Elsevier

The Lancet Psychiatry

Volume 8, Issue 7, July 2021, Pages 620-629
The Lancet Psychiatry

Review
The role of epigenetics in psychological resilience

https://doi.org/10.1016/S2215-0366(20)30515-0Get rights and content

Summary

There is substantial variation in people's responses to adversity, with a considerable proportion of individuals displaying psychological resilience. Epigenetic mechanisms are hypothesised to be one molecular pathway of how adverse and traumatic events can become biologically embedded and contribute to individual differences in resilience. However, not much is known regarding the role of epigenetics in the development of psychological resilience. In this Review, we propose a new conceptual model for the different functions of epigenetic mechanisms in psychological resilience. The model considers the initial establishment of the epigenome, epigenetic modification due to adverse and protective environments, the role of protective factors in counteracting adverse influences, and genetic moderation of environmentally induced epigenetic modifications. After reviewing empirical evidence for the various components of the model, we identify research that should be prioritised and discuss practical implications of the proposed model for epigenetic research on resilience.

Introduction

In times of adversity, some individuals develop stress-related disorders such as depression or post-traumatic stress disorder. However, a substantial proportion show psychological resilience, which is defined broadly as the maintenance of good mental health despite exposure to adversity.1 A comprehensive understanding of the development of resilience is important for the prevention and treatment of stress-related disorders.

Although resilience is generally considered the capacity of an individual to overcome adversity, the exact definition, and associated means of measuring it, differ considerably. Resilience can be conceptualised in three ways: a dynamic and malleable process, a stable trait, and an outcome in response to adversity. In line with contemporary thinking, we consider resilience to be a dynamic process or complex function of numerous individual (eg, genetic variation) and socioenvironmental factors (eg, social support), which allows an individual to maintain good psychological health despite major adversity.2, 3 Importantly, resilience reflects not simply the absence of risk factors but also includes the effect of protective factors that promote positive adaptation. Although resilience has become a common feature of mental health research, most psychiatric studies tend to focus on resilience reducing or risk-conferring factors, often overlooking the contribution of resilience-promoting factors.

Given the varied definitions, resilience has been measured in many ways. A common method uses binary segregation of individuals who have a single mental health disorder at a single point in time compared with individuals who have not.4 Other definitions consider a more nuanced longitudinal approach and use complex statistical models to identify discrete, longitudinal trajectories of mental health following adversity.1 Further methods focus less on the outcome and more on individual attributes that can contribute to resilience in an individual.3 Given the complexity of resilience, its assessment remains a challenge because individuals can exhibit varying resilience across time and psychological domains.

How do socioenvironmental factors become biologically embedded throughout the lifespan and cause long-term changes to biology that ultimately affect psychiatric outcomes? Epigenetic mechanisms are hypothesised to be one important molecular pathway involved in this process.5, 6 There are now numerous studies that support the hypothesis that adverse environments affect the epigenome, and that epigenetic differences might distinguish susceptible and resilient individuals.5, 6, 7 However, the specific roles of protective environments and associated epigenetic mechanisms that contribute to the development of resilience are often overlooked.

Our aim in this Review is to consider the multiple roles that epigenetic mechanisms might have in psychological resilience. We will consider the complex relationships between environmental factors and genetics across the lifespan, with particular attention to resilience-promoting factors. After introducing epigenetics, we present a theoretical model that is based on theoretical and empirical studies, which outlines three specific ways in which epigenetics could contribute to the development of psychological resilience. We then use this model to assess the current research, highlight existing knowledge gaps, and provide suggestions for future research.

The genome remains relatively stable throughout a person's life, but gene expression is highly variable. This variability is partially controlled by epigenetic mechanisms—a diverse group of potentially life-long lasting (but reversible) molecular changes that are heritable by mitosis—providing an important layer of control.8 Because of this diversity, there is some disagreement on which mechanisms constitute epigenetics, but the best understood and most commonly researched, particularly regarding mental health, are DNA methylation, histone modification, and non-coding RNAs (panel 1; appendix p 1). Acquiring, maintaining, and eliminating these various modifications allows for a dynamic and multifactorial system of control, affecting all stages of gene expression.9

The epigenome is modifiable in response to various environmental factors, including diet, physical health, and psychological trauma, allowing long-term adaptive changes to gene expression.10, 11 However, epigenetic changes also occur as a function of normal development (eg, cellular differentiation); therefore, epigenetic patterns tend to be cell and tissue specific. Although human post-mortem brain tissue studies have identified epigenetic signatures of resilience,12 most human studies rely on more easily accessible tissues such as blood, saliva, and buccal cells.13 The extent to which these epigenetic signatures mirror the nervous system epigenome is unclear, although there is evidence that peripheral changes in DNA methylation can reflect those occurring centrally, particularly in genes associated with psychiatric disorders,14 and can also reflect systemic changes relevant to resilience, such as inflammation.15

Section snippets

A conceptual model for the role of epigenetics in resilience

A wide range of epigenetic differences has been observed in individuals with good mental health by comparison with those with psychiatric disorders.5, 16, 17 These differences can arise in various ways, but some are thought to be affected by the environment and could mediate the effect of subsequent adversity on mental health.18 Epigenetic mechanisms have the potential to record, in a lasting manner, the effects of various life events. Most epigenetic research in psychiatry has focused on the

Epigenetic differences between psychiatric and resilient outcomes

Epigenetic differences have been observed between individuals with good mental health (ie, presumably resilient individuals) when compared with individuals who have psychiatric disorders, including post-traumatic stress disorder, depression, and anxiety disorders.16, 17, 21, 22 Most of the research has focused on differential DNA methylation in peripheral tissues (eg, blood) and have identified resilience-associated differences in various genes related to immune function, neuronal plasticity,

Inheritance of epigenetic resilience

Although epigenetic modifications are amenable to change throughout a person's lifespan, a particular proportion is set at conception and during embryogenesis. This early determination of the epigenome can be due to inherited genetic variation or direct inheritance of epigenetic marks themselves.

Environmental effects on epigenetic resilience

Although some epigenetic marks are inherited or set during organismal development, many show plasticity in response to the environment, allowing molecular adaptation throughout life. Despite monozygotic twins having relatively similar DNA methylation and histone acetylation patterns during their early years, large differences are observed in adulthood suggesting a substantial input from the environment during the lifespan.49, 50

Genetic moderation of the environment and epigenetic processes

Many studies suggest an important role for genetics in various stress-related disorders, with a substantial overlap between different dimensional outcomes suggesting some shared resilience loci.33, 34, 76, 77 Some of these genetic factors could contribute to resilience through direct effects upon the epigenome. Additionally, genetic factors might moderate the effect of the environment upon the epigenome.

Although the environment can have both scarring and steeling effects upon the epigenome,

Discussion

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 resilience. The epigenome is initially defined by direct or indirect inheritance but is subject to change because of environmental effects during early and later development. This plasticity could be moderated by genetically derived individual differences in environmental sensitivity. Therefore, the resulting epigenetic profile of

Search strategy and selection criteria

Studies for this Review were identified through searches of PubMed for articles published from database inception up to May 31, 2020. We searched article titles and abstracts for the specific keywords (and combinations thereof) “resilien*”, “mental health”, “depress*”, “anxi*”, “trauma*”, “stress”, “advers*”, “environment”, “inherit*”, “epigen*”, “methyl*”, “histone”, “RNA”. We reviewed the articles resulting from these searches and the relevant references cited in those articles, focusing on

Declaration of interests

We declare no competing interests.

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