Review

The role of epigenetics in psychological resilience

Demelza Smeeth, Stephan Beck, Elie G Karam, Michael Pluess

Lancet Psychiatry 2021; There is substantial variation in people’s responses to adversity, with a considerable proportion of individuals
8: 620–29 displaying psychological resilience. Epigenetic mechanisms are hypothesised to be one molecular pathway of how
Published Online adverse and traumatic events can become biologically embedded and contribute to individual differences in resilience.
April 26, 2021
However, not much is known regarding the role of epigenetics in the development of psychological resilience. In this
https://doi.org/10.1016/
S2215-0366(20)30515-0 Review, we propose a new conceptual model for the different functions of epigenetic mechanisms in psychological
Department of Biological and
resilience. The model considers the initial establishment of the epigenome, epigenetic modification due to adverse
Experimental Psychology, and protective environments, the role of protective factors in counteracting adverse influences, and genetic moderation
Queen Mary University of of environmentally induced epigenetic modifications. After reviewing empirical evidence for the various components
London, London, UK
of the model, we identify research that should be prioritised and discuss practical implications of the proposed model
(D Smeeth PhD,
Prof M Pluess PhD); UCL Cancer for epigenetic research on resilience.
Institute, University College
London, London, UK Introduction exhibit varying resilience across time and psychological
(Prof S Beck PhD); Department
In times of adversity, some individuals develop domains.
of Psychiatry and Clinical
Psychology, St George Hospital stress-related disorders such as depression or post­ - How do socioenvironmental factors become bio­
University Medical Center, ­traumatic stress disorder. However, a substantial pro­ logically embedded throughout the lifespan and cause
Institute for Development, portion show psychological resilience, which is defined long-term changes to biology that ultimately affect
Research, Advocacy and
broadly as the maintenance of good mental health psychiatric outcomes? Epigenetic mechanisms are
Applied Care, University of
Balamand, Beirut, Lebanon despite exposure to adversity.1 A comprehensive under­ hypothesised to be one important molecular pathway
(Prof E Karam MD) standing of the development of resilience is important involved in this process.5,6 There are now numerous
Correspondence to: for the prevention and treatment of stress-related studies that support the hypothesis that adverse
Prof Michael Pluess, Department disorders. environments affect the epigenome, and that epigenetic
of Biological and Experimental
differences might distinguish susceptible and resilient
Psychology, School of Biological
and Chemical Sciences, Resilience individuals.5–7 However, the specific roles of protective
Queen Mary University of Although resilience is generally considered the capacity environments and associated epigenetic mechanisms
London, London E1 4NS, UK of an individual to overcome adversity, the exact definition, that contribute to the development of resilience are often
[email protected]
and associated means of measuring it, differ considerably. overlooked.
Resilience can be conceptualised in three ways: a dynamic Our aim in this Review is to consider the multiple roles
and malleable process, a stable trait, and an outcome in that epigenetic mechanisms might have in psychological
response to adversity. In line with contemporary thinking, resilience. We will consider the complex relationships
we consider resilience to be a dynamic process or complex between environmental factors and genetics across the
function of numerous individual (eg, genetic variation) lifespan, with particular attention to resilience-promoting
and socioenvironmental factors (eg, social support), factors. After introducing epigenetics, we present a
which allows an individual to maintain good psychological theoretical model that is based on theoretical and
health despite major adversity.2,3 Importantly, resilience empirical studies, which outlines three specific ways in
reflects not simply the absence of risk factors but also which epigenetics could contribute to the development
includes the effect of protective factors that promote of psychological resilience. We then use this model to
positive adaptation. Although resilience has become a assess the current research, highlight existing knowledge
common feature of mental health research, most gaps, and provide suggestions for future research.
psychiatric studies tend to focus on resilience reducing or
risk-conferring factors, often overlooking the contribution Epigenetics
of resilience-promoting factors. The genome remains relatively stable throughout a
Given the varied definitions, resilience has been person’s life, but gene expression is highly variable.
measured in many ways. A common method uses binary This variability is partially controlled by epigenetic
segregation of individuals who have a single mental mechanisms—a diverse group of potentially life-long
health disorder at a single point in time compared with lasting (but reversible) molecular changes that are
individuals who have not.4 Other definitions consider a heritable by mitosis—providing an important layer of
more nuanced longitudinal approach and use complex control.8 Because of this diversity, there is some
statistical models to identify discrete, longitudinal disagreement on which mechanisms constitute epi­
trajectories of mental health following adversity.1 Further genetics, but the best understood and most commonly
methods focus less on the outcome and more on researched, particularly regarding mental health, are
individual attributes that can contribute to resilience in DNA methylation, histone modification, and non-coding
See Online for appendix an individual.3 Given the complexity of resilience, its RNAs (panel 1; appendix p 1). Acquiring, maintaining,
assessment remains a challenge because individuals can and eliminating these various modifications allows for a

