
is the clinical-trial finding of a parenting intervention
designed to promote secure attachment of infant tomother showing that the principle beneficiaries of the
documented experimental effect were highly negative

5

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Vulnerability genes or plasticity genes?
J Belsky et al6

and fearful infants.40 These findings pertaining tonegatively emotional infants demonstrate not onlythat such putatively vulnerable children are more
beneficially affected than other infants by someenriching rearing conditions but, in so doing, raise
the prospect that this could be because they arecarriers of short alleles on the serotonin transporter
gene. Only when investigators evaluate interactions
involving both the environment and genetics, and theenvironment and temperament will it be possible todetermine whether the same highly plastic individuals are being identified in different studies using
different (behavioral and genetic) markers.
DRD4
Recent research on G  E interaction involving the
7-repeat allele of the dopamine receptor gene, DRD4,
which meta-analysis reveals to be reliably associatedwith ADHD,1 also provides support for the claim thatthe so-called vulnerability genes may be better
conceptualized as plasticity genes. What makes thefirst two studies to be considered especially important is that the predictor variable, parenting, ranges
from quite limited to very competent, thus meaningthat a supportive environment is not just the one inwhich adverse experiences are absent. In a longitudinal investigation of 47 infants, greater maternal
insensitivity observed when children were 10 months
predicted greater externalizing problems reported by
the mother more than 2 years later, but only forchildren carrying the 7-repeat DRD4 allele.41 Moreover, although children with the 7-repeat DRD4 allele
displayed, consistent with a diathesis–stress model,
the most externalizing behavior of all children whenmothers were judged insensitive, they also manifested the least externalizing behavior when mothers
were highly sensitive (but see, for contradictory
results, Propper et al.42). Similar results emerged ina cross-sectional investigation of sensation seeking
involving 45 children who were 18–21-month-olds,
with toddlers carrying the 7-repeat allele rated byparents as showing, compared with children without
the 7-repeat allele, less sensation seeking behavior
when parenting quality was high and more when
parenting quality was low.43 Although parenting
proved significantly associated with sensation seeking in the 7-repeat individuals, it did not in otherchildren. Of importance is the fact that genotype did
not predict parenting or sensation seeking, fulfilling
important differential-susceptibility criteria.
Experimental intervention research involving theenhancement of parenting also documents a moderating effect of the 7-repeat allele; once again, then, thisG  E work does not simply define the ‘good’environment in terms of the absence of adversity.
Thus, when Bakermans-Kranenburg et al.44 looked at
the change over time in parenting—from before towell after a video-feedback parenting intervention
was provided on a random basis to 157 mothers of 1–
3-year-olds who scored high on externalizing problems—they not only found that the intervention

Molecular Psychiatry

succeeded in promoting more sensitive parenting andpositive discipline, but that experimental effects
extended to improvements in child behavior. This
proved to be the case, however, only for those children
carrying the DRD4 7-repeat allele, with most of theexperimental effect being carried by these genotypically susceptible children whose mothers showed themost improvement in their parenting. Much the same
was the case when, at post-treatment follow up, stress
reactivity was measured by means of change insalivary cortisol before and after administration of anexperimental stressor (that is, area under the curve44).
Indeed, DRD4 7-repeat children in the experimentalgroup not only showed the least physiological stress
reactivity of all children, but the most if their mothers
had been assigned to the control group.
The same team of Dutch investigators whose G  E
research has focused upon indisputably positiveenvironmental effects also found evidence that the
DRD4 7-repeat allele moderated the effect of amaternal psychological condition, unresolved loss ortrauma (as measured by means of the Adult Attachment Interview) on early infant development. Morespecifically, unresolved loss predicted infant attachment disorganization, an early developmental markerof psychological disturbance later in life,45 but only inthe case of infants carrying the 7-repeat allele.46
Indeed, these infants manifest both the most andleast disorganized attachment behavior when stressed
depending on whether their mothers had or had notexperienced unresolved loss or trauma in their own
lives. Importantly, genotype predicted neither unresolved loss nor disorganization, with the data thus
meeting criteria for differential susceptibility (rather
than just genetic vulnerability).
Finally, in a study with a focus rather different thanthe ones just considered, Seeger et al.47 evaluatedwhether the season of the year in which a child wasborn interacted with the dopamine DRD4 polymorphism in predicting the hyperkinetic conduct disorder(ADHD). Employing a cross-sectional design involving 64 children with the disorder and 163 healthy
controls (mean age 11–12±3 years), they found that it
did—and in ways consistent with what is known
about photoperiod exposure during pregnancy. When
comparing patients with controls, children with one
copy of the DRD4 7-repeat allele born in autumn andwinter (that is, long photoperiod during pregnancy)
had a 5.4-fold decreased relative risk for hyperkinetic
conduct disorder, whereas children with the same
genotype born in spring and summer (that is, shortphotoperiod) had a 2.8-fold increased relative risk for
hyperkinetic conduct disorder. Neither season ofbirth nor the presence of DRD4 7-repeat allele
represented a risk factor for hyperkinetic conductdisorder per se.

