Child Abuse and Epigenetic Mechanisms of Disease Risk

doi:10.1016/j.amepre.2012.10.012

American Journal of Preventive Medicine

Volume 44, Issue 2, February 2013, Pages 101-107

https://doi.org/10.1016/j.amepre.2012.10.012 Get rights and content

Background

Child abuse is highly prevalent and associated with increased risk for a range of health problems, including cancer, cardiovascular disease, diabetes, psychiatric disorders, and other health problems. Little is currently known about the mechanism by which early adversity confers risk for health problems later in life.

Purpose

To determine if there are epigenetic differences associated with child maltreatment that may help explain association between adverse childhood experiences and later health problems.

Methods

As part of a study examining genetic and environmental factors associated with depression, saliva DNA specimens were collected on 96 maltreated children removed from their parents due to abuse or neglect and 96 demographically matched control children between 2003 and 2010. In 2011, the Illumina 450K BeadChip was used on stored DNA specimens and analyzed to examine whole-genome methylation differences between maltreated and control children.

Results

After controlling for multiple comparisons, maltreated and control children had significantly different methylation values at 2868 CpG sites (p<5.0 × 10^–7, all sites; average methylation difference per site=17%; range=1%–62%). The gene set contained numerous markers of diseases and biological processes related to the health problems associated with early childhood adversity.

Conclusions

Although replication is required, this study suggests that epigenetic mechanisms may be associated with risk for health problems later in life in maltreated children. This study lays the groundwork for future studies examining health and methylation measures to further characterize the role of epigenetic mechanisms in conferring risk for medical problems in individuals with histories of early adversity.

Introduction

Child abuse occurs at epidemic rates, with nearly 700,000 substantiated reports of child maltreatment each year,¹ many reported cases of actual abuse referred to protective services that are not verified,² and countless other cases that never come to the attention of authorities.2, 3, 4 Child maltreatment and other adverse childhood experiences are nonspecific risk factors for multiple psychiatric disorders5, 6, 7 and several health risk behaviors including smoking, overeating, and excessive alcohol and drug use.8, 9, 10 Above and beyond the effect of these risk behaviors, however, adverse childhood experiences predict ischemic heart disease,9, 11, 12 stroke,⁹ respiratory problems,13, 14 diabetes,9, 12 and cancer.9, 15

How do experiences of early adversity confer risk for later psychiatric and medical problems? Epigenetics has been proposed as one possible mechanism.16, 17, 18 Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in DNA nucleotide sequence.¹⁹ These modifications regulate gene activity and play a role in acute regulation of genes in response to changes in the environment.20, 21

DNA methylation is one of the most studied epigenetic mechanisms.²² In mammalian cells, DNA methylation occurs mainly at discrete CpG sites in the genome, regions where cytosine nucleotides occur next to guanine nucleotides.23, 24 Although gene regulation is influenced by DNA methylation in other regions of the genome, the impact of methylation in promoters is best understood; it can lead to gene silencing.

The effect of a history of childhood abuse on methylation has been examined previously in candidate gene studies. In two reports, a history of childhood abuse was associated with increased methylation in lymphoblast DNA in the promoter region of the serotonin transporter (SLC6A4), a gene implicated in several neuropsychiatric disorders.25, 26 A third report found childhood abuse associated with differences in methylation at four CpG sites in nonpromoter regions of SLC6A4, but these did not withstand correction for multiple comparisons.²⁷ Methylation in the glucocorticoid receptor (NR3C1), a gene involved in the stress response and implicated in several neuropsychiatric disorders, also has been examined, and two independent research groups reported that a history of childhood abuse was associated with altered methylation of NR3C1 in hippocampal-derived DNA.28, 29

With the advent of methodologies to complete high-throughput methylation profiling of the entire genome,³⁰ novel epigenetic modifications associated with early adversity also can be identified. Two small-scale studies used the Illumina 27K BeadChip, which assays 27,578 CpG promoter-associated sites across the genome to examine methylation differences associated with early adversity. The first study included 28 children: 14 reared from birth in institutions and 14 reared with their parents.³¹ The second study included 100 adults: 25 who met criteria for posttraumatic stress disorder (PTSD) secondary to childhood abuse; 25 who met criteria for PTSD secondary to other traumas; 25 adults with histories of childhood abuse without PTSD; and 25 adults without PTSD and without histories of childhood abuse.³² The first study reported methylation differences between institution- and family-reared children in numerous CpG sites in genes involved in immune response and cellular signaling systems.³¹ These findings were not replicated in the second study with adults in which more-rigorous controls were used for multiple comparison testing and contained adults with PTSD secondary to other traumas in the non-abused control group.³²