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dynamic and multifactorial system of control, affecting

all stages of gene expression.9 Panel 1: The three major classes of epigenetic modification
The epigenome is modifiable in response to various DNA methylation
environmental factors, including diet, physical health, The addition and removal of methyl groups directly to the
and psychological trauma, allowing long-term adaptive DNA code, which affects the tightness of DNA packaging.
changes to gene expression.10,11 However, epigenetic DNA methylation is an important feature in gene promoters
changes also occur as a function of normal development and effectively suppresses expression of the associated gene.
(eg, cellular differentiation); therefore, epigenetic
patterns tend to be cell and tissue specific. Although Histone modification
human post-mortem brain tissue studies have identified The addition or removal of small chemical groups (eg, methyl
epigenetic signatures of resilience,12 most human groups) to the histone proteins that form the scaffold for
studies rely on more easily accessible tissues such as DNA, which modulates the tightness of DNA packaging and
blood, saliva, and buccal cells.13 The extent to which consequently the expression of nearby genes.
these epigenetic signatures mirror the nervous system Non-coding RNAs
epigenome is unclear, although there is evidence that Diverse types of RNA that can affect the many stages of gene
peripheral changes in DNA methylation can reflect expression from transcription to post-translational
those occurring centrally, particularly in genes modification. The most commonly studied type in psychiatric
associated with psychiatric disorders,14 and can also research is micro RNAs, which act by binding to messenger
reflect systemic changes relevant to resilience, such as RNAs to prevent them from being translated into proteins.
inflammation.15

A conceptual model for the role of epigenetics in can be present from conception, either determined by
resilience genetic variation or inherited directly. Second, some
A wide range of epigenetic differences has been observed aspects of the epigenome are more changeable and
in individuals with good mental health by comparison modified by the environment, particularly during
with those with psychiatric disorders.5,16,17 These dif­ prenatal development and childhood. Finally, specific
ferences can arise in various ways, but some are thought protective factors during exposure to adversity affect how
to be affected by the environment and could mediate the amenable the epigenome is to this negative event.
effect of subsequent adversity on mental health.18 Additionally, genetic factors also have an important role,
Epigenetic mechanisms have the potential to record, in a directly affecting resilience and moderating the effects of
lasting manner, the effects of various life events. Most the environment on the epigenome. It is necessary to
epigenetic research in psychiatry has focused on the consider all of these factors to understand the potential
effect of specific adverse events on the epigenome and ways in which epigenetic factors contribute to resilience.
how epigenetic differences translate into the development In the remainder of this Review, we will summarise the
of single psychiatric disorders.7,17–19 However, much less is literature that concerns each aspect of this model.
known about how epigenetics are affected by protective
factors (ie, factors that counteract the effect of adverse Empirical evidence
effects) and positive factors (ie, factors that have an Epigenetic differences between psychiatric and resilient
independent positive effect) of the environment and how outcomes
this contributes to the development of psychological Epigenetic differences have been observed between
resil­ience. Additionally, research often does not account individuals with good mental health (ie, presumably
for the main effects of genetic variation as well as genetic resilient individuals) when compared with individuals
moderation of environmental effects on epigenetics. who have psychiatric dis­orders, including post-traumatic
These considerations are particularly important because stress disorder, depression, and anxiety disorders.16,17,21,22
individuals have been shown to have variable sensitivity Most of the research has focused on differential DNA
to adverse and protective events.20 methylation in peripheral tissues (eg, blood) and have
We propose a conceptual model for three specific roles identified resilience-associated differences in various
of epigenetics in the development of psychological genes related to immune function, neuronal plasticity,
resilience across a person’s lifespan, building upon stress reg­ulation, neurotransmission, and other pathways
existing research and theories on the relationships with unclear mechanisms of action (eg, mitogen-
between adversity, epigenetics, and mental health activated protein kinase signalling). However, results are
outcomes (figure 1). At the model’s core lies a pathway of not always consistent and, with the advent of
resilience that results in good multidimensional mental hypothesis-free epigenome-wide studies, findings are
health, which is defined by the presence of adversity. often not replicated, particularly when controlling for
Outcome resilience can be affected by epigenetics in at crucial covariates (ie, cell-type composition and
least three ways, which can all occur throughout the smoking).23 Although studied far less frequently than
lifespan. First, an initial epigenetic signature of resilience DNA methylation, some case-control differences in

