Psychological Bulletin
2009, Vol. 135, No. 6, 885–908© 2009 American Psychological Association
0033-2909/09/$12.00 DOI: 10.1037/a0017376

Beyond Diathesis Stress:
Differential Susceptibility to Environmental Influences
Jay Belsky and Michael Pluess
Birkbeck University of London
Evolutionary-biological reasoning suggests that individuals should be differentially susceptible to environmental influences, with some people being not just more vulnerable than others to the negative effects
of adversity, as the prevailing diathesis-stress view of psychopathology (and of many environmental
influences) maintains, but also disproportionately susceptible to the beneficial effects of supportive andenriching experiences (or just the absence of adversity). Evidence consistent with the proposition that
individuals differ in plasticity is reviewed. The authors document multiple instances in which (a)phenotypic temperamental characteristics, (b) endophenotypic attributes, and (c) specific genes function
less like “vulnerability factors” and more like “plasticity factors,” thereby rendering some individuals
more malleable or susceptible than others to both negative and positive environmental influences.
Discussion focuses upon limits of the evidence, statistical criteria for distinguishing differential susceptibility from diathesis stress, potential mechanisms of influence, and unknowns in the differentialsusceptibility equation.
Keywords: parenting, differential susceptibility, diathesis stress, GXE, psychopathologyment), physiological or endophenotypic in nature (e.g., highly
physiologically reactive), or genetic in origin (e.g., 5-HTTLPR
short alleles)—are disproportionately or even exclusively likely tobe affected adversely by an environmental stressor. That stressor
may be child maltreatment, insensitive parenting, or negative life
events, to name but three that are well studied and figure prominently in this paper, which advances an alternative to the diathesisstress/dual-risk model of environmental influences and humandevelopment.
According to prevailing views, it is the child with a “difficult”(or negatively emotional) temperament, for example, or individuals carrying certain “vulnerability genes” or “risk alleles” who aremost likely to develop or function poorly, such as by manifestinga psychopathological condition (e.g., depression), when exposed toa stressor of interest. The dual-risk designation derives from thesynergistic effect of a risk (or diathesis) inherent in the individualinteracting with one operative in the environment. The point of thispaper is not so much to challenge the view that diathesis-stressphenomena exist or that processes related to them operate. That
seems incontestable. Nor is its intent to suggest that diathesisstress thinking and research have proven unproductive, either
theoretically or empirically. That, too, seems indisputable.
Rather, the goal in this effort is to assert—and demonstrateempirically—that in many cases where dual-risk/diathesis-stressprocesses appear to characterize human functioning and development, something of equal or perhaps even greater significance isgoing on. Indeed, it is our contention that this “something else” isoften missed as a result of expectations derived from the prevailingconceptual perspective that guides both inquiry and interpretationof findings. In fact, it is a central claim here that the disproportionate attention paid to the negative effects of contextual adversity, broadly defined and varied in its operationalization, on problematic functioning and disturbances in development and mental

Students of human development appreciate that individuals varyin whether and/or the degree to which they are affected, over the
shorter and longer term, by environmental experiences, includingchild-rearing ones. Perhaps the most striking evidence that person
characteristics condition or moderate environmental effects is to befound in developmental research on Temperament ⫻ Parenting
interaction (Rothbart & Bates, 2006) and psychiatric research on
Gene ⫻ Environment interaction (GXE; Burmeister, McInnis, &Zollner, 2008).
Work in both these areas of inquiry is guided primarily, even if
not exclusively, by what developmentalists regard as thetransactional/dual-risk model (Sameroff, 1983) and what psychiatrists and others studying and treating psychopathology regard as
the diathesis-stress model (Monroe & Simons, 1991; Zuckerman,
1999). Central to both these frameworks is the view that someindividuals, due to a “vulnerability” in their make-up—which may
be behavioral/temperamental in character (e.g., difficult tempera-

Jay Belsky and Michael Pluess, Institute for the Study of Children,
Families and Social Issues, Birkbeck University of London, 7 Bedford
Square, London WC1B 3RA, United Kingdom.
Preparation of the manuscript was supported by Swiss National Science
Foundation Grant PBBS1—120809, a grant for doctoral studies awarded toMichael Pluess. Special appreciation is expressed to Terrie Moffitt forstrongly encouraging the preparation of this article, to Bruce Ellis forclarifying our understanding of the biological-sensitivity-to-context thesis,
and to Marinus van IJzendoorn and Marian Bakermans-Kranenburg forsharing ideas and stimulating our thinking regarding mechanisms of biological action.
Correspondence concerning this article should be directed to Jay Belsky,
Institute for the Study of Children, Families and Social Issues, Birkbeck
University of London, 7 Bedford Square, London WC1B 3RA, United
Kingdom. E-mail: j.belsky@psychology.bbk.ac.uk
885

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BELSKY AND PLUESS

health may actually lead scholars to mischaracterize some environmental influences, as well as human development processes
and phenomena. In essence, then, this essay embraces the perspective of positive psychology (Diener & Biswas-Diener, 2008;
Seligman, 2003; Seligman, Parks, & Steen, 2004) and applies it to
the study of environmental influences on behavior and development, especially the moderating role of individual attributes.
The central thesis in this paper, as stipulated by the differentialsusceptibility hypothesis (Belsky, 1997a, 2005; Belsky,
Bakermans-Kranenburg, & van IJzendoorn, 2007; Belsky &Pluess, 2009), as well Boyce and Ellis’s (2005) biologicalsensitivity-to-context thesis, is that those putatively “vulnerable”
individuals most adversely affected by many kinds of stressors
may be the very same ones who reap the most benefit fromenvironmental support and enrichment, including the absence ofadversity. Thus, we should expect individual differences in developmental plasticity and, more generally, susceptibility to environmental influences, with some individuals being far more affected
than others by both negative and positive contextual conditions. In
the body of the paper we provide extensive, yet still just illustrative
evidence to this effect, most of it very recent and much of which
has gone unnoticed, even at times by the very investigators generating it (but see Taylor et al., 2006; Uher & McGuffin, 2008).
What follows should not be regarded as an exhaustive review ofthe literature, nor should it be seen to demonstrate, much less
imply, that evidence of differential susceptibility outweighs evidence of diathesis stress, either in the literature as a whole or ineach and every study cited for illustrative purposes. To make thecase, as we exclusively seek to, that differential susceptibility
appears operative in human development and functioning but that
individual differences in plasticity have been largely even if notentirely overlooked in favor of prevailing views that some individuals are simply more vulnerable to adversity than others, we
contend that an admittedly selective compilation of a multiplicity
of illustrative findings is exactly what is appropriate at the present
time. This would seem especially so in light of the fact that muchof the available research, most particularly that investigating GXEinteraction, focuses on both a restricted range of environments,
typically emphasizing the negative end of the spectrum and failingto 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, and thereby fails to assess
competent functioning (except for the absence of dysfunction). Of
course there are exceptions (e.g., Kaufman et al., 2004, 2006;
Wilhelm et al., 2006).
Nevertheless, as a result of the design characteristics of so many
investigations, it remains unclear whether extensive evidence consistent with a diathesis-stress model and seemingly inconsistent
with a differential-susceptibility framework is an accurate reflection of how human psychological and behavioral functioning operates or, instead, an artifact of study design. Quite conceivably,
simply treating the absence of adversity as the “good” end of theenvironmental-exposure spectrum and/or the absence of a disorderas the “good” end of the psychological-functioning continuum, as
so many studies do, may lead to the underdetection of differentialsusceptibility findings and an overrepresentation of vulnerability
ones. It is for these reasons that we consider it appropriate at thepresent time to provide extensive illustrative evidence of apparent
differential-susceptibility effects rather than to undertake a formal

meta-analysis of all findings involving person characteristics moderating environmental effects in hopes of determining whichmodel fits the data better.
Before extensive evidence is presented consistent with the claimthat the very same individuals who may be most adversely affectedby many kinds of stressors may simultaneously reap the mostbenefit from environmental support and enrichment (including theabsence of adversity), the evolutionary-biological bases of differential susceptibility are presented, followed by evidentiary criteria
used in this review to define differential susceptibility. Thereafter,
research highlighting phenotypic, endophenotypic, and genetic
susceptibility factors— or moderators of environmental effects—isreviewed in three separate subsections, with an exclusive focus onstudies and findings that point toward differential susceptibility. In
other words, this effort is not intended to be a general review ofTemperament ⫻ Parenting or GXE interaction research (or any
other). In a concluding section, ways of advancing the study ofdifferential susceptibility are proposed, with a focus upon (a)statistical criteria for evaluating differential susceptibility, (b) potential mediating mechanisms responsible for it, and (c) still-tobe-illuminated unknowns in the differential-susceptibility equation.

Theoretical Foundations
Two distinct, though by no means mutually exclusive,
evolutionary-inspired theoretical arguments advance the claim that
individuals should vary in their developmental plasticity and susceptibility to environmental influence, Belsky’s (1997a; 1997b;
2005) differential-susceptibility hypothesis and Boyce and Ellis’s(2005; Ellis, Essex, & Boyce, 2005; Ellis, Jackson, & Boyce,
2006) biological-sensitivity-to-context thesis. Whereas the former
has emphasized the role of nature in shaping individual differencesin plasticity, without excluding a role for nurture, the latter hasemphasized nurture, without excluding nature. Additionally,
whereas the theoretical argument for differential susceptibility
leads to no specific hypotheses about susceptibility factors or
mediating mechanisms and regards these as essentially empiricalquestions, such concerns are central to the biological-sensitivityto-context thesis. Both models nevertheless predict that somechildren and perhaps adults will be more susceptible than others toboth the adverse and beneficial effects of, respectively, unsupportive and supportive contextual conditions.

Differential Susceptibility
The view that children should vary in their susceptibility torearing is founded on evolutionary logic, which regards the dispersion of genes in future generations as the ultimate biologicalimperative and, thus, goal of all living things. Indeed, from theperspective of modern evolutionary biology, natural selection
shapes living things not just to survive but to reproduce. Such
reproduction can be direct, as when one produces immediate
descendants (i.e., children, grandchildren), but also indirect, as
when one’s kin—such as brother, sister, niece, or nephew—
reproduce and, in so doing, pass on genes that they share, invarying proportions, with the individual in question. “Reproductive fitness” refers to the dispersion of one’s genes in future
generations, and “inclusive fitness” calls attention to the fact that

BEYOND DIATHESIS STRESS

one’s genetic material is distributed both directly and indirectly.
This evolutionary-biological foundation forms the basis for thedifferential-susceptibility hypothesis.
Because the future is and always has been inherently uncertain,
ancestral parents, just like parents today, could not have known(consciously or unconsciously) what child-rearing practices would
prove most effective in promoting the reproductive fitness ofoffspring—and thus their own inclusive fitness. As a result, and as
a fitness-optimizing strategy involving the hedging of bets, natural
selection would have shaped parents to bear children varying indevelopmental plasticity (Belsky, 2005). This way, if an effect ofparenting proved counterproductive in fitness terms, those children
not affected by parenting would not have incurred the cost ofdeveloping in ways that ultimately proved “misguided” when it
came to passing on genes to future generations. In light ofinclusive-fitness considerations, the reduced susceptibility of theseless malleable children to parental influence would not only havebenefited themselves directly but their more malleable sibs aswell— but indirectly, given that sibs, like parents and children,
share 50% of their specific alleles. By the same token, had parenting influenced children in ways that enhanced fitness, not only
would more plastic or malleable offspring have benefited directly
by virtue of parental influence but so, too, would their parents andeven their less malleable sibs who did not benefit from the parenting they themselves had received, again for inclusive-fitness
reasons (i.e., shared genes).
Such evolutionary reasoning leads directly to the proposition
that children should vary in their plasticity and thus susceptibility
to parental rearing and perhaps to environmental influences moregenerally. To be clear, though, this is not in any way a groupselectionist argument but one that regards the individual as the unitof selection. After all, on the basis of the preceding analysis, it isconsidered adaptive for an individual child to be more or lessmalleable and to have siblings with contrasting susceptibilities,
thereby accruing potentially direct and/or indirect benefits, and for
an individual parent to bear children of both kinds, thereby benefiting directly (i.e., immediate offspring) and indirectly (e.g.,grandchildren).
As noted already, without denying the possibility of environmental influences on malleability, Belsky (1997a, 1997b, 2005)
presumed that individuals varied for genetic reasons in theirdevelopmental plasticity. Not inconsistent with this view isextensive cross-species evidence that plasticity is heritable(Bashey, 2006; Pigliucci, 2007) and may function as a selectable character in and of itself (Sinn, Gosling, & Moltschaniwskyj, 2007). Indeed, one wild bird population shows evidence
that selection favoring individuals that are highly plastic withregard to the timing of reproduction has intensified over the
past 3 decades, perhaps in response to climate change causinga mismatch between the breeding times of the birds and theircaterpillar prey (Nussey, Postma, Gienapp, & Visser, 2005).
Also noteworthy is Suomi’s (2006) observation that a single
genetic difference distinguishes the two primate species that fill
multiple niches around the world from all others that inhabit
singular and rather narrow ones, that being the presence (insome individuals) of the 5-HTTLPR short allele. This leads him
to regard humans and macaques as “weed species.”

