Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

Background: Sensitive periods are developmental stages of heightened plasticity when exposure to childhood adversity may exert lasting impacts. A few biological pathways are known to play key roles in regulating sensitive period plasticity across brain development. Epigenetic mechanisms including DNA methylation (DNAm) may provide a means through which life experiences during sensitive periods induce long-term biological changes. In the current study, we investigated the possibility that adversity during sensitive periods led to DNAm changes in genes that regulate the timing and duration of sensitive periods in development. Methods: Using childhood adversity data and genome-wide DNAm profiles from the Avon Longitudinal Study of Parents and Children (n=785), we summarized DNAm variation of CpG sites in the promoters of genes regulating sensitive periods with the first two principal components (PCs). DNAm summaries were calculated for genes regulating sensitive period opening (ngenes=15), closing (ngenes=36), and expression/duration (ngenes=8). We then performed linear discriminant analysis to test associations between these DNAm summaries and the timing of exposure to seven types of adversity. Results: Sexual or physical abuse and financial hardship during middle childhood (6-7 years) were associated with DNAm of genes regulating the onset and duration of sensitive periods. Sensitivity analyses assessing the presence of any exposure before age 7 and a composite measure of adversity yielded fewer signals, highlighting the importance of accounting for timing and adversity type. Conclusions: With our novel gene set-based approach, we have uncovered suggestive evidence that epigenetic regulation of developmental plasticity may be affected by early life adversity. The complementarity of our gene-level view of the epigenome to the more common and granular epigenome-wide association study may yield novel mechanistic insights not only for adversity but also for other exposures and outcomes.

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Sensitive periods for the effect of childhood interpersonal violence on psychiatric disorder onset among adolescents

The British Journal of Psychiatry ◽

10.1192/bjp.bp.117.208397 ◽

2017 ◽

Vol 211 (6) ◽

pp. 365-372 ◽

Cited By ~ 5

Author(s):

Erin C. Dunn ◽

Yan Wang ◽

Jenny Tse ◽

Katie A. McLaughlin ◽

Garrett Fitzmaurice ◽

...

Keyword(s):

Substance Use ◽

Psychiatric Disorder ◽

Physical Abuse ◽

Middle Childhood ◽

Interpersonal Violence ◽

Childhood Adversity ◽

Elevated Risk ◽

First Episode ◽

Cross Sectional ◽

Sensitive Periods

BackgroundAlthough childhood adversity is a strong determinant of psychopathology, it remains unclear whether there are ‘sensitive periods’ when a first episode of adversity is most harmful.AimsTo examine whether variation in the developmental timing of a first episode of interpersonal violence (up to age 18) associates with risk for psychopathology.MethodUsing cross-sectional data, we examined the association between age at first exposure to four types of interpersonal violence (physical abuse by parents, physical abuse by others, rape, and sexual assault/molestation) and onset of four classes of DSM-IV disorders (distress, fear, behaviour, substance use) (n=9984). Age at exposure was defined as: early childhood (ages 0–5), middle childhood (ages 6–10) and adolescence (ages 11–18).ResultsExposure to interpersonal violence at any age period about doubled the risk of a psychiatric disorder (odds ratios (ORs) = 1.51–2.52). However, few differences in risk were observed based on the timing of first exposure. After conducting 20 tests of association, only three significant differences in risk were observed based on the timing of exposure; these results suggested an elevated risk of behaviour disorder among youth first exposed to any type of interpersonal violence during adolescence (OR = 2.37, 95% CI 1.69–3.34), especially being beaten by another person (OR = 2.44; 95% CI 1.57–3.79), and an elevated risk of substance use disorder among youth beaten by someone during adolescence (OR=2.77, 95% CI 1.94–3.96).ConclusionsChildren exposed to interpersonal violence had an elevated risk of psychiatric disorder. However, age at first episode of exposure was largely unassociated with psychopathology risk.

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What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: recency, accumulation, or sensitive periods?

Psychological Medicine ◽

10.1017/s0033291718000181 ◽

2018 ◽

Vol 48 (15) ◽

pp. 2562-2572 ◽

Cited By ~ 29

Author(s):

Erin C. Dunn ◽

Thomas W. Soare ◽

Miriam R. Raffeld ◽

Daniel S. Busso ◽

Katherine M. Crawford ◽

...