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 Review

Importantly, although epigenetic markers might differ­

Adversity
4b entiate resilient individuals from those with mental illness,
Stable epigenetic effects 2
it is not clear when and how these differences arise. They
Mental health

Epigenome

could represent epigenetic differences present at con­

Pathway of resilience 1
ception, epigenetic differences that accumulate during
Outcome of
6 resilience
development, or epigenetic differences triggered by acute
5 Epigenetic
modification (ie, good multi- traumatic events and downstream coping mechanisms.
4a 7a dimensional
Protective factors mental health
Genetic moderation
7b despite adverse Inheritance of epigenetic resilience
experiences Although epigenetic modifications are amenable to
Genotype

Genetic moderation
change throughout a person’s lifespan, a particular
Environmental quality
proportion is set at conception and during embryo­
4a Stable genetic effects genesis. This early determination of the epigenome can
be due to inherited genetic variation or direct inheritance
3 of epigenetic marks themselves.
Life course
Genetic determination of epigenetic variation
Figure 1: Theoretical model outlining the contribution of epigenetics in the development of psychological
Genetic variation contributes to the epigenome present
resilience at conception. Although monozygotic twins tend to have
This model focuses on the development of multidimensional resilience (1), defined by the presence of an adverse similar epigenetic profiles, at least at birth,27,28 and
event (2). This resilient outcome can be affected by epigenetics in three key ways, which occur at different stages allele-specific patterns can be passed from parent to child,29
throughout the lifespan (3). First, resilience-associated epigenetic differences can be determined by genetic
variation (4a) or inherited from previous generations (4b). Second, the epigenome can be modified by the
epigenetic profiles can differ substantially between indi­
environment, particularly during infancy and childhood (5). Third, specific protective factors during adversity viduals with different ancestral back­ grounds.30 The
exposure can affect how modified the epigenome is (6). Genetic factors can directly affect resilience itself (7a) genome can directly affect the epigenome in numerous
and can moderate the effects that the environment and protective factors have on the epigenome (7b). ways. For example, genetic variation can directly affect the
specific sites where DNA methylation can occur, 31 and can
histone modifications and micro RNA expression have also affect the efficacy of sequence-dependent actions of
also been associated with psycho­pathology.22 non-coding RNAs.32
Although these studies have attempted to identify Genome-wide variants associated with risk for or
epigenetic signatures of resilience, their approach often protective against psychopathology have been discovered,
focuses on the absence of a single psychiatric outcome but the majority of these variants lie within non-coding
and rarely considers the presence of adversity. This regions with unclear functional importance.33,34 In some
approach has identified some similar epigenetic cases, resilience-associated genetic variation is hypo­
signatures of good mental health between different thesised to affect gene expression via epigenetic
psychological domains, although this association is intermediates. For example, single-nucleotide poly­
often due to the overlap in selected candidate genes. For morphisms (SNPs) associated with psychiatric disorders
example, increased DNA methylation of a gene have been found to be enriched for multiple methylation
important for neuronal development (eg, BDNF)4,24 and quantitative trait loci,35,36 and SNPs in the FKBP5 gene, a
increased biological age estimated from a defined key component of the stress response, have been
selection of DNA methylation loci have been observed associated with the risk of depression and the extent of
in individuals with various psychopathologies.12,25 Other methylation at the locus.37,38 Therefore, genetic variation
findings differ considerably between disorders, which is probably an important source of epigenetic resilience.
could result from methodological differences, represent Distinguishing genetic from epigenetic effects is complex
mechanisms more closely aligned to the development but statistical approaches have been developed, and
of specific symptoms, or result from a greater burden of successfully applied to methylation quantitative trait
adversity. loci.39,40 Similar approaches are needed to achieve the
Studies over the past 5 years have attempted to identify same for phenotypes like resilience.
DNA methylation signatures of multidimensional
resilience within the same cohort. One such study did Intergenerational transmission of epigenetic variation
not find shared DNA methylation differences across Epigenetic marks can also be inherited via a direct
different psychopathologies in blood from survivors of mechanism, independent of genetic variation. Although
the Sept 11, 2001 World Trade Centre attacks,23 whereas a a controversial subject within mammalian biology,
second found multiple differentially methylated regions studies show that this direct epigenetic inheritance
in resilient Brazilian adolescents when considering occurs in some animal models (eg, Caenorhabditis elegans
multidimensional psychopathology.26 Hence, evidence and Mus musculus).41,42 This inheritance can occur via
for the existence of a general resilient epi­ genome is intergenerational transmission, whereby germline cells
currently not conclusive. or the developing fetus are exposed to the same