887

Biological Sensitivity to Context
Boyce and Ellis (2005) argued that for adaptive reasons, children in both especially supportive and especially unsupportive
developmental contexts should develop or maintain high levels ofphysiological stress reactivity, which they regard as a susceptibility factor and thus plasticity mechanism (i.e., the endophenotypic
instantiation of susceptibility to environmental influence). Thus,
they expect a curvilinear, U-shaped relation between levels of
supportiveness versus stressfulness in early childhood environments and the development of stress-reactive profiles, with highreactivity disproportionately emerging in both highly stressful andhighly protected social environments.
For children fortunate enough to grow up in particularly supportive contexts, Boyce and Ellis (2005) contended, it would be
adaptive to be maximally influenced by the developmental environment. Indeed, the physical, behavioral, and psychological embodiment of the rich resource base provided by the family and thebroader ecology would enhance the social competitiveness of theindividual through the development of a broad range of competencies, thereby increasing his or her mate value and eventual
reproductive fitness. In contrast, those growing up under harsh anddangerous conditions would increase their chances of survival andeventual reproduction if they developed heightened vigilance tothreat and proved highly prepared to actively combat risks thatthey might face. For them, too, heightened physiological reactivity
is presumed to be the vehicle for getting this developmental job
done. Thus, it is Boyce and Ellis’s thesis that the stress-response
system operates as a conditional adaptation, selected to enable
individuals to fit environments that, starting early in life, would
enhance their fitness prospects: “Natural selection has favored
developmental mechanisms (conditional adaptations) that function
to adjust levels of BSC [biological sensitivity to context] to match
familial and ecological conditions encountered early in life” (2005,
p. 292).
Irrespective of whether plasticity is considered to be principallya function of nature or of nurture— or their interaction—the claimthat individual differences in plasticity have evolved is central toboth evolutionary arguments under consideration. Of importance,
therefore, are the results of a recent simulation study that sought todetermine whether plasticity could evolve and clearly showed thisto be the case, with some individuals being more responsive thanothers to environmental conditions (Wolf, van Doorn, & Weissing,2008).
Both arguments also define individual differences in developmental plasticity to mean that some children and even adults will
be more susceptible than others to both the adverse and beneficial
effects of, respectively, unsupportive and supportive contextual
conditions. This view contrasts markedly with traditional dualrisk/diathesis-stress frameworks, which regard certain putatively“vulnerable” individuals as more likely than others to be adversely
affected by unsupportive contextual conditions but stipulate nothing about differential responsiveness to supportive conditions. Just
as important, diathesis-stress thinking does not propose, asdifferential-sensitivity and biological-sensitivity-to-context theorizing does, that the very individual attributes that make someindividuals disproportionately susceptible to adversity simultaneously make them disproportionately likely to benefit from supportive ones. Notably, and as is documented more extensively in888

BELSKY AND PLUESS

this paper, Uher and McGuffin (2008) recently observed that some
GXE findings fit a pattern whereby individuals carrying certain
alleles prove more susceptible to both adverse and supportive
environmental conditions; that is, they are affected in a “for-betterand-for-worse” manner (Belsky et al., 2007).

Evidentiary Criteria for Establishing Differential
Susceptibility
A series of empirical requirements— or steps—for establishingevidence of differential susceptibility to environmental influence,that is, individual differences in plasticity, has recently been delineated (Belsky et al., 2007). Some of these steps guide theselective review of evidence presented herein. The first concerns
the application of conventional statistical criteria for evaluating
genuine moderation of a putative environmental influence by anorganismic plasticity or susceptibility factor (Dearing & Hamilton,
2006), with some emphasis placed on excluding interactions withregression lines that do not cross (sometimes referred to as removable interactions). The next steps distinguish differential susceptibility from person– environment correlations that may reflect evocative effects of person characteristics on environmental
experiences and from diathesis-stress/dual-risk models. If the susceptibility factor and the outcome are related, dual risk (or gain,
when positive factors are involved) is suggested. For example,
early negativity would itself lead to externalizing behavior but
even more so when combined with negative parenting. The specificity of the differential-susceptibility effect is demonstrated if themodel is not replicated when other susceptibility factors (i.e.,moderators) and outcomes are used (Caspi & Moffitt, 2006; Rutter, 2006). Differential susceptibility is thus demonstrated whenthe moderation reflects a crossover interaction that covers both thenegative and the positive aspects of the environment. The slope forthe susceptible subgroup should be significantly different fromzero and at the same time significantly steeper than the slope forthe non- (or less) susceptible subgroup.
Throughout the next three sections, we present extensive evidence of differential susceptibility to environmental influence thatis consistent with the view that individuals differ in their plasticity,with some being more affected than others by experiential influences in a for-better-and-for-worse manner. We begin by considering research that addresses behavioral or phenotypic characteristics of individuals that moderate environmental influence andthus function as potential markers of plasticity (e.g., difficult
temperament). We next turn to work that highlights similar moderational effects of endophenotypic characteristics of individuals,
with endophenotype defined as attributes of individuals that lie
between the gene and behavior (e.g., physiological reactivity).
Finally, we consider evidence from the ever-expanding literature
on GXE interaction in which genes moderate environmental effects, again in a for-better-and-for-worse manner, not just in adiathesis-stress or dual-risk manner (see also Uher & McGuffin,2008).
Perhaps because so much of the work to be cited is new—and
was often conducted with a diathesis-stress/dual-risk frame ofreference in mind—it is actually rare for investigations to address
all or even most of the statistical criteria mentioned above for
empirically establishing differential susceptibility to environmental influence, to say nothing of additional ones that are outlined in

the concluding section of this report. Indeed, even when investigators detect statistical interactions of a crossover nature, as was
the case in all the research to be cited, different strategies offollowing up and illuminating the nature of such interactions are
adopted. Whereas some investigations employ a grouping approach for dealing with the interacting predictor variables, plotting
or tabling subgroup means, others calculate and contrast slopes
reflecting the differential predictive relation between the continuously measured environmental predictor and outcome for subgroups that differ on the moderating susceptibility factor (e.g., easy
vs. difficult infants). Only rarely is it reported whether such slopes
differ significantly from each other, as would be preferable whenthe moderator does not have a natural break point but is a continuous dimension; this, of course, is not needed when the moderator
is naturally binary. Perhaps analogously, it is not always reported,
when subclass means are plotted, exactly which means differ
significantly from which others. And most significantly (see Conclusion), in only one case has an investigatory team explicitly
sought to determine whether subclass-mean differences hold atboth the “for better” and “for worse” sides of the differential
susceptibility equation (Taylor et al., 2006), that is, whether theputatively susceptible group functioned more poorly than the othersubgroup under negative environmental conditions and functioned
better under positive environmental conditions.
Given this less-than-ideal situation for evaluating differential
susceptibility, we adopt a liberal standard of evidence once asignificant crossover interaction has been detected when it comesto regarding results as evidence of differential susceptibility toenvironmental influence. For example, with regard to subgroupmeans, if one subgroup shows both the highest and lowest mean of
all susceptibility-factor-defined subgroups (e.g., short vs. longallele of the 5-HTTLPR) on an outcome with regard to the environmental effect in question, this is interpreted as being in linewith a for-better-and-for-worse, differential-susceptibility patterning of results. Similarly but with regard to slopes, whenever they
indicate that one subgroup defined on the basis of the susceptibility
factor in question would score highest and lowest, given theenvironmental influence under investigation (i.e., steepest slope),
this, too, is interpreted as evidence of differential susceptibility.
Presented in Tables 1–3 are all the empirical studies and specificfindings that inform this review, in order of appearance in the text,
though not all will be considered at the same level of detail. Tables
1, 2, and 3, pertain, respectively, to studies and findings involving
phenotypic, endophenotypic, and genetic susceptibility factors. In
addition to information on (a) study author, (b) publication year,
and (c) sample, each table provides information on (d) the specificsusceptibility factor (e.g., difficult temperament, 5-HTTPLR) andplasticity marker (e.g., high difficulty, short allele) being studied;(e) the environmental predictor investigated (e.g., parenting, life
events); (f) the extent to which the predictor captured a full range
of environmental variation across negative-to-positive poles (i.e.,
adversity 7 absence of adversity; adversity 7 support/enrichment; support/enrichment 7 absence of support/enrichment); (g) the outcome being predicted (e.g., depression, externalizing behavior); (h) the extent to which the outcome reflected a fullrange of variation across negative-to-positive poles (i.e., negative 7
absence of negative; negative 7 positive; positive 7 absence of
positive); (i) whether the association between susceptibility factor
and environmental predictor was significant, not significant, taken

BEYOND DIATHESIS STRESS

into account statistically, or unreported; (j) the relation between
moderator or susceptibility factor and outcome (same categorization); and (k) whether the analysis that followed detection of asignificant crossover interaction was based exclusively on contrasting regression lines of subgroups that varied on the susceptibility factor (e.g., high vs. low difficult temperament) or involved
contrasting subgroup means on the dependent variable.

Phenotypic Markers of Differential Susceptibility
Evidence of differential susceptibility comes from researchshowing that temperamental and emotional characteristics of(mostly very young) children moderate the effect of developmental
experience on behavioral development (see Table 1). Some of thiswork highlights the role of early negative emotionality/difficult
temperament vis-à-vis parenting effects, some of it the role ofother temperamental traits, some of it the moderated influence ofchild-care experience, some of it individual differences in plasticity beyond the early childhood years, and some of it experimental
investigations that manipulated contextual conditions. Each set ofevidence is considered in turn. Unless otherwise indicated, thework cited throughout this and the next two major sections was
conducted without regard to the differential-susceptibility hypothesis and, if anything, was informed by diathesis-stress thinking.