Conclusion
In some respects, it should not be surprising that
putative vulnerability genes may actually function

Vulnerability genes or plasticity genes?
J Belsky et al

more like plasticity genes, resulting in certain
individuals being more responsive than others toboth positive and negative environmental experiences, including the simple absence of contextual
adversity. Not only has plasticity been found to be
heritable in many species,48,49 functioning perhaps asa selectable character in and of itself,50 but recent
computer simulations show that individual differences in responsiveness to the environment could
most certainly evolve.51 In fact, one wild bird
population shows evidence that selection favoring
individuals who are highly plastic with regard to thetiming of reproduction has intensified over the past
three decades, perhaps in response to climate change
causing a mismatch between the breeding times of thebirds and their caterpillar prey.52 Of note too is
Suomi’s53 observation that only two species ofprimates fill diverse ecological niches around theworld, humans and rhesus macaques, and that what
distinguishes both of these ‘weed species’, as he calls
them, from all other primates is the presence of 5HTTLPR short allele in some individuals. It seems
unlikely that that which might afford these two
species such an adaptive advantage would only be‘vulnerability genes’ that predispose carriers to
depression in the face of contextual stress.
Given the focus in psychiatric genetics on adversity
in the form of environmental risk factors and vulnerability in the form of genes associated with pathological conditions, it is not surprising that thepossibility that the so-called vulnerability genes
actually function more like plasticity genes could go
unnoticed. It is almost as if, metaphorically speaking,sailors are so busy—and wisely—looking under thewater line for extensions of icebergs that could sinktheir ship that they fail to appreciate that by climbing
on top of the iceberg it might prove possible to chart a
clear passage through the ice-laden sea. To the extent
that it is appropriate to think in terms of plasticity
rather than vulnerability, research will be requiredthat extends the purview of the molecular-genetic
study of behavior well beyond the investigation of
dysfunction and environmental adversity. Once again
Caspi et al.54 have served as groundbreakers, discovering that, with respect to intelligence, children
carrying one variant of FADS2, a gene involved in thegenetic control of fatty acid pathways, benefit frombreastfeeding, whereas those carrying a different
allele are not so affected. What has not been
determined as of yet, because all mothers in thisstudy were apparently in relatively good nutritional
state, is whether those individuals found tobenefit from breastfeeding for genetic reasons actually
are adversely affected by it when mothers arein poor nutritional condition. Not only is this justwhatadifferential-susceptibility
perspective
would predict, but is also what might explain why
the gene associated with increased intelligence inthe context of breastfeeding, most certainly theuniversal condition in ancestral times, has not gone
to fixation.

Although the primary purpose of this essay has
been to argue that the virtually exclusive focus onadverse environmental conditions and psychopathology in psychiatric genetic research risks mischaracterizing individuals who are more susceptible thanothers to the negative consequences of adversity andto the benefits of environmental support and enrichment as being exclusively the former—that is,
genetically vulnerable—it would be a mistake to view
these orientations as mutually exclusive. Indeed,
thinking about plasticity and vulnerability together
raises the following three interrelated questions: Are
there some polymorphisms that make some individuals more responsive than others to supportive andadverse environments, just as a differential-susceptibility framework presupposes? Are there some polymorphisms that only cause some individuals to be
more susceptible than others to adversity, just as adiathesis–stress/genetic-vulnerability framework presupposes? And are there still other polymorphismsthat only make individuals more susceptible thanothers to enriching environmental conditions? Ofnote, with regard to the last possibility is that,
although the English language has terms to characterize those highly susceptible to both positive andnegative conditions (that is, plastic/malleable) andhighly susceptible to adversity (that is, vulnerable), it
is difficult to find a term which would characterize
those disproportionately responsive to supportive
conditions only—besides lucky!
Owing to the inherent limits of so many of thestudies that we have considered, both in terms ofwhat has been measured and how the data have been
analyzed and presented in primary publications, itremains impossible to be certain whether the extensive findings considered throughout this paper as
evidence of differential susceptibility should be
regarded as such. Recall in this regard that rather
liberal standards of interpretation have, by necessity,
been applied to G  E findings, most of which
emerged from investigations designed to evaluate
diathesis–stress hypotheses. To enable both primaryresearchers and reviewers of the literature in the
future, including meta-analysts, to address thisfundamental issue about how human development
operates, investigatory and reporting practices willneed to change; and hopefully, this selective review,by calling attention to the possibility of differential
susceptibility, will stimulate such change.
Thus, in addition to meeting the Belsky et al.13
criteria for establishing differential susceptibility
summarized earlier, which informed the interpretation of study findings considered herein, several otherresearch desiderata are called for. First, studies
should measure not just the presence of adversity
and its absence, but environmental support, like
Taylor et al.24 did in assessing positive life events
and Bakermans-Kranenburg and van IJzendoorn41 didin measuring sensitive parenting. Second and relatedly, human functioning should be measured along acontinuum ranging from dysfunction to competence,7

Molecular Psychiatry

Vulnerability genes or plasticity genes?
J Belsky et al

8

not just from dysfunction to its absence or just fromcompetence to its absence, to avoid the masking ofdifferential susceptibility by ceiling or floor effects;
should this not prove possible for some reason,
separate measurements of negative and positive
functioning should be obtained and examined vis-àvis G  E. In addition, once a G  E interaction has
been discerned, follow-up analysis should determine
whether significant differences in the functioning ofindividuals hypothesized to be more and less susceptible to environmental influences are obtained whenthe environmental circumstances are adverse as wellas when they are supportive (that is, at both ends ofthe environmental continuum). It is when significant
differences are obtained for both comparisons thatdifferential susceptibility rather than diathesis–stresswould be the correct inference.

Conflict of interest
The authors report no biomedical financial interests
or potential conflicts of interest.

Acknowledgments
This research was supported by the National Heart,
Lung, and Blood Institutes grant 3P01 HL036587; theNational Institute on Aging grant R01AG19605, with
co-funding by National Institute of Environmental
Health Sciences; the Duke Clinical Research Unit
grant M01RR30l; and the Duke Behavioral Medicine
Research Center.

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