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environment as the parent. More interesting is the having relatively similar DNA methylation and histone
potential for transmission of epigenetic information to acetylation patterns during their early years, large
further generations that are not present at the time of differences are observed in adulthood suggesting a
exposure (ie, transgenerational inheritance). These substantial input from the environment during the
processes could allow molecular adaptation to the lifespan.49,50
environment to be passed from parent to child and,
importantly, suggest that the parental environment can Environmental quality is associated with epigenetic
affect the health of subsequent generations. changes
The majority of preclinical research in this area has There is a large body of evidence that suggests that the
focused on the epigenetic inheritance of adverse epigenome is susceptible to adversity, including prenatal
environments, which is associated with increased stress, early life trauma, maltreatment, and social
psycho­pathology in successive generations. In studies stress.5,25,51,52 The epigenome is particularly sensitive
of rodents, various stress paradigms can produce during early developmental stages and resulting epi­
depressive-like and anxious-like behaviours in multiple genetic changes last far beyond the time of adversity.5
subsequent generations and are associated with specific Although epigenetic outcomes of these events are often
epigenetic marks hypothesised to elicit their effect studied in isolation, evidence exists for cumulative and
through neurodevelopmental or endocrinological mech­ longitudinal effects. Time since adversity can moderate
anisms.43,44 The specific molecular mechanisms per­ the magnitude of epigenetic change,53 and repeated or
mitting this inheritance remain to be elucidated and it is varied sources of adversity can accumulate to produce
unclear whether these specific epigenetic signatures are larger epigenetic responses.54,55 These epigenetic changes
con­sistently conserved at the cellular level throughout related to adversity have been associated with sensitivity
the generations or are re-established in each subsequent to adversity in later life and consequently reduced
generation. resilience.5
Currently, the existence of transgenerational epigenetic Less well understood is the effect that protective or
inheritance in humans has yet to be proven. True positive environmental factors have on the epigenome.
transgenerational inheritance is difficult to ascertain The absence of negative or detrimental factors is expected
because of the number of generations necessary to to shift the trajectory of mental health towards resilience,
determine an association and the confounding effect of however, it is important to understand the factors that
genetic inheritance and shared prenatal and postnatal directly promote resilience itself. Parental care is
environments affected by psychopathology. Multiple one protective factor that has been found to promote
studies have suggested that traumas such as combat resilience alongside epigenetic changes. Research inves­
exposure, forced displacement, genocide exposure, tigating the epigenetic and psychological con­sequences
and low maternal bonding might be passed on inter­ of naturally occurring variation in mothering behaviours
generationally, and have been associated with both in rats found that high-quality care resulted in offspring
psychopathology in children and altered DNA methylation with more robust stress hormone responses and reduced
in the FKBP5 gene.45,46 Currently, the only evidence that depressive-like and anxious behaviours together with
the effects of damaging environments can be passed reduced DNA methylation at the gene encoding a key
trans-generationally come from rare cohorts exposed to receptor in the glucocorticoid stress system (Nr3c1) and
non-replicable events, and have yet to identify related increased histone acetylation in hippocampal tissue.56 In
epigenetic changes.42 humans, preliminary research suggests that aspects of
The evidence suggests that psychological resilience parental care such as breast­feeding and physical contact
could be degraded because of inherited epigenetic marks; are also associated with decreased methylation of N3CR1
however, it is unclear whether resilience could also be and BDNF, and increased methylation of the pro­
promoted through similar mechanisms. Resilience- inflammatory gene TNF.57
promoting factors such as exercise and environmental Positive aspects of the environment such as cognitive
enrichment have been shown to reduce depressive, anxiety, stimulation, healthy diet, and exercise might also
and fear-related behaviours in at least one subsequent promote resilience through epigenetic mechanisms.
generation in studies of mice,47,48 but further research will Environ­mental enrichment during early development in
be needed to ascertain whether epigenetic modifications mice has been found to alter micro RNA expression and
allow this inheritance of resilience and whether similar histone acetylation at the Bdnf gene58,59 and also rectified
processes occur in humans. epigenetic changes induced by inherited trauma.59
Similarly, individual dietary components, such as dietary
Environmental effects on epigenetic resilience phytochemicals, have been found to reduce depressive-
Although some epigenetic marks are inherited or set like behaviours through epigenetic mechanisms tar­
during organismal development, many show plasticity geting systemic inflammation and neuronal plasticity in
in response to the environment, allowing molecular mice.60 Although these studies are challenging to
adaptation throughout life. Despite monozygotic twins replicate in humans, healthy lifestyle factors such as