Negative Emotionality and Difficult Temperament as
Plasticity Markers
After advancing the differential-susceptibility hypothesis, which
included no claims regarding proximate factors or mechanismsthat should make some children more susceptible than others tochild-rearing effects, Belsky (1997a, 1997b) sought to identify
evidence of differential-susceptibility factors in existing and continually emerging developmental research. Well before any GXE
research on humans was reported, attention was called to infant
and toddler negative emotionality and difficult temperament as
potential differential-susceptibility factors (for review, see Belsky,2005).
Cross-sectional and longitudinal studies by Kochanska (1993);
Belsky, Hsieh, and Crnic (1998); and Feldman, Greenbaum, andYirmiya (1999) showed, for example, that diverse measures ofrearing of infants and toddlers (e.g., discipline, interactional synchrony, positive and negative parenting) accounted for substantially more variance in self-control, externalizing problems, and/or
inhibition in the case of more negatively emotional infants/toddlers
than of other children, whether operationalized in terms of difficult
temperament, irritability, fearfulness, or inhibition. (All but the
Kochanska, 1993, study were explicitly designed to test differential susceptibility.) But it was not just in research on very young
children that such moderating effects of negativity emerged. Morris et al. (2002) found, for example, that harsh and hostile mothering also proved to be a stronger predictor of teacher-reported
externalizing problems in first and second grade when childrenscored high rather than low on irritable distress.
Even though most of the research reviewed by Belsky (2005)
showed that greater variance in a variety of developmental outcomes could be explained by rearing experiences in the case of
more negatively emotional children, statistical analyses in thestudies reviewed often did not afford determination of whether this889

result was itself a function of a for-better-and-for-worse pattern ofparenting effects. In consequence, it remained unclear whether
individual differences in plasticity— or just vulnerability—were
responsible for the repeatedly detected finding that more variance
was explained in one group’s functioning than in another’s by theenvironmental factor investigated.
Fortunately, a growing number of studies have overcome thislimitation, revealing for-better-and-for-worse rearing effects andthus differential susceptibility. Van Aken, Junger, Verhoeven, vanAken, and Dekovic (2007) found, for example, that 16- to 19month-old boys with difficult temperament showed the smallest
increase 6 months later in externalizing problems scores whenreared by highly sensitive mothers who only infrequently usednegative control but the largest increase when highly insensitive
mothers relied heavily on negative control. These striking parenting effects simply did not obtain in the case of other children.
In a series of investigations Kochanska, Aksan, and Joy (2007)
evaluated whether child temperament moderated parenting effects
on positive developmental outcomes. In one study, children’s
fearfulness, maternal power assertion, and mother– child positive
relations were assessed behaviorally when children were 22 and 33
months old, and children’s moral self was measured (via puppet
interview) at 56 months. Although no parenting effects emerged in
the case of children who, as toddlers, scored low in fear, those who
were highly fearful evinced a greater moral sense if their mothers(at 22 months only) relied little on power assertion to regulate their
behavior but a limited one if their mothers relied heavily on power
to control earlier child behavior. Similar fear-moderated findings
emerged when Kochanska et al. (2007) investigated effects offathers’ power-assertive behavior (15 months) on children’s rulecompatible conduct (38 months). Because child fearfulness wasitself significantly and negatively related to maternal power assertion in the first study summarized, questions arise about the confidence that can be placed in an interpretation highlighting individual differences in plasticity. A preferable way to proceed in thiscircumstance would be to statistically adjust the environmental
predictor (i.e., maternal power assertion) for the susceptibility
factor (i.e., child fearfulness), thereby controlling for the evocative
effect of the latter on the former before testing Temperament ⫻Parenting interactions.
A series of reports using data from the large-scale National
Institute of Child Health and Human Development (NICHD)
Study of Early Child Care and Youth Development (NICHD Early
Child Care Research Network, 2005) and focusing upon maternally reported difficult temperament at 1 and/or 6 months explicitly tests differential susceptibility to parenting. In one study,
Bradley and Corwyn (2008) found that quality of parenting (observed and averaged across multiple measurement occasions from
infancy through first grade) negatively predicted teacher-reported
problems in first grade but that this anticipated parenting effectwas moderated by early temperament. Thus, evidence showingthat better quality parenting predicted fewer problems and that
poorer quality parenting predicted more problems proved strongest
for those with difficult temperaments, weaker for those with intermediate levels of difficult temperament, and weaker still for
those scoring very low on difficult temperament (i.e., easy temperament). This suggests that rather than categorically conceptualizing some children as malleable (i.e., difficult temperament) andothers as not (i.e., easy temperament), studies might more appro-

Year

2007

2007

2008

2008

2009a

2000

2007

1995

2009

2008

Authorvan Aken et al.

Kochanska et al.

Bradley & Corwyn

Dopkins-Stright et al.

Pluess & Belsky

Lengua et al.

Smeekens et al.

Volling & Feagans

Pluess & Belsky

Lengua118 8- to 12-yearold boys andgirls

36 14- to 48month-old boys
and girls
761–915 4.5- to
5-year-old boys
and girls

231 9- to 12-yearold boys andgirls
116 5-year-old
boys and girls

1,364 10- to 11year-old boys
and girls

1,007 6-year-old
boys and girls

Study 1: 74 4.5year-old boys
and girls
Study 2: 100 3year-old boys
and girls
929 6-year-old
boys and girls

115 16- to 19month-old boys

SampleTemperament: highanxiousness, highfrustration, lowfrustration

Temperament: difficult

Temperament: social
fear

Temperament: highanger proneness

Temperament: highimpulsivity

Temperament: difficult

Temperament: difficult

Temperament: difficult

Temperament: highfearfulness

Temperament: difficult

Susceptibility:
Plasticity marker

Study characteristics

Maternal
parentingstyle

Child-carequality

Maternalinconsistentdiscipline
Parentaleffective
guidance
Child-carequality

Parentingquality,Child-carequality

Maternal
sensitivity,
Negative
control
Maternal
power
assertion
Paternal
power
assertion
Maternal
sensitivity,
Productive
activity
Parentingquality

Environmental
predictor

Child moral self
Rule-compatible
conduct
Externalizing
behavior
Academiccompetence,
Social skills,
Teacher–childrelationships,
Peer status
Reading, social
competence
Externalizing
behavior,
teacher–childconflicts
Depression
symptoms
Externalizing
behavior
Nonsocialactivity
Externalizing
behavior,
Socialcompetence
Externalizing
behavior,
Internalizing
behavior

A7S
A7S
A7S

A7S

A7S
A7S
A7S

A7S

A7S

A7S

A7S

A7S

Change inexternalizing
behavior

Outcome

A7S

Range ofpredictor

Table 1
Characteristics of Study Findings Providing Empirical Evidence for Differential Susceptibility as a Function of Phenotype

significant
significant(adjusted)
ns

N7P
N7P

significant
significant

N 7 ANns

P 7 APN 7 ANns

not reported

ns

N 7 AN

N7P

N 7 ANN 7 ANsignificant

significant
significant

P 7 AP
N7P

N 7 ANsignificant

not reported

ns

significant

ns

Moderator/
predictor
correlation

P 7 APN 7 AN

N7P

N7P

N7P

Range ofoutcomesignificant

ns

ns

ns

ns

ns

significant

ns

ns
ns

ns
ns

significant

ns

ns

ns

significant

regression
lines
regression
lines
regression
lines

regression
lines

regression
lines

regression
lines

regression
lines
regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

Subgroup
contrasts

Follow-up
analysisa(table continues)

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

890
BELSKY AND PLUESS

2006

2005

2008

2005

2006

Mezulis et al.

Leve et al.

Gilissen et al.

Aron et al.

Velderman et al.

81 mothers

213 male andfemale students

170 4- or 7-yearold boys andgirls

373 17-year-old
boys and girls

289 11-year-old
boys and girls

SampleTemperament: highreactivity

Sensory-processing
sensitivity: highsensitivity

Temperament: highwithdrawal
negativity
Temperament: highimpulsivity, low
fear/shyness
Temperament: highfearfulness

Susceptibility:
Plasticity marker

Study characteristics

Adverseparental
environment,
ExperimentallyinducedstressParentingintervention

Attachment
quality

Negative life
events (peerdomain)Harshdiscipline

Environmental
predictor

Negative
affectivity
Attachment
security ofchild

S 7 AS

Negative
cognitive
style
Externalizing
behavior
slope
Skin
conductancelevel
reactivity
Shyness

OutcomeA7S

A 7 AA

A7S

A 7 AA

A7S

Range ofpredictor

N7P

N 7 ANN 7 AN

N7P

N 7 ANN 7 AN

Range ofoutcomens

not reported

significant

not reported

significant

ns

Moderator/
predictor
correlationns

not reported

significant

significant(only
impulsivity)ns

ns

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

means

regression
lines

regression
lines

means

regression
lines

regression
lines

Subgroup
contrasts

Follow-up
analysisa

Note. A ⫽ adversity; AA ⫽ absence of adversity; S ⫽ support/enrichment; AS ⫽ absence of support/enrichment; N ⫽ negative outcome; AN ⫽ absence of negative outcome; ns ⫽ nonsignificant;P ⫽ positive outcome; AP ⫽ absence of positive outcome.
aAfter detecting significant crossover interaction between moderator and predictor on outcome.

Year

AuthorTable 1 (continued)

BEYOND DIATHESIS STRESS

891

892

BELSKY AND PLUESS

priately conceptualize and measure individual differences in plasticity dimensionally, in terms of a plasticity gradient (Belsky,2000).
Notably, Dopkins Stright, Cranley Gallagher, and Kelley (2008)
extended work on parenting effects in this sample by documenting
similar temperament-moderated, differential-susceptibility-like effects on positive, not just negative, developmental outcomes (i.e.,teacher-rated academic competence, social skills, teacher– childrelationships, and peer status at first grade). The fact, though, thatthe temperament susceptibility factor proved related to the parenting predictor (as well as at least one outcome measured) in thiswork raises questions about conclusions the investigators drew
regarding differential susceptibility. Pluess and Belsky (2009a)
overcame this problem in their study of differential susceptibility
using the same sample (but not measures). After finding thatparenting quality prior to school entry predicted reading and social
competence in fifth grade and socioemotional functioning in sixth
grade more strongly for children with difficult temperaments as
infants than for those with easy temperaments—and in a for-betterand-for-for worse manner—they reran the analyses, discounting
discerned evocative effects of a putative susceptibility factor (i.e.,
temperament) on the environmental predictor (i.e., parenting quality). After adjustment of the parenting predictor for the effect ofinfant difficult temperament, differential-susceptibility findings remained virtually unchanged.

Beyond Negative Emotionality/Difficult Temperament
Negative emotionality/difficult temperament is not the only
temperamental trait that apparently moderates rearing influence ina manner consistent with differential susceptibility, thereby highlighting individual differences in plasticity. Impulsivity emerged
as such a susceptibility factor in Lengua, Wolchik, Sandler, andWest’s (2000) cross-sectional study of recently divorced mothers
and their 9- to 12-year-old children. Highly impulsive children
manifested the least depressive symptoms when their mothers
provided consistent discipline but the most when discipline proved
highly inconsistent. And here, too, a plasticity gradient emerged,
with the parenting– depression relation proving strongest for themost impulsive, weakest (and insignificant) for those least impulsive, and intermediate for those in between.
In longitudinal work with toddlers, anger proneness, which isconceptually related to impulsivity (and negative emotionality),emerged as a plasticity marker (Smeekens, Riksen-Walraven, &van Bakel, 2007). Toddlers who scored high in proclivity to getangry at 15 and 28 months were more and less likely than otherchildren to manifest behavior problems at age 5 years (according
to averaged parent and teacher report) if they had experienced,
respectively, ineffective and effective parental guidance during thetoddler years. Effective guidance involved the provision of structure and limit setting, clear instructions, and a supportive presence.

Beyond Parenting: Child-Care Quality
All the rearing effects considered through this point pertain toparenting. But as children, especially in the contemporary Westernworld, are routinely cared for by alternative caregivers in childcare settings, the question arises as to whether similar differentialsusceptibility-like effects emerge in this context. In perhaps theearliest pertinent study, Volling and Feagans (1995) detected a
relevant and thus noteworthy interaction between children’s social
fear (i.e., negative emotionality), as rated by mothers, and theobserved quality of center-based child care in the prediction ofobserved nonsocial activity (i.e., solitary play, onlooker behavior)a year later when children were 14 – 48 months of age. The highly
fearful children manifested both the most and least nonsocial
activity, depending upon the quality of child care, whereas no such
effect emerged in the case of the low-fear children.
Given Volling and Feagan’s (1995) limited sample size, perhaps
more convincing evidence that differential susceptibility characterizes some effects of child care comes from a recent analysis ofdata from the large-sample NICHD Study of Early Child, which
examined both negative and positive developmental outcomes(Pluess & Belsky, 2009b). In this work explicitly testing differential susceptibility, the effect of observed quality of care (averaged
across measurements at 6, 15, 24, 36, and 54 months) on behavior
problems and social competence rated by caregivers in the year
before school entry and by teachers in the first year of school was
moderated by child temperament. Children with difficult temperament (averaged across the first 6 months) had more behavior
problems when reared in low-quality environments and fewer
problems when quality was high than did children with easytemperaments, and the regression lines (i.e., slopes) proved significant only for the children who scored high on difficult temperament as infants. Similar results emerged when Pluess and Belsky(2009a) extended this research to determine if differential susceptibility to the effects of good- and poor-quality child care in thefirst 4.5 years of life extended to teacher-reported behavior problems and teacher– child conflicts when children were 10 –11 yearsof age.