Keyword(s):

Theoretical Model ◽

Life Course ◽

Emotional Abuse ◽

Financial Stress ◽

Childhood Adversity ◽

Sensitive Period ◽

Sensitive Periods ◽

Legal Problems ◽

Best Fitting ◽

Psychopathology Symptoms

BackgroundAlthough childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.MethodsProspective data came from the Avon Longitudinal Study of Parents and Children (n= 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.ResultsRecencywas the best fitting theoretical model for the effect of physical/sexual abuse (girlsr2= 2.35%; boysr2= 1.68%). Bothrecency(girlsr2= 1.55%) andaccumulation(boysr2= 1.71%) were the best fitting models for caregiver physical/emotional abuse.Sensitive periodmodels were chosen alone (parent legal problems in boysr2= 0.29%) and withaccumulation(financial stress in girlsr2= 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22–1.18).ConclusionsChild psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.

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Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression

10.1101/2021.05.13.21257179 ◽

2021 ◽

Author(s):

Yiwen Zhu ◽

Min-Jung Wang ◽

Katherine M Crawford ◽

Juan Carlos Ramirez-Tapia ◽

Alexandre A Lussier ◽

...

Keyword(s):

Animal Studies ◽

Socioeconomic Disadvantage ◽

Developmental Expression ◽

Sensitive Period ◽

Genetic Pathways ◽

Gene Set ◽

Sensitive Periods ◽

Depression Risk ◽

Genome Wide ◽

A Genome

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects in shaping brain structure or function, behavior, and disease risk. Sensitive periods for depression likely arise through a complex interplay of genes and experience, though this possibility has not been explored. We examined the effect of sensitive period-regulating genetic pathways identified in preclinical animal studies, alone and in interaction with socioeconomic disadvantage, a common childhood adversity, on depression risk. Using a translational approach, we: (1) performed gene-set association analyses using summary data from a genome-wide association study of depression (n=807,553) to assess the effects of three gene sets (60 genes) shown in animal studies to regulate sensitive periods; (2) evaluated the developmental expression patterns of these sensitive period-regulating genes using data from BrainSpan (n=31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay by analyzing the combined effect of common variants in sensitive period genes and timing of exposure to socioeconomic disadvantage within a population-based birth cohort (n=6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, six of the 15 genes in this set showed developmentally regulated gene-level expression. A genome-wide polygenic risk score-by-environment analysis showed socioeconomic disadvantage during ages 1-5 years were independently associated with depression risk, but no gene-by-development interactions were found. Genes involved in regulating sensitive periods may be implicated in depression vulnerability and differentially expressed across the life course, though larger studies are needed to identify developmental interplays.

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Predicting cellular aging following exposure to adversity: Does accumulation, recency, or developmental timing of exposure matter?

10.1101/355743 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sandro Marini ◽

Kathryn A. Davis ◽

Thomas W. Soare ◽

Matthew J. Suderman ◽

Andrew J. Simpkin ◽

...

Keyword(s):

Middle Childhood ◽

Repeated Measures ◽

Selection Procedure ◽

Cellular Aging ◽

Sensitive Period ◽

Developmental Timing ◽

Biological Aging ◽

Sensitive Periods ◽

Epigenetic Aging ◽

Epigenetic Age

AbstractExposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous health problems, including neuropsychiatric disease. In recent years, measures of DNA methylation-based epigenetic age – known as “epigenetic clocks” – have been used to estimate accelerated epigenetic aging. Yet, few studies have been conducted in children. Using data from the Avon Longitudinal Study of Parents and Children (n=973), we explored the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated the effects of the developmental timing, accumulation, and recency of adversity exposure. We found that exposure to sexual or physical abuse, financial stress, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of the Hannum epigenetic age from the chronological age. Secondary sex-stratified analyses identified particularly strong sensitive period effects, such that by age 7, girls who were exposed to abuse at age 3.5 were biologically older than their unexposed peers by almost 2 months. These effects were undetected in analyses comparing children “exposed” versus “unexposed” to adversity. Our results suggest that exposure to adversity may alter methylation processes in ways that perturb normal cellular aging and that these effects may be heightened during sensitive periods in development. Research is needed to demonstrate the effect of accelerated epigenetic aging on negative health outcomes following childhood adversity exposure.

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Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

10.1101/271122 ◽

2018 ◽

Cited By ~ 1

Author(s):

Erin C. Dunn ◽

Thomas W. Soare ◽

Andrew J. Simpkin ◽

Matthew J. Suderman ◽

Yiwen Zhu ◽

...