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moderate physical activity, dietary quality, and cognitive human studies that show that specific protective factors
stimulation are associated with resilience building.61 can moderate the epigenetic outcomes of adversity. For
Research on the effect of these factors upon the example, the effect of perinatal depression upon the
epigenome is scarce, but fruit and vegetable con­ offspring’s DNA methylation of stress-related genes
sumption, moderate exercise, and minimal alcohol NR3C1 and SLC6A4 has been found to be moderated by
intake have been associated with a reduced epigenetic the quality of maternal care.57 Additionally, mothers’
age, which is a resilience-associated epigenetic factor.62,63 cognitive appraisal of a natural disaster during pregnancy
Further research is needed to understand whether these moderated the effect of the disaster upon methylation of
healthy lifestyle-induced epigenetic changes have a the inflammation-related LTA gene in their children.75
downstream effect on resilience. However, further research is needed on the specific
Along with their therapeutic effect, psychotherapeutic protective nature of maternal care and cognitive appraisal
interventions might also affect the epigenome. For on the epigenome.
example, changes in DNA methylation of candidate
stress-related genes (eg, FKBP5 and SLC6A4) have Genetic moderation of the environment and
been observed in patients undergoing psychological epigenetic processes
treatments for post-traumatic stress disorder, phobia, or Many studies suggest an important role for genetics in
anxiety symptoms.64–66 In a hypothesis-free epigenome- various stress-related disorders, with a substantial overlap
wide study, treatment responsive individuals showed between different dimensional outcomes suggesting
reduction of post-traumatic stress disorder symptoms some shared resilience loci.33,34,76,77 Some of these genetic
and differential DNA methylation in multiple genes.67 factors could contribute to resilience through direct
However, although epigenetic changes occur at the same effects upon the epigenome. Additionally, genetic factors
time as symptom reduction, it is not clear whether the might moderate the effect of the environment upon the
psychological therapies rectify the biological effect of epigenome.
previous negative events or have their own independent Although the environment can have both scarring and
promotive effect. steeling effects upon the epigenome, there is large
Negative aspects of the environment tend to be variation in response to these experiences. This disparity
considered as sensitising individuals to further adversity, could be explained by sensitivity conferring genetic
however, some negative factors can actually increase variants that increase vulnerability to negative environ­
resilience through a so-called steeling effect.68,69 For ments or might also promote favourable outcomes in
example, in studies of mice, some mild stress paradigms response to positive exposures. This theory represents
have been associated with subsequent increased individual differences in environmental sensitivity—ie,
resilience.70–72 Similarly, in one cohort study, Brazilian the extent to which people respond to positive and
children who observed their mothers experiencing negative environments (figure 2A).78–83 Research has
personal violence had increased resilience to postnatal shown that environmental sensitivity is a measurable,
maternal violence compared with those who only common, complex, heritable, and polygenic trait.84
experienced violence postnatally.73 Differentially methyl­ Studies suggest that genetics can moderate the effect
ated sites were identified in the FKBP5 and NR3C1 of negative environmental factors on epigenetic modi­
genes between prenatal maternal violence versus fications.85 For example, epigenome-wide neonate DNA
prenatal and postnatal maternal violence, suggesting a methylation has been shown to result from an interaction
prenatally derived stress-adaptive mech­ anism to over­ between genetic variation in nearby cis variants and
come subsequent adversity. Although this preliminary prenatal factors such as maternal smoking, maternal
research suggests that negative life events can promote depression, and gestational age.86 Individual genetic
later resilience through epigenetic changes, more variants in the FKBP5 gene have also been shown to
research is needed to confirm these findings and to moderate the effect of adversities such as childhood
improve understanding of the threshold at which such maltreatment or the synthetic glucocorticoid dexa­
events become detrimental to resilience. methasone on FKBP5 DNA methylation.87–89
Of particular relevance to resilience building is the
Protective environmental effects on epigenetic observation that people differ substantially in their
resilience response to the positive effects of nurturing experiences
The epigenetic response to adversity varies among as described by vantage sensitivity—ie, the extent to
individuals. Some of this variation could be due to which individuals benefit from positive environments
specific protective factors that act concurrently to (figure 2B).20 Little research has been done to understand
dampen or counteract the adversity. Individual and the genetic moderation of protective influences on the
socioenvironmental factors, such as good emotional epigenome, although it is possible that variants that
regulation, strong social support, and good familial moderate adversity also moderate positive factors. Poly­
relationships, have been shown to promote resilience.74 genic scores for environmental sensitivity have been
Research on this topic is scarce, but there are some shown to moderate the beneficial outcomes of cognitive