Beyond the Early Childhood Years
Although the just-cited research indicates that differentialsusceptibility effects pertaining to early parenting and child-care
experience and involving phenotypic susceptibility factors extend
beyond the early childhood years, the question arises as to whether
rearing and related experiences thereafter operate in a similarmanner. Indication that they do comes from Lengua’s (2008)
Temperament ⫻ Parenting interaction study, which sought toexplain change in internalizing and externalizing problems using acommunity sample of 8- to 12-year-old boys and girls (see also
Mezulis, Hyde, & Abramson, 2006). The effects of mothers’
parenting style, as reported by children (i.e., rejection/acceptance,
inconsistent discipline), on change over a 1-year period in motherreported internalizing and externalizing problems varied by childtemperament. Children highly prone to negative emotion in theform of frustration increased in externalizing problems over time
when mothers were rejecting but decreased in externalizing problems when mothers manifested little rejection; no such effects ofrejection emerged in the case of children scoring low on frustration. Inconsistent discipline did not affect the development ofinternalizing problems in low-anxious boys but did so in the caseof high-anxious ones and in a manner consistent with differential
susceptibility. It needs to be noted, however, that not all of Lengua’s (2008) results were in line with these indicating that children
scoring higher on some index of negativity prove more susceptible
to the effects of more and less competent parenting. Leve, Kim,

BEYOND DIATHESIS STRESS

and Pears’s (2005) work on the determinants of behavior-problem
trajectories from ages 5 to 17 documents similarly contrastingfindings.
Perhaps especially worthy of consideration is research treating
endophenotypic traits, rather than just behavioral functioning, as
developmental outcomes shaped by developmental experience.
Gilissen, Bakermans-Kranenburg, van IJzendoorn, and van derVeer (2008) detected a significant interaction between child fearfulness (parent report) and observed parent– child relationshipquality in the prediction of skin conductance level (SCL) reactivity
in response to a fear-inducing film clip. This cross-sectional investigation of 4- and 7-year-olds—specifically testing differential
susceptibility—found that more fearful children manifest lowerand higher SCL reactivity than do all low-fear children, depending
upon whether their parent– child relationships were, respectively,
secure or insecure. Of indisputable interest is that SCL reactivity—a marker for the activity of the sympathetic nervous system— has been found to moderate effects of the environment in adifferential susceptibility manner, as is reported in the next major
section dealing with endophenotypes. The Gilissen et al. (2008)
findings would thus seem consistent with Boyce and Ellis’s (2005)
claim that plasticity may itself be a function of environmental
influence (Belsky & Pluess, 2009).
Intriguingly, there is also suggestive evidence of the legacy oreven operation of differential susceptibility in early adulthood.
Especially worthy of consideration is a series of cross-sectional
studies testing hypothesized interactions between sensoryprocessing sensitivity, a personality characteristic measureable bymeans of the Highly Sensitive Person Scale (see Aron & Aron,
1997), and various environmental factors in predicting adult shyness and negative affectivity (Aron, Aron, & Davies, 2005). According to Aron and Aron (1997), about 20% of individuals arecharacterized by a high-sensitive personality; this encompasses a
sensitive nervous system, awareness of subtleties in surroundings,
and a tendency to be more easily overwhelmed when in a highly
stimulating environment. The studies of most relevance to thisreport (Aron et al., 2005, Study 2 and 3) indicated that a problematic (and retrospectively reported) child-rearing history predictedhigh levels of (self-reported) shyness and negative affectivity
among undergraduate students, whereas its absence predicted low
levels of these same dependent constructs; this relation obtained
principally in the case of students scoring high on sensoryprocessing sensitivity, resulting in significant differences between
regression lines (i.e., slopes) for high- and low-sensitivity groups.

Beyond Field Studies: Experimental Evidence
Evidence of a similar differential-susceptibility effect emergedin other research on sensory-processing sensitivity when the environmental influence, stress (or lack thereof), was experimentallyinduced by requiring students to take easy and difficult tests before
negative affectivity was assessed (Aron et al., 2005, Study 4). In
view of the fact that all research considered through this point canbe regarded as limited due to its correlational (and often crosssectional) nature, such an experimental demonstration of an environmental effect operating in a differential-susceptibility-like manner must regarded as important. After all, the possibility exists thatthat relations detected between experience and development in
virtually all the work cited through this point could be a function893

of some unmeasured third variable, most notably, perhaps, genesthat both elicit environmental experiences and influence development.
For this very reason, particular importance is accorded to two
additional experimental studies, each of which explicitly tested
Belsky’s (1997a, 2005) differential-susceptibility-derived proposition that negatively emotional infants would disproportionately
benefit from supportive environments. In one, Velderman,
Bakermans-Kranenburg, Juffer, and van IJzendoorn (2006) sought
to enhance the sensitivity of mothers at risk for rearing insecure
infants due to their own less-than-secure state of mind regarding
attachment. Results revealed that improvements in parenting following participation in a video-feedback-based intervention translated, as theorized, into secure attachment but only for infants whoscored high on negative reactivity (before the intervention).
The second experimental study involved a reanalysis of datafrom the Infant Health and Development Program (1990), a wellknown early intervention that involved the random assignment ofpoor, low-birth-weight infants and their families to treatment orcontrol condition, putatively generating positive, across-the-board
program effects. Blair (2002) found, as predicted, thatexperimental-group infants— exposed to educational day care in
the second and third year of life and home visiting and parent
support over their first 3 years—who were highly negatively
emotional scored substantially lower on externalizing problems at
3 years of age than did similarly tempered infants randomly
assigned to the control group; no such treatment effect occurred in
the case of other infants. Especially intriguing given the fact that
virtually all research considered through this point has focused on
differential susceptibility vis-à-vis social and emotional functioning is that exactly the same results emerged when the outcome inquestion was severely impaired cognitive functioning. Highly negative infants assigned to the experimental intervention were fivetimes less likely to score at or below 75 on an IQ test at age 3 thanwere their negatively emotional counterparts assigned to the control condition. No such experimental effect was detected in thecase of infants scoring low on negative emotionality.

Comment
The repeatedly discerned moderational effect of negative emotionality/difficult temperament in the case of parenting, child-carequality, and other environmental experiences raises the question of
why this should be the case. This issue is especially significant
given the fact that even though the differential-susceptibility hypothesis stipulates that children should vary in their susceptibility
to environmental influences (i.e., plasticity) for evolutionarybiological reasons (Belsky, 1997a, 2005), it does not predict that
more negatively emotional children or those with difficult temperament would prove especially malleable; this was an empiricalobservation (Belsky, 2005). One possible reason why those high innegative emotionality, operationalized as it has been in a variety ofways, may prove most susceptible to environmental influence isbecause a negatively emotional/difficult temperament reflects ahighly sensitive nervous system, one on which experience registers
especially strongly; this is so irrespective of whether the experience is positive and growth promoting or negative and undermining of well-being (Aron & Aron, 1997; Belsky, 2005).

894

BELSKY AND PLUESS

Whatever the mechanisms involved in making more negatively
emotional children seemingly more malleable—in an often forbetter-and-for-worse manner, consistent with differentialsusceptibility thinking—it would be a mistake to conclude that thisis the most important phenotypic marker of plasticity. Even though
this could be the case, it could well be an artifact of the disproportionate attention that investigators guided by diathesis-stress/
dual-risk perspective have devoted to investigating individual “riskfactors” that interact with contextual adversity in producing problematic functioning (Belsky & Pluess, 2009). If this is so, then it
certainly behooves the field to consider other potential behavioral
markers of plasticity/malleability rather than reify one. Nevertheless, the evidence considered through this point clearly suggeststhat differential susceptibility is operative—and not just perhaps in
the opening years of life—and that conceptualizing negatively
emotional or difficult infants and children as “at risk” and “vulnerable” may misrepresent their more general highly malleable/
plastic nature.

Endophenotypic Markers of Differential Susceptibility
Recall that central to Boyce and Ellis’s (2005) biologicalsensitivity-to-context proposition is the claim that children who arehighly physiologically reactive to stress manifest the most developmental plasticity. Given that many such children probably begin
life as highly negative infants or ones with difficult temperaments,
it seems likely that many of the very same children Belsky (1997a,
2005) first called attention to in this regard are being identified bydifferent means. In any event, what Boyce and Ellis’s (2005)
viewpoint highlights is that endophenotypic characteristics, notjust the behavioral ones considered in the preceding section, might
moderate environmental influences and thereby function as plasticity markers. In this section, we consider evidence consistent
with the claim (see Table 2) after providing a brief summary of thetwo separate physiological systems—the autonomous nervous system and the neuroendocrine system—and their specific functions.
The so-called fight-or-flight response to stress is primarily controlled by the autonomous nervous system, which is further divided into the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). The SNS controls those
activities that are mobilizing during stress and anxiety (e.g., accelerated heart rate, increased blood pressure, enhanced blood flow
to the skeletal muscles/decreased blood flow to the internal organs
and extremities, sweating). Physiologically opposing activities under PNS control serve the basic functions of rest, repair, andrelaxation of the body and restoration of energy stores (e.g.,decreases in heart rate and blood pressure, stimulation of thedigestive system, sexual arousal, sleep). The neuroendocrine response to stress is primarily controlled by the hypothalamus–
pituitary–adrenal axis (HPA). Corticotropin releasing hormone(CRH)—which is released from the hypothalamus in response tostress—activates the secretion of adrenocorticotropic hormone(ACTH) from the pituitary gland, which then causes the adrenal
cortex to release cortisol into the general bloodstream. Finally,
cortisol leads to a large number of diverse physiological andmetabolic changes in order to prepare the organism for optimalfunctioning under stressful conditions (e.g., increase of bloodpressure and blood sugar, breakdown of lipids and proteins, mobilization of amino acids, reduction of immune responses).

In the earliest pertinent investigation of physiological reactivity
presenting differential-susceptibility-like effects, Gannon, Banks,
Shelton, and Luchetta (1989) studied undergraduates on whom arange of SNS markers of physiological reactivity were obtained(before and after a math-problems’ stress test; plasticity factor).
These students also reported on daily hassles (environmental factor), as well as common physical symptoms and depression. Compared to individuals showing low reactivity of blood volume pulse
amplitude, high-reactive students reported both few physicalsymptoms when experiencing few daily hassles and many physicalsymptoms when experiencing many hassles. Those students showing slow heart rate recovery after the stress test reported fewer
depressive symptoms when experiencing fewer daily hassles andmore symptoms when experiencing more daily hassles than did
individuals with a fast recovery, a result also consistent withdifferential-susceptibility thinking.
Findings in line with those just presented, but evident at muchyounger ages, emerged in Boyce et al.’s (1995) test of the hypothesis that mean arterial blood pressure reactivity to a stress test atage 3–5 years would interact with a composite measure of childcare quality (measured across a 2-year period) in predicting frequency of respiratory illness during the 6 months following thephysiological-reactivity assessment. In particular, children withhigher blood pressure reactivity exhibited higher rates of respiratory illness than other children when growing up in stressful
rearing contexts, yet under low-stress conditions such highreactive children had a significantly lower incidence of respiratory
illnesses than did other children.
Reactivity-moderated effects of environmental experiences arealso evident when SCL reactivity serves as the index of physiological functioning. This seems noteworthy in view of the fact that
SCL is controlled solely by the SNS, in contrast to the othercardiovascular-reactivity measures, which are generally innervatedand controlled by both SNS and PNS. Thus, El-Sheikh, Keller, andErath (2007) investigated associations between SCL reactivity(assessed during a star-tracing problem-solving task), marital conflict (parent report), and change (from 9 to 11.5 years) in adjustment problems (parent report). Compared to girls with low SCL
reactivity, highly reactive girls showed the largest increase ininternalizing problems if from highly conflicted homes but thesmallest increase when marital conflict was low in their families.
The same research team also used vagal tone (indexed byrespiratory sinus arrhythmia; RSA) and vagal suppression (duringexposure to an audio recording of a male–female verbal conflict)to investigate whether and how PNS measures moderate effects ofmarital conflict on child adjustment in middle childhood(El-Sheikh, Harger, & Whitson, 2001). Compared to children withhigh vagal tone (who were not seemingly affected by maritalconflict), those scoring low in vagal tone proved less anxious whengrowing up in families with little marital conflict but more anxious
when residing in high-conflict homes. Similar crossoverinteraction results emerged with respect to vagal suppression but
for boys only.
In a recent, large cross-sectional study of 5-year-olds,
Obradovic, Bush, Stamperdahl, Adler, and Boyce (in press) provided yet more evidence of the role of RSA in moderating environmental effects, along with some pertaining to cortisol reactivity(both assessed during a stress test). In this research, a composite
index of childhood adversity (based on parental reports of financial

1995

2007

2001

in pressBoyce et al.