The present investigation examines methylation profile differences in a sample of maltreated and nontraumatized comparison children using the new Illumina 450K BeadChip, which examines a broader range of CpG sites involved in gene regulation. In addition to examining promoter-associated CpG sites, this array also assays CpG sites involved in gene regulation located on the gene body, 3′-untranslated regions (3′UTR), 5′UTRs, and intergenic regions.³⁰ The goal of the current study is to identify novel pathways and mechanisms by which child abuse and other adverse early experiences may confer risk for a range of health problems later in life.

Section snippets

Methods

Participants included 192 children recruited between 2003 and 2010: of these, 96 were maltreated children removed from their parents' care due to reports of abuse and/or neglect within 6 months of study enrollment, and 96 were controls with no history of maltreatment or exposure to intrafamilial violence. All maltreated children in this investigation also participated in a prior published report of genetic and environmental factors associated with depression³³; the cohort of controls was

Group Differences in Methylation

After controlling for demographic factors (e.g., race, gender, age), and multiple comparisons, maltreated and control children had significantly different methylation values at a total of 2868 CpGs sites of the 485K sites included on the array (p<5.0 × 10^–7, all sites). On average, methylation values of maltreated and control children differed by 17% (range: 1%–62%). Significant CpG sites were identified on all 23 chromosomes: 2113 (74%) at sites with low methylation values (<0.2); 288 (10%) at

Discussion

Child maltreatment was associated with widespread differences in methylation across the entire genome. After rigorously controlling for demographic factors and multiple comparisons, group differences in methylation values emerged at a total of 2868 CpGs sites of the 485K sites included on the array. A general pattern emerged, such that maltreated children had elevated methylation values at CpG sites with methylation values in the low to mid range, and reduced methylation values at CpG sites

References (72)

G.D. Wolfner et al.
A profile of violence toward children: a national study
Child Abuse Negl
(1993)
N.J. Burke et al.
The impact of adverse childhood experiences on an urban pediatric population
Child Abuse Neglect
(2011)
V.J. Felitti et al.
Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adultsThe Adverse Childhood Experiences (ACE) Study
Am J Prev Med
(1998)
R.F. Anda et al.
Adverse childhood experiences and chronic obstructive pulmonary disease in adults
Am J Prev Med
(2008)
B.S. McEwen et al.
Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress
Neuropharmacology
(2012)
E.J. Nestler
Epigenetic mechanisms in psychiatry
Biol Psychiatry
(2009)
M. Szyf
The early life environment and the epigenome
Biochim Biophys Acta
(2009)
F.A. Champagne et al.
Maternal regulation of estrogen receptor alpha methylation
Curr Opin Pharmacol
(2008)
B. Labonte et al.
Differential glucocorticoid receptor exon 1(b), 1(c), and 1(h) expression and methylation in suicide completers with a history of childhood abuse
Biol Psychiatry
(2012)
M. Bibikova et al.
High density DNA methylation array with single CpG site resolution
Genomics
(2011)

J. Kaufman et al.

Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children

Biol Psychiatry

(2006)

N. Weder et al.

MAOA genotype, maltreatment, and aggressive behavior: the changing impact of genotype at varying levels of trauma

Biol Psychiatry

(2009)

J. Kaufman et al.

Genetic and environmental predictors of early alcohol use

Biol Psychiatry

(2007)

E. Hodges et al.

Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment

Mol Cell

(2011)

J. Yang et al.

Chromatin insulators: a role in nuclear organization and gene expression

Adv Cancer Res

(2011)

D. Cotnoir-White et al.

Evolution of the repertoire of nuclear receptor binding sites in genomes

Mol Cell Endocrinol

(2011)

I.A. Qureshi et al.