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behavioural therapy on anxiety symptoms,90 and genome- A

wide variation and single locus variation in the
SCL6A4 gene can moderate the effects of good parenting
on the psychopathology of their children.90,91 Individuals

Resilience
promoting
with the parenting-sensitive SCL6A4 genotype did not
manifest increased susceptibility to poor parenting,
ivity
suggesting that this variant could specifically provide nsit
e se

Epigenetic outcome
tag
vantage sensitivity rather than general environmental Van
sensitivity.92 How­ever, it is unclear whether these psy­
ity
chological outcomes are due to epigenetic changes, and tibil
suscep
genetic moderators of the effect of positive factors on tial
eren
Diff
epigenetics have yet to be identified.
s
tres
Resilience sis s
eroding
Discussion the
Dia
In this Review we have presented a theoretical model
describing the multiple ways in which epigenetics could
contribute to the long-term development of psychological Environmental quality
resilience. The epigenome is initially defined by direct or
indirect inheritance but is subject to change because of Negative Positive
environmental effects during early and later development. B
This plasticity could be moderated by genetically derived
individual differences in environmental sensitivity. Vantage
h

Therefore, the resulting epigenetic profile of resilience sensitivity

Mental health

reflects an accumulation of these individual and

socioenvironmental factors, and, together with stable
genetic influences, allows for the successful adaptation
M

to adversity and the maintenance of good mental health. Vantage

Although moderate evidence exists for several aspects of resistance
this model, we highlight areas that need further research
and make practical suggestions for future studies
(panel 2).
First, the concept of resilience in epigenetic research
Positive
should be studied in its own right, rather than simply as effect
a disease-free state.2 Some studies include only people
who have experienced adversity,23 or consider the severity
of adversity;97 however, other studies do not. Therefore,
Life course
identified epigenetic differences might reflect true
resilience in some individuals, whereas in others they
might simply reflect the presence or severity of adversity. Figure 2: Models of environmental sensitivity and vantage sensitivity
Additionally, the consideration of multiple psychiatric (A) Illustration of the three models of environmental sensitivity: vantage
sensitivity, differential susceptibility, and diathesis stress. These models describe
outcomes will allow understanding of the general
the interindividual differences in response to both positive and negative
mechanisms that underlie psychological resilience more environmental factors, and have been applied to epigenetic changes in the
broadly, rather than the development of specific sets of context of resilience. Diathesis stress describes individual differences in response
mental health symptoms. Therefore, adversity must be to negative factors, whereas vantage sensitivity describes variability regarding
positive factors. Differential susceptibility represents a combination of diathesis
addressed and, when appropriate, multidimensional stress and vantage sensitivity with heightened sensitivity to negative and
psychiatric outcomes should also be considered. positive experiences. Adapted from Pluess and colleagues.78 (B) The vantage
Second, we must widen our search for environmental sensitivity model which outlines the differential variation in benefit specifically
factors that promote resilience through epigenetic from positive influences. Adapted from de Villiers and colleagues.79
changes. There is moderate evidence that various forms
of adversity can affect the epigenome and consequently suggested that reduced resilience could be inherited
resilience, although results are not always consistent, through inter­generational transmission of epigenetics,
and studies rarely consider adversity, epigenetics, and this hypothesis is far from proven in humans and it is
resilience within the same cohort. However, there has unknown whether such mechanisms can promote
been little invest­igation into how positive or protective resilience. Future lines of inquiry should take genetic
aspects of the environment could have their own variation into account to appreciate fully the degree to
independent or counteracting actions in the epigenetic which the environment can affect the epigenome in
development of resilience. Furthermore, although it is different genetic contexts.

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Third, the longitudinal trajectory towards epigenetic