El-Sheikh et al.

El-Sheikh et al.

Obradovic et al.

75 8- to 12-yearold boys andgirls
338 5-year-old
boys and girls

110 9-year-old
boys and girls

137 3- to 5-yearold boys andgirls

50 male andfemale students

SamplePNS reactivity: high
RSA reactivity,
cortisol reactivity

PNS reactivity: low
vagal tone

Cardiovascular
reactivity: highblood volume pulse
amplitude reactivity,
slow heart raterecovery
Cardiovascular
reactivity: higharterial bloodpressure reactivity
SNS reactivity: highskin conductancereactivity

Childhoodadversity

Maritalconflict

MaritalconflictChild-carestressors

Daily hassles

Environmental
predictor

Prosocial
behavior,
Schoolengagement,
Change inacademiccompetence

A 7 AAA 7 AA

Internalizing
andexternalizing
problems
AnxietyA 7 AA

ns
ns
ns

N7P
N7P

ns

ns

not reported

N7P

N 7 ANN 7 AN

N7P

Depression
symptoms
Respiratory
illness
incidence

not reported

N 7 AN

Physical
symptoms

A 7 AAA 7 AAnot reported

N 7 AN

OutcomeModerator/
predictor
correlation

Range ofpredictor

Range ofoutcome

ns

ns

ns

ns

ns

ns

ns

ns

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

regression
lines
regression
lines
regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

Subgroup
contrasts

Follow-up
analysisa

Note. A ⫽ adversity; AA ⫽ absence of adversity; S ⫽ support/enrichment; AS ⫽ absence of support/enrichment; N ⫽ negative outcome; AN ⫽ absence of negative outcome; ns ⫽ nonsignificant;P ⫽ positive outcome; AP ⫽ absence of positive outcome; SNS ⫽ sympathetic nervous system; PNS ⫽ parasympathetic nervous system; RSA ⫽ respiratory sinus arrhythmia.
aAfter detecting significant crossover interaction between moderator and predictor on outcome.

1989

Year

Gannon et al.

AuthorSusceptibility factor:
Plasticity marker

Study characteristics

Table 2
Characteristics of Study Findings Providing Empirical Evidence for Differential Susceptibility as a Function of Endophenotype

BEYOND DIATHESIS STRESS

895

BELSKY AND PLUESS

896

stress, parenting overload, marital conflict, negative/anger expressiveness, maternal depression, and harsh and restrictive parenting)proved predictive of externalizing symptoms, prosocial behaviors,
school engagement, and academic competence (based on parent,teacher, and child self-reports); this proved true more so in the caseof children with a more reactive PNS (for contrasting evidence, see
El-Sheikh, Erath, & Keller, 2007; El-Sheikh et al., 2001). In
particular, children with high RSA reactivity were rated as moreprosocial under low-adversity conditions and as less prosocial
under high-adversity conditions than were children with low RSA
reactivity. High RSA reactivity children also scored higher onschool engagement under low-adversity conditions and lower under high-adversity conditions than did children with low RSA
reactivity.
Despite the fact that multiple PNS investigations have provided
evidence in line with the differential-susceptibility hypothesis,
only a single investigation involving the neuroendocrine systemappears to provide comparable evidence. In the just summarized
work by Obradovic et al. (in press), children with high cortisol
reactivity were rated as more prosocial under low adversity andless prosocial under high adversity relative to children with low
cortisol reactivity. It is difficult to be sure that this apparent
imbalance in evidence across the autonomous nervous system andthe neuroendocrine system is due to the two stress reactivity
systems playing fundamentally different roles vis-à-vis environmental influences; the alternative possibility is that one has justreceived more empirical attention as a moderator of environmental
effects. This would seem likely, given that most developmentalists
measuring cortisol reactivity treat it as an outcome to be explainedby environmental factors rather than as a moderator of environmental influences ( Fernald, Burke, & Gunnar, 2008; Gunnar &Quevedo, 2007).

Genetic Markers of Differential Susceptibility
Whereas almost all the evidence cited through this point derives
from research on children, GXE interaction findings consistent
with the differential-susceptibility hypothesis typically come fromstudies of adults; this is especially true of psychiatric research
focused upon pathological outcomes (e.g., depression, antisocial
behavior). The fact that most of this work has been guided bytraditional diathesis-stress thinking means that on many occasions
evidence that those carrying a putative “risk allele” actually function better than others when not exposed to the risk condition being
studied (e.g., negative life events) frequently goes unnoticed or atleast is not discussed in primary reports. Recently, Uher and
McGuffin (2008) called attention to such differentialsusceptibility-like findings (but not in those terms) in their review
of GXE work on life events, the serotonin-transporter gene, anddepression. Here we call attention to many more GXE findings
seemingly reflective of differential susceptibility across a diverse
array of candidate genes (see Table 3).

Two sets of evidence, one linking the low-activity MAOA allele toantisocial behavior and another linking abuse and neglect in childhood to the same developmental outcome, led Caspi et al. (2002)
to hypothesize that inconsistency in findings in both literatures
could be a result of the fact that maltreatment effects are moderated by genotype; this is exactly what they discovered in their
groundbreaking GXE research carried out on a New Zealand birthcohort followed into young adulthood. It was principally young
men—young women were not studied—with one form of the gene,that associated with low MAOA activity, who proved most violence prone if they had been subjected to child maltreatment. For
those children with the high-MAOA-activity allele, a substantiallysmaller effect of child maltreatment emerged.
Although most have interpreted these findings, not unreasonably, in diathesis-stress terms, few seem to have noticed that thosemost vulnerable to the adverse effects of maltreatment actually
scored lowest in antisocial behavior when not exposed to maltreatment, suggesting perhaps greater plasticity rather than just greater
vulnerability to adversity. This interpretation is buttressed by results of a reasonably large number of studies that sought toreplicate the Caspi et al. (2002) findings. For example, Kim-Cohenet al. (2006) found that at age 7 years boys with the low-MAOAactivity variant were rated by mothers and teachers as having moremental health problems—and specifically symptoms of attentiondeficit/hyperactivity disorder (ADHD)—if they had been victimsof abuse, but fewer problems if they had not, than were boys withthe high-MAOA-activity genotype. In a large longitudinal study ofadolescent twin boys age 8 –17 years, Foley et al. (2004) observedthat compared to boys with the high-MAOA-activity allele, thosewith the low-MAOA-activity allele were more likely to be diagnosed with conduct disorder if exposed to higher levels of childhood adversity and were less likely if exposed to lower levels ofadversity. Similar results emerged in Nilsson et al.’s (2006) crosssectional investigation of adolescent boys when the predictor was
psychosocial risk, operationalized in terms of maltreatment experience and living arrangement, and the outcome to be explained
was criminal behavior (composite of vandalism, violence, stealing).
Three additional studies generated results documenting theheightened susceptibility to environmental influences of individuals carrying the low-MAOA allele. One was a prospective investigation of the long-term effects of (court-substantiated) childabuse and neglect on White male and female violent and antisocial
behavior in adolescence and through the early 40s (Widom &Brzustowicz, 2006). The second was a retrospective study of adultpsychiatric outpatients and healthy controls linking trauma experienced in childhood with physical aggression in adulthood(Frazzetto et al., 2007). And the third was a retrospective study offemale American Indians that investigated effects of childhood
sexual abuse on symptoms of antisocial personality disorder(Ducci et al., 2008).

5-HTTLPR
MAOA
The neurotransmitter-metabolizing enzyme monoamine oxidase
A gene, or MAOA, is located on the X chromosome. It encodes the
MAOA enzyme, which metabolizes neurotransmitters such as norepinephrine, serotonin, and dopamine, rendering them inactive.

Far more studied than GXE interactions involving MAOA havebeen those involving 5-HTTLPR. The serotonin-transporter-linked
polymorphic region (5-HTTLPR) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonintransporter. Most research focuses on two variants—those carrying

BEYOND DIATHESIS STRESS

at least one short allele (s/s, s/l) and those homozygous for the longallele (l/l)—though more variants than these have been identified(Nakamura, Ueno, Sano, & Tanabe, 2000). The short allele has
generally been associated with reduced expression of the serotonintransporter molecule—which is involved in the reuptake of serotonin from the synaptic cleft—and is thus considered to be related
to depression, either directly or in the face of adversity.
Again breaking empirical ground in GXE research, Caspi et al.
(2003) were the first to show that 5-HTTLPR moderates effects ofstressful life events during early adulthood on depressive symptoms, as well as on probability of suicide ideation/attempts and ofmajor depression episode at age 26 years. Individuals with two s
alleles proved most adversely affected, whereas effects on l/l
genotypes were weaker or entirely absent. Of special significance,
however, is that carriers of the s/s allele scored best on theoutcomes just mentioned when stressful life events were absent,
though, just as was true among low-MAOA-activity individuals in
Caspi et al. (2002), not by very much.
Multiple research groups have attempted to replicate Caspi etal.’s (2003) findings of increased vulnerability to depression in
response to stressful life events for individuals with one or more
copies of the s allele; many have succeeded (see below) but
certainly not all (Risch et al., 2009; Surtees et al., 2006). The data
presented in quite a number of studies indicate, however, that
individuals carrying short alleles (s/s, s/l) not only functioned mostpoorly when exposed to many stressors but functioned best—
showing least problems—when they encountered few or none(e.g., Wilhelm et al., 2006; Zalsman et al., 2006). Calling explicit
attention to such a pattern of results, Taylor et al. (2006) reported
that young adults homozygous for short alleles (s/s) manifested
greater depressive symptomatology than did individuals with otherallelic variants when they had been exposed to early adversity (i.e.,
problematic child-rearing history), as well as many recent negative
life events, yet manifested the fewest symptoms when they had
experienced a supportive early environment or recent positive
experiences. The same for-better-and-for-worse pattern of results
concerning depression was evident—and noted—in Brummett etal.’s (2008) investigation of middle-aged and aging adults who did
and did not serve as caregiver of a relative with Alzheimer’s
disease and in Eley et al.’s (2004) research on adolescent girls who
were and were not exposed to risky family environments.
The effect of 5-HTTLPR in moderating environmental influences in a manner consistent with differential susceptibility is not
restricted to depression and its symptoms. It also emerges, perhaps
unsurprisingly, in studies of anxiety (Gunthert et al., 2007; Stein,
Schork, & Gelernter, 2008) and ADHD, particularly of ADHD thatpersists into adulthood (Retz et al., 2008). In all these cases,
whether studies examined effects of negative life events (Gunthert
et al., 2007), emotional abuse in childhood (Stein et al., 2008), ora generally adverse child-rearing environment (Retz et al., 2008),
it proved to be those individuals carrying short alleles who responded to developmental or concurrent experiences in a forbetter-and-for-worse manner, depending on the nature of the experience in question.
The final differential-susceptibility-relevant finding involving
5-HTTLPR to be considered that emanates from a field study
comes from Manuck, Flory, Ferrell, and Muldoon’s (2004) investigation of the effect of socioeconomic status on adult central
nervous serotonergic responsivity. Central serotonergic responsiv-

897

ity was measured indirectly by means of the fenfluramine challenge test. Fenfluramine increases serotoneric neurotransmission
by release of serotonin stores and reuptake inhibition. Such stimulation of hypothalamic serotonin receptors promotes as well thepituitary release of the hormone prolactin. This relative release incirculating prolactin concentration provides an index of the serotonergic responsivity in the HPA axis. Consistent with all thefindings summarized above pertaining to depression, anxiety, andpersistent ADHD, s/s individuals manifested the most and least
serotonergic responsivity, depending on whether they were, respectively, of low or high socioeconomic status (SES).
Experimental evidence that those carrying short alleles benefit
disproportionately from a supportive environment comes from
Brody, Beach, Philibert, Chen, and Murry (2009), who evaluatedeffects of a family-based intervention designed to reduce adolescent risk taking among rural African American children at highrisk for engaging in such behavior. The multisession intervention
conducted at a community center sought to promote nurturant–
involved parenting practices and children’s proclivities to follow
family rules and establish goals for the future. Results revealed thatthose explicitly labeled as at “genetic risk” due to the fact that they
carried one or two short alleles on 5-HTTLPR were the ones most
likely to benefit from the program. These participants engaged in
substantially less drinking, drug use, or sexual activity than did
those carrying the same alleles who were not randomly assigned tothe intervention.