Long non-coding RNAs in nervous system function and disease

Brain Res

(2010)

M. Hanson et al.

Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms

Prog Biophys Mol Biol

(2011)

K. Ogoshi et al.

Genome-wide profiling of DNA methylation in human cancer cells

Genomics

(2011)

Y. Watanabe et al.

Methylation of DNA in cancer

Adv Clin Chem

(2010)

A.S. Wilson et al.

DNA hypomethylation and human diseases

Biochim Biophys Acta

(2007)

S.R. Dube et al.

Adverse childhood experiences and personal alcohol abuse as an adult

Addict Behav

(2002)

N. Mori et al.

Ccdc85c encoding a protein at apical junctions of radial glia is disrupted in hemorrhagic hydrocephalus (hhy) mice

Am J Pathol

(2012)

K.P. Suijkerbuijk et al.

Improving early breast cancer detection: focus on methylation

Ann Oncol

(2011)

N. Weder et al.

Critical periods revisited: implications for intervention with traumatized children

J Am Acad Child Adolesc Psychiatry

(2011)

D.T. Redden et al.

Nonreplication in genetic association studies of obesity and diabetes research

J Nutr

(2003)

M.H. vanIJzendoorn et al.

Methylation matters: interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma

Biol Psychiatry

(2010)

G.H. Boxer et al.

Neglect contributing to tertiary hospitalization in childhood asthma

Child Abuse Negl

(1988)

Child maltreatment, 2009

(2010)

A.J. Sedlak et al.

Fourth National Incidence Study of Child Abuse and Neglect (NIS–4): report to Congress, executive summary

(2010)

M. Dowd

Penn State's Culpability

New York Times

(2011, Nov 8)

K.S. Kendler et al.

Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis

Arch Gen Psychiatry

(2000)

B.E. Molnar et al.

Child sexual abuse and subsequent psychopathology: results from the National Comorbidity Survey

Am J Public Health

(2001)

J. Kaufman

Child Abuse. Lewis' child and adolescent psychiatry: a comprehensive textbook

(2007)

R.F. Anda et al.

Adverse childhood experiences and smoking during adolescence and adulthood

JAMA

(1999)

M. Dong et al.

Insights into causal pathways for ischemic heart disease: adverse childhood experiences study

Circulation

(2004)

Cited by (194)