Panel 2: Practical suggestions for future research change and resilience must be investigated, with
Measure resilience in a consistent and appropriate way consideration for the developmental context and time
• Consider multiple dimensions of mental health since exposure. The direction of causality between
(eg, through the concurrent use of multiple scales or the environmental factors, epigenetic changes, and psy­chiatric
p factor)93 outcomes should be assessed, which is rarely done. Hence,
• Do repeated measures over time following a defined and it is crucial to adopt a life course perspective using
measurable adverse event longitudinal studies with repeated assessments allowing
the investigation of within-person epigenetic changes
Characterise epigenetic changes throughout the lifespan across different developmental periods and before the
• Use prospective studies that examine the effect of development of pathological outcomes. Environmental
predictable adverse influences on epigenetics (eg, military factors are typically studied in isolation but are unlikely to
deployment) occur alone and have been shown to have cumulative
• Examine intra-individual variation in DNA methylation effects on the epigenome, and could alter the epigenome
across development (eg, EpiDelta)94 and resilience in the form of developmental cascades,
• Use cumulative risk and protective scores that capture the affecting the response to further events.54,55
combined exposure to the environment Finally, the search for epigenetic factors involved in
Understand the interplay between genetics and resilience must be expanded to include a wider variety of
epigenetics mechanisms, such as non-coding RNA expression, non-
• Use parallel genome-wide epigenetic and genetic coding RNA modification, and histone modifications, as
approaches to tease apart genetic and epigenetic effects well as previously unknown effects of DNA methylation.98,99
• Use polygenic and (poly)-epigenetic risk scores As these modifi­ cations accumulate and interact to
produce tightly regulated changes in gene expression, it is
Consider a wider variety of epigenetic mechanisms in an not sufficient to study differences only in single DNA
unbiased and genome-wide manner methylation loci.9
• Use advanced methods that have become more Although our model aims to encapsulate and summarise
economically viable (eg, whole-genome bisulphite the key components involved in the development of
sequencing) resilience, we acknowledge that further factors might be
Identify the biological mechanisms underpinning involved. For example, genetic variation might moderate
epigenetically derived resilience the effect of epigenetic changes on resilience.87 We have
• Investigate the cross-tissue correspondence of peripheral also not fully considered the specific biological mechanisms
epigenetic signatures to interpret findings using existing by which changes in the epigenome result in psychological
tools (eg, BECon)95 resilience. The iden­tification of biological mechanisms is
• Identify multi-site signatures that correspond to systemic made more challenging because much of the research
changes (eg, epigenetic ageing clocks)96 studies epigenetics in peripheral tissues and data from
central nervous tissue is scarce. Although clear aetiological
pro­cesses can be assigned to particular epigenetic changes,
such as those affecting the systemic stress response system
(ie, FKBP5 and NR3C1), hypothesis-free epigenome-wide