HTR2A
Additional evidence consistent with differential-susceptibility
thinking emerges from GXE studies of another serotonergic gene,
the serotonin receptor gene (HTR2A), which comes in two forms:
the C and T alleles. Whereas some research has revealed an
association between the C allele and depression (see, e.g., Du,
Bakish, Lapierre, Ravindran, & Hrdina, 2000), other studies havefound the T allele to confer depression risk (Eley et al., 2004).
Recent work by Jokela and associates (Jokela, KeltikangasJarvinen, et al., 2007; Jokela, Lehtimaki, & Keltikangas-Jarvinen,
2007a, 2007b)— drawing on data from a large-scale, populationbased, longitudinal study in Finland, the Cardiovascular Risk inYoung Finns Study—suggests that individuals carrying the T
allele are generally more affected than others by environmental
factors in a for-better-and-for-worse manner. When nurturance
reported by mother was averaged across baseline (i.e., when study
participants were 3– 8 years old) and again 3 years later, offspringwith at least one T allele scored highest and lowest on self-reported
depression some two decades after baseline, depending on whether
they had experienced, respectively, more or less nurturant care
(Jokela, Keltikangas-Jarvinen, et al., 2007). Similar results
emerged when the effects of residence in very rural Finland were
contrasted with those of living in urban Finland (Jokela et al.,2007a). And the same differential-susceptibility-like results occurred when the predictor was family SES and the outcome to be
explained was self-reported harm avoidance; those carrying one ormore T alleles scored highest on harm avoidance if they had grown
up in low-SES households but lowest if they had grown up in
high-SES ones (Jokela et al., 2007b). This latter finding led theinvestigators to suggest that this allele might function as an “opportunity” allele, not just a risk gene.

2002

2006

2004

2006

2006

2007

2008

2003

2006

2006

2006

2008

2004

2007

2008

Kim-Cohen et al.

Foley et al.

Nilsson et al.

Widom &
Brzustowicz

Frazzetto et al.

Ducci et al.

Caspi et al.

Wilhelm et al.

Zalsman et al.

Taylor et al.

Brummett et al.

Eley et al.

Gunthert et al.

Stein et al.

Year

Caspi et al.

Author631 male andfemaleadults
235 male andfemaleadults291 adult
women
847 26-yearold men andwomen
127 male andfemaleadults
316 male andfemaleadults
118 young
adult men
and women
215 male andfemaleadults
377 female
and maleadolescents
350 male andfemalestudents
247 male andfemalestudents

514 8- to 17year-old
boys
81 adolescentboys

442 26-yearold men
975 7-year-old
boys

Sample5-HTTLPR: s allele

5-HTTLPR: s allele

5-HTTLPR: s allele

5-HTTLPR: s allele

5-HTTLPR: s allele

5-HTTLPR: s allele

5-HTTLPR: s allele

MAOA: low-activity
allele5-HTTLPR: s allele

MAOA: low-activity
allele

MAOA: low-activity
allele

MAOA: low-activity
allele

MAOA: low-activity
allele

MAOA: low-activity
allele
MAOA: low-activity
alleleSusceptibility factor:
Plasticity marker

Environmental
predictor

Childhoodemotional
abuse

Early familyrisk, stressful
life events
Caregiver of
Alzheimer
patient
Familyenvironmental
risk
Daily event
stressStressful life
eventsStressful life
eventsChildhoodtraumatic life
eventsChildhoodsexual abuse
Stressful life
events

Maltreatment
and living
conditions
Childhoodabuse/neglect

Childhoodadversity

Childhoodmaltreatment
Physical abuse

Study characteristics

Criminal behaviors
Antisocial
behavior
Physicalaggression
Antisocial
personality
Depression
symptoms,
suicide ideation
Probability for
major
depression
Depression
symptoms

A 7 AAA 7 AAA 7 AAA 7 AA

Depression
symptoms
Depression
symptoms
Depression
symptoms
Evening anxiety
Anxiety sensitivity

A7S
A 7 AAA 7 AAA 7 AAA 7 AAA 7 AAA 7 AAA 7 AAA 7 AAA 7 AA

OutcomeAntisocial
behavior
Mental healthproblems,
ADHD
Conduct disorder

A 7 AA

Range ofpredictor

Table 3Characteristics of Study Findings Providing Empirical Evidence for Differential Susceptibility as a Function of Genotype

N 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 ANN 7 AN

Range ofoutcome

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

Moderator/
predictor
correlation

ns

ns

regression
lines

regression
lines

regression
lines

regression
lines

means

regression
lines

regression
lines

regression
lines

means

regression
lines

means

regression
lines

regression
lines

regression
lines
regression
lines

Subgroup
contrasts

Follow-up
analysisa(table continues)

significant

ns

ns

significant

ns

ns

ns

ns

ns

ns

ns

significant

ns

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

898
BELSKY AND PLUESS

2004

2007

2007a

2007b

2007

2007

2006

2007

2007

2008

Manuck et al.

Jokela, KeltikangasJärvinen, et al.

Jokela, Lehtimaki,
et al.

Jokela, Lehtimaki,
et al.

Jokela, Räikkönen,
et al.

Keltikangas-Järvinen
et al.

van IJzendoorn &BakermansKranenburg
BakermansKranenburg & vanIJzendoorn
Propper et al.

Sheese et al.

BakermansKranenburg, vanIJzendorn, Pijlman,
et al.

2006

2008

Year

Retz et al.

AuthorTable 3 (continued)

139 male andfemaleadults820–1212
male andfemaleadults1185–1224
male andfemaleadults966–1246
male andfemaleadults
341 male andfemaleadults
341 male andfemaleadults
63 male andfemaletoddlers
47 male andfemaleinfants
169 male andfemalechildren
45 male andfemaleinfants
157 male andfemaletoddlers

184 adult maledelinquents

SampleDRD4: 7-repeat allele

DRD4: 7-repeat allele

DRD4: short allele

DRD4: 7-repeat allele

DRD4: 7-repeat allele

THP1: A allele

THP1: A allele

HTR2A: T allele

HTR2A: T allele

HTR2A: T allele

5-HTTLPR: s allele

5-HTTLPR: s allele

Susceptibility factor:
Plasticity marker

Environmental
predictor

Parentingintervention

Parentingquality

Parentingquality

Maternal
unresolved
loss/trauma
Maternal
sensitivity

Hostile childenvironment

Social support

Parental socioeconomic
statusRural/urban
residency

Maternal
nurturanceChildhoodadverseenvironment
Socioeconomic
statusStudy characteristics

Central nervous
serotonergic
responsivity
Depression
symptoms
Depression
symptoms
Harm avoidance

Depression
symptoms
Harm avoidance
Disorganizedattachment
Externalizing
behavior
Externalizing
behavior
Sensation seeking
Externalizing
behavior

A 7 AA

A7S

A7S

S 7 ASA 7 AAA 7 AA
A7S
A7S
A7S
S 7 ASS 7 AS

ADHD

OutcomeA 7 AA

Range ofpredictor

N 7 AN

N7P

N 7 ANN 7 ANN 7 AN

N7P

N 7 AN

N7P

N 7 ANN 7 AN

N7P

N 7 AN

Range ofoutcomens

ns

not reported

ns

ns

ns

ns

ns

ns

ns

ns

not reported

Moderator/
predictor
correlation

ns

ns

ns

ns

ns

ns

ns

regression
lines

regression
lines

regression
lines

regression
lines

means

regression
lines

regression
lines

means

means

means

means

regression
lines

Subgroup
contrasts

Follow-up
analysisa(table continues)

significant

ns

ns

ns

not
reported

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

BEYOND DIATHESIS STRESS

899

176 mothers

2008

1997

2007

2007

2008

2007

2009

2009c

Berman & Noble

Elovainio et al.

Mills-Koonce et al.

Propper et al.

Keltikangas-Järvinen
et al.

Sonuga-Barke et al.

Belsky et al.

DRD2: A1 allele
DRD4: 7 repeat allele
COMT: Val allele

DAT1: 9R allele
5-HTTLPR: s allele

DRD2: A1 allele

DRD2: A1 allele

DRD2: A1 allele

DRD2: A2 allele

DRD2: A1 allele

DRD4: 7-repeat allele
COMT: Val allele

DRD4: 7-repeat allele

Susceptibility factor:
Plasticity marker

Environmental
predictor

Maternal
expressed
emotionParental divorce

Birth weightMaternal
sensitivity

Maternal
sensitivity

Stressful life
eventsFamily stress

Daily hassles

Parentingintervention

Study characteristics

Maternal
sensitivity
Visuospatial
ability, P300
amplitude
Depression
symptoms

A 7 AAA 7 AA

Affective problems
RSA
Educational
achievement
Conduct disorder
Adult relationshipstability

A7S
A7S
A7S
S 7 ASA 7 AAA 7 AA

Salivary cortisol

OutcomeS 7 AS

Range ofpredictor

N 7 ANN 7 AN

N7P

N7P

N 7 ANN 7 AN

N7P

N7P

N7P

Range ofoutcome(significant
for COMT
Val)

ns

ns

ns

significant

significant

ns

ns

ns

ns

Moderator/
predictor
correlation

ns

ns

ns

ns

significant

ns

ns

ns

ns

Moderator/
outcomecorrelation

Statistical criteria fordifferential susceptibility

regression
lines

means

regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

regression
lines

means

Subgroup
contrasts

Follow-up
analysisaaNote. A ⫽ adversity; AA ⫽ absence of adversity; S ⫽ support/enrichment; AS ⫽ absence of support/enrichment; N ⫽ negative outcome; AN ⫽ absence of negative outcome; P ⫽ positive outcome;AP ⫽ absence of positive outcome; ADHD ⫽ attention-deficit hyperactivity disorder; RSA ⫽ respiratory sinus arrhythmia.
After detecting significant crossover interaction between moderator and predictor on outcome.

168 10- to
13-year-old
boys
1,636 maleand female
adults172 3-year-old
boys andgirls
206 male andfemaleinfants
1,512 maleand female
adults728 5- to 17year-oldboys
183 male andfemaleadults

130 male andfemaletoddlers

Sample2008

Year

BakermansKranenburg, vanIJzendoorn,
Mesman, et al.
van IJzendoorn et al.