The cognitive tasks and event-related potentials associated childhood adversity: A systematic review
2024, Neuroscience and Biobehavioral Reviews
In this systematic review, 18 articles met inclusion criteria to be qualitatively analyzed for converging evidence of brain activity, measured using event-related potential (ERP), related to retrospectively reported childhood adversity/trauma. Using the PRISMA guidelines for systematic reviews, 917 articles were assessed for inclusion and were filtered using study parameters. The most common ERP components listed in the literature were P100, N170, N200, P200, P300, ERN, and LPP. We discuss levels of evidence for changed brain activity, each ERP component, and the tasks used to evoke them. The Childhood Trauma Questionnaire was found to be the most commonly cited measure. We note the need to assess the duration and intensity of childhood adversity/trauma measurements in the strengths and limitations of the reported childhood adversity/trauma measurements. No concrete converging evidence was found to support a relationship between ERP-measured brain activity and retrospectively reported childhood adversity/trauma. Thus, a discussion of limitations and future directions for this field of research is presented.
Systemic lupus erythematosus in American Indian/Alaska natives: Incorporating our new understanding of the biology of trauma
2023, Seminars in Arthritis and Rheumatism
To review the literature regarding systemic lupus erythematosus (SLE) in American Indian/Alaska Native (AI/AN) people and relate prevalence and/or disease severity to our emerging understanding of the biology of trauma and toxic stress.
We conducted a search and review of the literature using search terms “lupus and American Indians” “ACEs and disease outcome” “Biology of Adversity” “lupus and ACE scores,” “ lupus and childhood abuse.” These search criteria were entered into Google Scholar and articles retrieved from PubMed, NBCI. This approach yielded a small numbers of papers used throughout this review. We excluded articles that were not published in a peer reviewed journals, as well as editorial commentaries.
In the AI/AN population, SLE shows high prevalence rates and severe disease manifestations, comparable to the African American population. AI/AN populations also have high rates of childhood trauma. Toxic stress and trauma such as those catalogued in the Adverse Childhood Experiences (ACE) study have broad-reaching immunologic and epigenetic effects that are likely to be relevant to our understanding of SLE in AI/AN people.
AI/AN people have high rates of SLE. These high rates are likely to be driven by many complex factors, not all of which are genetic. Future research is needed to establish (or refute) a causal connection between the biology of adversity and SLE in socially marginalized and historically traumatized populations.
Greater maltreatment severity is associated with smaller brain volume with implication for intellectual ability in young children
2023, Neurobiology of Stress
Childhood maltreatment profoundly alters trajectories of brain development, promoting markedly increased long-term health risks and impaired intellectual development. However, the immediate impact of maltreatment on brain development in children and the extent to which altered global brain volume contributes to intellectual development in children with maltreatment experience is currently unknown. We here utilized MRI data obtained from children within 6 months after the exposure to maltreatment to assess the association of maltreatment severity with global brain volume changes. We further assessed the association between maltreatment severity and intellectual development and tested for the mediating effect of brain volume on this association.
We used structural MRI (3T) in a sample of 49 children aged 3–5 years with maltreatment exposure, i.e. emotional and physical abuse and/or neglect within 6 months, to characterize intracranial and tissue-specific volumes. Maltreatment severity was coded using the Maternal Interview for the Classification of Maltreatment. IQ was tested at study entry and after one year using the Snijders Oomen Nonverbal Test.
Higher maltreatment severity was significantly correlated with smaller intracranial volume (r = -.393, p = .008), which was mainly driven by lower total brain volume (r = -.393, p = .008), which in turn was primarily due to smaller gray matter volume (r = -.454, p = .002). Furthermore, smaller gray matter volume was associated with lower IQ at study entry (r = -.548, p < .001) and predicted IQ one year later (r = -.493, p = .004). The observed associations were independent of potential confounding variables, including height, socioeconomic status, age and sex.
We provide evidence that greater maltreatment severity in early childhood is related to smaller brain size at a very young age with significant consequences for intellectual ability, likely setting a path for far-reaching long-term disadvantages. Insights into the molecular and neural processes that underlie the impact of maltreatment on brain structure and function are urgently needed to derive mechanism-driven targets for early intervention.
Stage 2 Registered Report: Epigenetic Intergenerational Transmission: Mothers’ Adverse Childhood Experiences and DNA Methylation
2023, Journal of the American Academy of Child and Adolescent Psychiatry
Individual differences in risk for mental disorders over the lifespan are shaped by forces acting before the individual is born—in utero, but likely even earlier, during the mother’s own childhood. The environmental epigenetics hypothesis proposes that sustained effects of environmental conditions on gene expression are mediated by epigenetic mechanisms. Recent human studies have shown that adversities in childhood are correlated with DNA methylation (DNAm) in adulthood. In the current study, we tested the following pre-registered hypotheses: Mothers’ adverse childhood experiences (ACEs) are correlated with DNAm in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women’s depression and anxiety symptoms during pregnancy mediate the association between mothers’ ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3).
Data were from the Avon Longitudinal Study of Parents and Children Accessible Resource for Integrated Epigenomic Studies substudy. Women provided retrospective self-reports during pregnancy of ACE exposure. We conducted an epigenome-wide association study testing whether mothers’ ACE exposure, cumulative score (0-10), was associated with DNAm in maternal antenatal blood and infant cord blood in more than 450,000 CpG (point on DNA sequence where cytosine and guanine base pairs are linked by a phosphate, where methylation usually occurs) sites on the Illumina 450K BeadChip. Analyses for cord blood were separated by infant sex, a pre-registered analysis.
Hypothesis 1: In 896 mother−infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers’ ACE score and DNAm from antenatal peripheral blood, after controlling for covariates. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers’ ACEs (false discovery rate [FDR] < .05), but only in male offspring. Effect sizes were medium, with partial eta squared values ranging from 0.060 to 0.078. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers’ ACEs score and DNAm in the significant CpG sites in male cord blood. Mediation was not tested in antenatal peripheral blood, because no direct association between mothers’ ACE score and antenatal peripheral blood was found.
Our results show that mothers’ ACE exposure is associated with DNAm in male offspring, supporting the notion that DNAm could be a marker of intergenerational biological embedding of mothers’ childhood adversity.
Epigenetic Intergenerational Transmission: Mothers’ Adverse Childhood Experiences and DNA Methylation; https://doi.org/10.1016/j.jaac.2020.03.008
Methylome changes associated with functional movement/conversion disorder: Influence of biological sex and childhood abuse exposure
2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Epigenetic changes, such as DNA methylation (DNAm), may represent an important mechanism implicated in the etiopathogenesis of functional movement/conversion disorder (FMD). Here, we aimed to identify methylomic variations in a case-control cohort of FMD and to uncover specific epigenetic signatures associated with female sex and childhood abuse, two key risk factors for FMD and other functional neurological disorders.
Genome-wide DNAm analysis was performed from peripheral blood in 57 patients with FMD and 47 healthy controls with and without childhood abuse. Using principal component analysis, we examined the association of principal components with FMD status in abused and non-abused individuals, in the entire study sample and in female subjects only. Next, we used enrichment pathway analysis to investigate the biological significance of DNAm changes and explored differences in methylation levels of genes annotated to the top enriched biological pathways shared across comparisons.
We found that FMD was associated with DNAm variation across the genome and identified a common epigenetic ‘signature’ enriched for biological pathways implicated in chronic stress and chronic pain. However, methylation levels of genes included in the top two shared pathways hardly overlapped, suggesting that transcriptional profiles may differ as a function of childhood abuse exposure and sex among subjects with FMD.
This study is unique in providing genome-wide evidence of DNAm changes in FMD and in indicating a potential mechanism linking childhood abuse exposure and female sex to differences in FMD pathophysiology. Future studies are needed to replicate our findings in independent cohorts.
Childhood maltreatment and DNA methylation: A systematic review
2023, Neuroscience and Biobehavioral Reviews
Child maltreatment (CM) encompasses sexual abuse, physical abuse, emotional abuse, neglect, and exposure to domestic and family violence. Epigenetic research investigating CM has focused on differential DNA methylation (DNAm) in genes associated with the stress response, but there has been limited evaluation of the specific effects of subtypes of CM. This systematic review of literature investigating DNAm associated with CM in non-clinical populations aimed to summarise the approaches currently used in research, how the type of maltreatment and age of exposure were encoded via methylation, and which genes have consistently been associated with CM. A total of fifty-four papers were eligible for review, including forty-one candidate gene studies, eight epigenome-wide association studies, and five studies with a mixed design. The ways in which the various forms of CM were conceptualised and measured varied between papers. Future studies would benefit from assessments that employ conceptually robust definitions of CM, and that capture important contextual information such as age of exposure and subtype of CM.