Keyword(s):

Dna Methylation ◽

Longitudinal Study ◽

Early Life ◽

Multiple Testing ◽

Sensitive Period ◽

Multiple Testing Correction ◽

Early Life Adversity ◽

Prospective Longitudinal Study ◽

Sensitive Periods ◽

Prospective Longitudinal

AbstractBackgroundExposure to “early life” adversity is known to predict DNA methylation (DNAm) patterns that may be related to prolonged psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.MethodsUsing a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternative explanations: an accumulation hypothesis, in which the effect of adversity on DNAm increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=670-776).ResultsAfter covariate adjustment and multiple testing correction, we identified 40 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=32) were predicted by the timing of adversity, namely exposures during infancy. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.ConclusionsThe developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Infancy appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to “early life” adversity may dilute observed effects.

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Socioeconomic changes predict genome-wide DNA methylation in childhood

10.1101/2021.06.23.21259418 ◽

2021 ◽

Author(s):

Jiaxuan Liu ◽

Janine Cerutti ◽

Alexandre A. Lussier ◽

Yiwen Zhu ◽

Brooke J. Smith ◽

...

Keyword(s):

Dna Methylation ◽

Middle Childhood ◽

Well Being ◽

Sensitive Period ◽

Public Programs ◽

Early Life Adversity ◽

Socioeconomic Environment ◽

Socioeconomic Changes ◽

Genome Wide ◽

Using Data

Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity "gets under the skin". Using data from a large, longitudinal birth cohort, we showed that changes in the socioeconomic environment may influence DNAm at age 7. We also showed that middle childhood (ages 6-7) may be a potential sensitive period when socioeconomic instability, reflected in parental job loss, is especially important in shaping DNAm. Our findings highlight the importance of socioeconomic stability during childhood, providing biological evidence in support of public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity during childhood.

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Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2014.16.3/canacker ◽

2014 ◽

Vol 16 (3) ◽

pp. 321-333 ◽

Cited By ~ 47

Keyword(s):

Stress Responses ◽

Childhood Adversity ◽

Adrenal Function ◽

Early Life Adversity ◽

Hypothalamic Pituitary Adrenal ◽

Expression Of Genes ◽

Epigenetic Programming ◽

Social Adversity ◽

Wide Range ◽

Nonhuman Species

We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.

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Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases

Epigenomics ◽

10.2217/epi.11.17 ◽

2011 ◽

Vol 3 (3) ◽

pp. 279-294 ◽

Cited By ~ 51

Author(s):

Felicia M Low ◽

Peter D Gluckman ◽

Mark A Hanson

Keyword(s):

Cardiovascular Diseases ◽

Developmental Plasticity ◽

Epigenetic Mechanisms

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Experience-Driven Plasticity and the Emergence of Psychopathology: A Mechanistic Framework Integrating Development and the Environment into the Research Domain Criteria (RDoC) Model

10.31234/osf.io/nue3d ◽

2021 ◽

Author(s):

Katie A McLaughlin ◽

Laurel Joy Gabard-Durnam

Keyword(s):

Developmental Plasticity ◽

Learning Mechanisms ◽

Early Life Adversity ◽

Developmental Variation ◽

Units Of Analysis ◽

Environmental Experience ◽

Dependent Learning ◽

The Life Course ◽

Research Domain ◽

Specific Learning

Despite the clear importance of a developmental perspective for understanding the emergence of psychopathology across the life-course, such a perspective has yet to be integrated into the RDoC model. In this paper, we articulate a framework that incorporates developmentally-specific learning mechanisms that reflect experience-driven plasticity as additional units of analysis in the existing RDoC matrix. These include both experience-expectant learning mechanisms that occur during sensitive periods of development and experience-dependent learning mechanisms that may exhibit substantial variation across development. Incorporating these learning mechanisms allows for clear integration not only of development but also environmental experience into the RDoC model. We demonstrate how individual differences in environmental experiences—such as early-life adversity—can be leveraged to identify experience-driven plasticity patterns across development and apply this framework to consider how environmental experience shapes key biobehavioral processes that comprise the RDoC model. This framework provides a structure for understanding how affective, cognitive, social, and neurobiological processes are shaped by experience across development and ultimately contribute to the emergence of psychopathology. We demonstrate how incorporating an experience-driven plasticity framework is critical for understanding the development of many processes subsumed within the RDoC model, which will contribute to greater understanding of developmental variation in the etiology of psychopathology and can be leveraged to identify potential windows of heightened developmental plasticity when clinical interventions might be maximally efficacious.

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