AuthorTable 3 (continued)

900
BELSKY AND PLUESSBEYOND DIATHESIS STRESS

THP1The same Finish research group, drawing on the same
population-based sample, identified similar interaction effects involving yet another serotonin gene, a polymorphism in the tryptophane hydroxylase 1 gene (THP1; Jokela, Raikkonen, Lehtimaki, Rontu, & Keltikangas-Jarvinen, 2007); this gene codes for arate-limiting enzyme in the biosynthesis of serotonin. Of the twovariants A and C, the A allele has been associated with low
serotonin levels (Jönsson et al., 1997) and suicidal behavior/depression, though findings are not consistent across studies (see,e.g., Bellivier, Chaste, & Malafosse, 2004; Lalovic & Turecki,2002).
Jokela, Raikkonen, et al. (2007) detected a moderating effect of
TPH1 on the association between social support and depressive
symptoms. Depressive symptoms and social support were assessed
when participants were between 20 and 35 years of age, with theformer measurements taken again 4 years later. Compared with allother individuals, A/A individuals experienced the most and leastdepression, whenever depression was assessed, depending onwhether they had experienced, respectively, low or high social
support. This proved to be even more the case when change indepressive symptoms was the outcome to be explained. Comparable differential-susceptibility-like results emerged when the environmental predictor was hostile childhood environment (basedon maternal report) and harm avoidance in adulthood was theoutcome to be explained (Keltikangas-Jarvinen, Puttonen, et al.,2007).

DRD4
We now move from the serotonergic to the dopaminergic system, which is engaged in attentional, motivational, and reward
mechanisms. A polymorphism of the dopamine receptor D4(DRD4) gene has stimulated much GXE research. Variants of
DRD4 differ by the number of 48-base-pair tandem repeats in exon
III, which ranges from 2 to 1. The 7-repeat variant has been
identified as a vulnerability factor due to its links to ADHD
(Faraone, Doyle, Mick, & Biederman, 2001), high novelty-seeking
behavior (Kluger, Siegfried, & Ebstein, 2002), and low dopamine
reception efficiency (Robbins & Everitt, 1999), among other correlates.
A number of studies indicate that individuals carrying thisputative risk allele not only are more adversely affected by poorer
environmental conditions, broadly conceived, but also benefit
more than others from good-quality ones (van IJzendoorn &Bakermans-Kranenburg, 2006). Four related inquiries focused onparenting are considered particularly important, because a “good”
environment was operationalized not just as the absence of adversity but in terms of high-quality parenting. In a longitudinal investigation, maternal sensitivity observed when children were 10
months of age predicted externalizing problems reported by themother more than two years later, but only for children carrying
the 7-repeat DRD4 allele (Bakermans-Kranenburg & van IJzendoorn, 2006). Whereas such children displayed the most externalizing behavior of all children when mothers were judged insensitive, they also manifested the least externalizing behavior whenmothers were highly sensitive (for contradictory results, see Propper, Willoughby, Halpern, Carbone, & Cox, 2007). A cross-901

sectional study of sensation seeking in 18- to 21-month-old children generated results in line with those just summarized. Toddlers
carrying the 7-repeat allele were rated by parents as showing,compared to children without the 7-repeat allele, less sensationseeking behavior when parenting quality was high but more when
it was low (Sheese, Voelker, Rothbart, & Posner, 2007).
Experimental intervention research designed to enhance parenting also reveals a moderating effect of the 7-repeat allele. When
Bakermans-Kranenburg, van IJzendorn, Pijlman, Mesman, andJuffer (2008) looked at change over time in parenting—from
before to well after a video-feedback parenting intervention wasprovided on a random basis to mothers of 1- to 3-year-olds whoscored high on externalizing problems—they found that the intervention succeeded in promoting more sensitive parenting andpositive discipline. Moreover, this intervention effect translated
into improvements in child behavior but only for those children
carrying the DRD4 7-repeat allele. The same was true when, at
posttreatment follow up, stress reactivity was measured by meansof change in salivary cortisol before and after the administration ofan experimental stressor (Bakermans-Kranenburg, van IJzendoorn,
Mesman, Alink, & Juffer, 2008). In fact, children in the experimental group who carried the DRD4 7-repeat allele not only
showed the least physiological stress reactivity of all children but
showed the most if their mothers had been assigned to the control
group.
Of special interest is that the most pronounced reduction inchildren’s problem behavior occurred when two conditions obtained: (a) the parenting intervention substantially improved themother’s use of positive discipline techniques and (b) the child
carried the 7-repeat allele. One cannot but wonder why somemothers benefited more from the experimental treatment thanothers in terms of (substantially) improved parenting. Recent evidence that the effect of daily hassles on sensitive parenting isdependent on the mother’s own genotype and operates in a forbetter-and-for-worse manner certainly raises the possibility thatGXE processes could account for why some mothers proved tobenefit, in terms of their parenting, more from the intervention
than did others (van IJzendoorn, Bakermans-Kranenburg, & Mesman, 2008). Thus, could an untested GXGXE interaction havebeen responsible for the problem-behavior findings discerned in
the Bakermans-Kranenburg, van IJzendoorn, Pijlman, et al. (2008)
intervention study? Indeed, could it have been that mothers withcertain susceptibility genes proved most responsive to the intervention and that it was this responsiveness, in combination with
their child’s genetic susceptibility to rearing, that generated theresults described? These questions raise a more general one: When
parenting interventions prove effective in changing child behavior,
is a small subset of parent– child dyads responsible for the overall
treatment effect (i.e., those comprising a parent and a child who areboth highly malleable for genetic reasons)? As no intervention
investigation has considered parent as well as child genotype, thispossibility remains to be evaluated.

DRD2
Another polymorphism in the dopaminergic system that has
been a focus of GXE research is located on the DRD2 gene, which
encodes the D2 subtype of the dopamine receptor. Of special
interest is the Taq1A (A1) polymorphism—a C to T substitution

902

BELSKY AND PLUESS

located in a noncoding region of the DRD2 locus—which isthought to affect dopamine receptor D2 availability in postmortem
striatal samples (Thompson et al., 1997). The A1 allele has been
associated with low dopamine density and lower mean relative
glucose metabolic rate in dopaminergic regions in the human brain(Noble, Gottschalk, Fallon, Ritchie, & Wu, 1997), high novelty
seeking (Suhara et al., 2001), and a number of substance use
disorders, particularly alcoholism (Bowirrat & Oscar-Berman,
2005).
A number of study findings suggest that the DRD2 polymorphism moderates environmental influences in differential susceptibility terms (Berman & Noble, 1997; Elovainio et al., 2007), withindividuals carrying the A1 allele proving more susceptible toenvironmental influences in a for-better-and-for-worse manner.
Mills-Koonce et al. (2007) found this in research linking sensitive
mothering when infants were 6 and 12 months of age with children’s affective problems at age 3 years. Propper et al. (2008)
chronicled the same moderating influence using maternal sensitivity at 6 months to predict 12-month-olds’ RSA. And finally,
Keltikangas-Jarvinen, Elovainio, et al. (2007), drawing on thelarge Finnish study, also reported differential-susceptibility-like
effects upon examining the association between birth weight,
presumed to reflect quality of the uterine environment to which thefetus has been exposed, and educational achievement at age 27–34.

Cumulative Genetic Plasticity
Through this point, all GXE investigations cited have examined
the interaction of some environmental factor and a single gene. Inview of the fact that an individual could carry multiple plasticity
alleles—say short alleles in the case of 5-HTTLPR and 7-repeat
alleles in the case of DRD4—the possibility arises that the more
plasticity alleles an individual carries, the more susceptible he or
she will prove to be to environmental influences. Some evidence
consistent with this proposition comes from two recent studies, one
addressing this issue in a post hoc fashion and the other on an apriori basis. In the former, Sonuga-Barke et al. (2009) discovered,after identifying two separate GXE interactions, that children
carrying alleles other than 10R/10R in the case of DAT1 and otherthan two long alleles in the case of 5-HTTLPR proved mostsusceptible to the anticipated adverse effects of high levels ofmaternal expressed (negative) emotion on conduct disorder in theirstudy of 5- to 17-year-olds diagnosed with ADHD. In the second
study (Belsky, Pluess, Comings, & MacMurray, 2009), individuals
were scored in terms of whether they carried 0, 1, 2, or 3 putative
plasticity alleles—DRD4 7-repeat, DRD2 A1, and COMT Val—totest the hypothesis that those with more plasticity alleles would be
more affected than those carrying fewer by childhood exposure to
divorce when the outcome to be explained was relationship instability in adulthood; this is exactly what was found. More thananything else, what these two preliminary inquiries suggest is that
individuals carrying more plasticity alleles do appear more susceptible to at least some environmental influences than do thoseindividuals carrying fewer. Indeed, the Belsky, Pluess, et al. (2009)
work suggests that further efforts should be made to measure
cumulative genetic plasticity by creating a composite score basedon multiple plasticity alleles, in much the same way that multiple
environmental risk factors are often combined to create indices ofcumulative contextual risk (e.g., Belsky & Fearon, 2002).

Conclusion
The preceding review was designed to highlight findings consistent with the differential-susceptibility hypothesis that haveappeared—mostly recently—within much larger literatures addressing principally, even if not exclusively, Parenting ⫻ Temperament and Gene ⫻ Environment interactions. The research considered should be regarded as providing at least suggestive even if
not conclusive evidence that there exist individual differences inplasticity. That is, some individuals are more affected than others
by rearing experiences and, apparently, environmental circumstances more generally. In particular, some individuals appear
more susceptible to the adverse effects of unsupportive contextual
conditions and the beneficial effects of supportive ones.
One of the most striking features of the work reviewed is thediversity of the evidence base suggesting that individuals differ intheir plasticity. As indicated in Tables 1–3, the evidence pertaining
to environmental factors highlights differential-susceptibilityrelated effects of parenting, child-care quality, life events, ruralversus-urban residence, and even birth season. That pertaining tooutcomes seemingly affected by these diverse environmental influences includes disorganized infant attachment; externalizing
problems in the toddler, preschool, and childhood years; antisocial
behavior in adolescence, young adulthood, and even middle age;depression throughout adulthood, children’s respiratory health,and endophenotypes like RSA. Findings pertaining to moderatorsof diverse environmental effects on these diverse outcomes, socalled susceptibility—not just vulnerability—factors, include temperamental and other phenotypic attributes of children, endophenotypic characteristics, and genotypic ones.
The contention that some individuals are more susceptible thanothers to both the adverse and beneficial effects of, respectively,
unsupportive and supportive contextual conditions is strikingly
different from diathesis-stress/dual-risk thinking. The latter model
regards some individuals as simply more vulnerable to adversity
with respect to problematic outcomes and has informed, if notdirectly guided, so much Parenting ⫻ Temperament and GXEinteraction research, including much of that considered herein. The
traditional view seems so deeply entrenched that some investigators have failed to notice when their own data reveal differentialsusceptibility-like findings, not just vulnerability-related ones. Indeed, two secondary analyses of such studies have shown that thebeneficial effects of a benign environment on children presumed to
be vulnerable for genetic reasons are actually larger than theoriginally—and exclusively—anticipated, detected and discussed
negative effects of the contextual adversity under investigation(Belsky et al., 2009; Pluess, Belsky, & Neuman, 2009).
Because of the inherent limits of so many of the studies considered, both in terms of what has been measured and of how data
have been analyzed and presented in primary publications, itremains impossible to know how much confidence should beplaced in the differential-susceptibility interpretation given to thefindings assembled in this paper. Recall in this regard that rather
liberal standards of interpretation have, by necessity, been applied
to virtually all the evidence cited, most of which emerged frominvestigations designed to evaluate diathesis-stress hypotheses. In
order to enable both primary researchers and reviewers of theliterature, including meta-analysts, to better address this fundamental issue about how human development operates, investiga-

BEYOND DIATHESIS STRESS

tory and reporting practices must change. We hope that this selective review, by calling attention to the possibility of differential
susceptibility, will stimulate such change. Toward that end, in theremainder of this section we consider (a) additional statistical andmeasurement criteria for evaluating differential susceptibility, (b)potential mechanisms responsible for it, and (c) still-to-beilluminated unknowns in the differential-susceptibility equation.