View all citing articles on Scopus

: This activity is available for CME credit. See page A3 for information.

View full text

Research articleChild Abuse and Epigenetic Mechanisms of Disease Risk

Background

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Group Differences in Methylation

Discussion

Child Abuse Negl

Child Abuse Neglect

Am J Prev Med

Am J Prev Med

Neuropharmacology

Biol Psychiatry

Biochim Biophys Acta

Curr Opin Pharmacol

Biol Psychiatry

Genomics

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Mol Cell

Adv Cancer Res

Mol Cell Endocrinol

Brain Res

Prog Biophys Mol Biol

Genomics

Adv Clin Chem

Biochim Biophys Acta

Addict Behav

Am J Pathol

Ann Oncol

J Am Acad Child Adolesc Psychiatry

J Nutr

Biol Psychiatry

Child Abuse Negl

Child maltreatment, 2009

Fourth National Incidence Study of Child Abuse and Neglect (NIS–4): report to Congress, executive summary

Penn State's Culpability

New York Times

Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis

Arch Gen Psychiatry

Child sexual abuse and subsequent psychopathology: results from the National Comorbidity Survey

Am J Public Health

Child Abuse. Lewis' child and adolescent psychiatry: a comprehensive textbook

Adverse childhood experiences and smoking during adolescence and adulthood

JAMA

Insights into causal pathways for ischemic heart disease: adverse childhood experiences study

Circulation

Research article
Child Abuse and Epigenetic Mechanisms of Disease Risk