studies increasingly highlight epigen­etic changes without
Search strategy and selection criteria clear downstream effects.
Studies for this Review were identified through searches of In conclusion, we have outlined the complex mech­
PubMed for articles published from database inception up to anisms by which aspects of the environment can become
May 31, 2020. We searched article titles and abstracts for the biologically embedded through epigenetic changes and
specific keywords (and combinations thereof) “resilien*”, contribute to the development of psy­chological resilience.
“mental health”, “depress*”, “anxi*”, “trauma*”, “stress”, We have outlined the knowledge gaps and highlighted
“advers*”, “environment”, “inherit*”, “epigen*”, “methyl*”, strategies that will improve future research. First, the
“histone”, “RNA”. We reviewed the articles resulting from importance of clearly defining resilience in well designed
these searches and the relevant references cited in those epigenetic studies. Second, the need for more studies on
articles, focusing on papers published within the past 5 years. the role of the environment on epigenetics and resilience
Given the number of studies that some keyword that include protective and positive factors, the inheri­tance
combinations yielded, we restricted our selection of papers to of epigenetic resilience, and the role of genetic moderation
peer-reviewed papers that covered unique areas of our informed by theories of environ­mental sensitivity. Third,
proposed model. We supplemented these search results with the importance of longitudinal and cumulative effects
important publications from our personal files. Only articles of the environment on the epigenome and resilience.
published in English were included. Finally, the value of improving and expanding upon the
commonly studied epigenetic mechanisms.

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Contributors 21 Barker ED, Walton E, Cecil CAM. Annual research review:

DS was responsible for searching for articles included in this Review. DNA methylation as a mediator in the association between risk
DS and MP contributed to the design, writing, preparation, and discussion exposure and child and adolescent psychopathology.
of the manuscript. SB and EGK provided feedback and edited the J Child Psychol Psychiatry 2018; 59: 303–22.
manuscript. All authors read and approved the final manuscript. 22 Penner-Goeke S, Binder EB. Epigenetics and depression.
Dialogues Clin Neurosci 2019; 21: 397–405.
Declaration of interests 23 Kuan P-F, Waszczuk MA, Kotov R, et al. An epigenome-wide DNA
We declare no competing interests. methylation study of PTSD and depression in World Trade Center
Acknowledgments responders. Transl Psychiatry 2017; 7: e1158.
The writing of this manuscript was supported by funding from the 24 Januar V, Ancelin M-L, Ritchie K, Saffery R, Ryan J. BDNF
Eunice Shriver National Institute of Child Health & Human promoter methylation and genetic variation in late-life depression.
Transl Psychiatry 2015; 5: e619.
Development (reference R01HD083387). We sincerely thank
Prof Elisabeth Binder and Prof Vardhman Rakyan for their invaluable 25 Wolf EJ, Maniates H, Nugent N, et al. Traumatic stress and
accelerated DNA methylation age: a meta-analysis.
comments and feedback in the development of this Review.
Psychoneuroendocrinology 2018; 92: 123–34.
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