Statistical and Measurement Criteria for Evaluating
Differential Susceptibility
Future studies should pursue several research desiderata while
meeting the criteria for establishing differential susceptibility,
summarized earlier, that informed the interpretation of study findings considered herein (Belsky et al., 2007). First, studies shouldmeasure not just the presence of adversity and its absence but
environmental support, as Taylor et al. (2006) did in assessing
positive life events and Bakermans-Kranenburg and van IJzendoorn (2006) did in measuring sensitive parenting. Second, human
functioning should be measured along a continuum ranging from
dysfunction to competence, whenever possible, not just from dysfunction to its absence. Such measurement should avoid the masking of differential susceptibility by ceiling effects. Should this notprove possible for some reason (e.g., positive pole of depression),separate measurements of negative and positive functioning should
be obtained and examined.
Additionally, once a Temperament ⫻ Parenting, GXE, or otherinteraction has been discerned, follow-up analysis should determine whether significant differences in the functioning of individuals hypothesized to be more and less susceptible to environmental
influence obtain when environmental circumstances are supportive, as well as when they are adverse (i.e., at both ends of theenvironmental spectrum). Those putatively susceptible should differ from those putatively not so (or less so) under both supportiveand unsupportive conditions. It is when significant differences are
obtained for both comparisons, revealing a for-better-and-forworse pattern of environmental effects, that differential susceptibility rather than diathesis stress would be the correct inference.
Only a single study reviewed considered—and met—this criterion(Taylor et al., 2006).

Mediating Mechanisms
As much as anything else, the central thesis upon which thiseffort is based and the evidence assembled suggesting that individuals differ in plasticity and thus susceptibility to environmental
influence raise many issues in need of further investigation. One
concerns whether some individuals could be especially susceptible
to just adversity, some to just environmental support and enrichment, some to both, and some to neither. Another is whether
investigators working in different fields and studying the moderating effects of different susceptibility factors are actually identifying the same more-and-less-susceptible individuals by different
means. Consider in this regard that the very children who scorehigh in negative emotionality and physiological stress reactivity
and who have short alleles on the 5-HTTPLR gene could often be
one and the same (Auerbach et al., 1999).
This possibility raises the critical issue of mechanism or process,one mentioned only in passing in this effort reviewing evidence of903

differential susceptibility. Recall that this review was stimulatedby two evolutionary-based propositions. Whereas one stipulated
that there should be individual differences in developmental plasticity, not just vulnerability, and advanced no hypotheses concerning process (Belsky, 1997a, 1997b, 2005), the other highlighted
physiological reactivity as a plasticity mechanism (Boyce & Ellis,2005). Although evidence that negative emotionality and shortalleles on the serotonin-transporter gene (5-HTTLPR) should beconsidered plasticity markers raises the possibility that these traits
function, at least partly, via this putative mechanism when it comesto environmental inputs shaping developmental and behavioral
outcomes, it seems unlikely that this is the only process involved
in differential susceptibility. Therefore, much more work on mediating mechanisms is clearly required. Some may contend, in
contrast, that jumping into the study of mechanism is premature
before evidence of differential susceptibility stronger than that
reviewed herein is reported.
Nevertheless, here we offer some indisputably speculative comments on the issue of mechanism. It occurs to us that perhaps thereason why some are more responsive than others to environmental conditions is because they have lower thresholds for experiencing pleasure and/or displeasure and thus are more sensitive andresponsive than others to, respectively, rewards and/or punishments, very broadly conceived (Gray, 1981, 1982). Although it israther easy to see how having a lower threshold for discomfort
might make an individual more likely to respond in a negative,
problematic way to adverse and displeasure-inducing experiences,perhaps by becoming depressed, anxious, and/or antisocial, it isperhaps more difficult to see why such individuals would also be
more likely to prove susceptible, as the differential-susceptibility
viewpoint presupposes, to the benefits of positive environments.
By the same token, although it is easy to imagine how having a low
threshold for pleasure might increase an individual’s responsiveness to rewards and thus enable that individual to benefit morefrom positive, supportive experiences, it is difficult to imagine
how this proclivity could translate into being more adversely
affected by negative experiences. Perhaps, though, this conundrum
is more apparent than real, if only because the reduction of
discomfort and the loss or denial of a rewarding experience mayregister most powerfully on those who have low thresholds for,respectively, displeasure and pleasure.
The GXE work highlighting differential susceptibility may beconsistent with this line of reasoning. After all, it calls attention toboth the serotonergic system (i.e., 5-HTTLPR, HTR2A, MAOA,
THP1), which is implicated in the experience of displeasure (e.g.,
depression, anxiety), and the dopaminergic one (i.e., DRD4,
DRD2, MAOA), which has been linked to reward sensitivity andsensation seeking (Robbins & Everitt, 1999). Our line of reasoning, along with the GXE evidence implicating these two neurotransmitter systems, would seem not unrelated to Gray’s (1981,1982) behavioral inhibition and behavioral activation systems andto Bakermans-Kranenburg and van IJzendoorn’s (2009) modelwith dopamine-related variance in attention and the processing of
positive versus negative feedback (Klein et al., 2007; Tripp &Wickens, 2008) as mechanisms.
The amygdala also seems likely to be involved in at least somedifferential-susceptibility-related processes. Not only have differences in the amygdala been linked to responsiveness to fearfulstimuli in healthy adults, but individuals with 5-HTTLPR short

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BELSKY AND PLUESS

alleles—a putative plasticity marker—are the ones who manifest
the greatest amygdala activity/reactivity. The same is true of yet
another putative plasticity gene, one conferring low MAOA activity(Meyer-Lindenberg et al., 2006). In fact, the observation thatseveral putative plasticity genes are associated with negative emotionality in infancy (e.g., 5-HTTLPR short alleles, DRD4 7-repeat:
Auerbach, Faroy, Ebstein, Kahana, & Levine, 2001) and a morereactive amygdala (e.g., 5-HTTLPR short alleles: Hariri et al.,2002, 2005; MAOA low-activity allele: Meyer-Lindenberg et al.,2006) lends empirical support to the hypothesis that heightenedsusceptibility to environmental influences may be characterized
and driven by a more sensitive central nervous system (e.g.,
serotonoergic, dopaminergic systems).

Unknowns in the Differential Susceptibility Equation
It is not just mediating mechanisms involved in the process ofdifferential susceptibility for which more research is required.
There is also a need for future work to determine whether individual differences in plasticity are best conceptualized in typological or dimensional terms. Adopting evolutionary terminology
pertaining to reproductive strategy, we can ask whether there exist“plastic and fixed strategists” who are and are not, respectively,
susceptible to environmental experiences, thereby following “conditional” and “alternative” pathways of development (Belsky,2000). But perhaps it makes more sense to think in terms of a“plasticity gradient,” as mentioned earlier, with individuals varying in degree of susceptibility to environmental influences? Conceivably, the choice between a typological and dimensional conceptualization and a parameterization of plasticity is a false one, as
the approach that proves best will vary across conceptual purposesand empirical inquiries.
Another question that arises is whether to regard more and lessplasticity as a global, macro, traitlike characteristic of individuals
or to consider it in more domain-specific terms. Are some people
simply more malleable than others across the board, almost irrespective of the environmental factor and aspect of functioning
under consideration? Or are individuals a complex mosaic ofcomponents that are more and less susceptible to particular environmental influences vis-à-vis particular aspects of functioning,
thus making them both more and less malleable relative to others?
Whereas the latter conceptualization might make more intuitive
sense, of interest is the aforementioned simulation study designed
to determine whether individual differences in susceptibility toenvironmental influences could evolve through natural selection(Wolf et al., 2008). In addition to revealing that they could, thiswork further indicated that such evolution would occur in a moredomain-general, across-the-board manner rather than a domainspecific one.
A final issue of the many that could be raised for future researchpertains to whether, or at least the extent to which, plasticity
should be regarded as principally a function of nature or of nurture.
Certainly the GXE evidence calls attention to heritable individual
differences in plasticity, as well as to the fact that so-called
vulnerability genes or risk alleles might in many cases be better
conceptualized as “plasticity genes” (Belsky et al., 2009). After all,and with regard to the latter point, why would natural selection, forexample, maintain much less select genes that functioned only tofoster depression in the face of negative life events or antisocial

behavior in the face of child maltreatment? Were these perhaps
downside costs of selecting and preserving genes that engenderedbenefit in the face of supportive contextual conditions or that even
operated as adaptations when also functioning in a diathesis-stresslike manner, it would seem to make more sense for them to be
selected.
Although GXE studies are replete with evidence, often unnoticed, of differential susceptibility, this should not lead to thepresumption that plasticity is only a function of genetics. Central
to Boyce and Ellis’s (2005) thinking, it will be recalled, is the roleof extremely supportive and unsupportive environments in fostering physiological reactivity and, thereby, developmental plasticity.
Especially notable, in fact, is recent research on the putatively
adverse effects of maternal stress during pregnancy. This is because so-called fetal programming appears to influence several ofthe very susceptibility factors identified in this review (Belsky &Pluess, 2009; Pluess & Belsky, 2009c). Consider in this regard
research showing (a) that maternal stress during pregnancy predicts difficult temperament at 3 months of age (Huizink, deMedina, Mulder, Visser, & Buitelaar, 2002); (b) that stressful life
events during pregnancy predict toddler fearfulness at age 17months (Bergman, Sarkar, O’Connor, Modi, & Glover, 2007); (c)that prenatal maternal depression and elevated cortisol levels inlate pregnancy predict negative reactivity at age 2 (Davis et al.,2007); and (d) that maternal prenatal anxiety predicts awakening
cortisol in 10-year-olds (O’Connor et al., 2005).
On one hand, such data suggest that very early experience—in
the womb—may shape plasticity, as the “outcomes” just mentioned are among the very child characteristics found in work citedherein to demarcate heightened susceptibility to environmental
influences. Just as important, this reinterpretation of putatively
negative effects of prenatal stress raises fundamental questions
about the problem-centered perspective that pervades virtually all
research and theory on fetal programming: Is it the case thatprenatal stressors compromise later development, as prevailingthinking presumes, or do these prenatal experiences promote plasticity—and thus the organism’s openness to future experiential
input, be it positive or negative in character? That is, is there
prenatal programming of postnatal plasticity (Pluess & Belsky,
2009c)? Oberlander et al.’s (2008) recent epigenetic findings
showing that maternal depressed mood in pregnancy predicts
increased methylation of the human glucocorticoid receptor gene
(NR3C1, measured in neonatal cord blood), which itself forecasts
elevated cortisol stress reactivity at age 3 months, illuminates atleast one biological mechanism that may be central to such fetal
programming of postnatal plasticity, in fact, the very one thatBoyce and Ellis (2005) heralded in their biological-sensitivity-tocontext thesis.
Before concluding on the basis of fetal programming researchthat plasticity is a function of experience as much as a function ofgenetics, we should not lose sight of the fact that GXE interaction
may characterize the fetal programming process (Gluckman &Hanson, 2005). New evidence showing that prenatal smoking
effects on ADHD in childhood are genetically moderated (Neuman
et al., 2007)—in fact, in a differential-susceptibility manner(Pluess et al., 2009)— certainly provides reason to suppose that
fetal programming of postnatal plasticity could be geneticallymoderated, too. This leads to the final unanswered differentialsusceptibility question to be raised: Are some fetuses more sus-

BEYOND DIATHESIS STRESS

ceptible to fetal programming than others, for genetic reasons? Ifthey are—and as of yet we simply do not know—it would suggestthat plasticity is a function not just of nature or nurture but of theirinteraction (Belsky & Pluess, 2009). That is, some individuals may
be more likely than others to be affected by experience, mostnotably perhaps, fetal experience, in ways that subsequently affectwhether or to what degree they will be influenced by the postnatal
world they encounter.

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Received February 9, 2009
Revision received June 26, 2009
Accepted August 12, 2009 䡲