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The association of epigenetic age acceleration and depressive and anxiety symptom severity among children recently exposed to substantiated maltreatment
Abstract
Child maltreatment is a major risk factor for both depressive and anxiety disorders. However, many children exposed to maltreatment never meet diagnostic threshold for either disorder while experiencing only transitory symptoms post-exposure. Recent research suggests DNA methylation adds predictive value in explaining variation in the onset and course of multiple psychiatric disorders following exposure to child maltreatment. Epigenetic age acceleration (EAA), the biological aging of cells not attributable to chronological aging, is a stress-sensitive biomarker capturing genome-wide variation in DNA methylation with the potential to identify children who have been maltreated at greatest risk for depressive and anxiety disorders. The current study examined two EAA clocks appropriate for the pediatric population, the Horvath and Pediatric Buccal Epigenetic (PedBE) clocks, and their associations with depressive and anxiety symptom severity following child maltreatment. Children (N = 71) 8-15 years of age, all of whom were exposed to substantiated child maltreatment in the 12 months prior to study entry, were enrolled. Risk modeling adjusting for several confounders revealed that EAA estimated via the Horvath clock was significantly associated with more severe depressive and anxiety symptoms. The PedBE clock was not associated with either depressive or anxiety symptom severity. Sensitivity analyses demonstrated that EAA via the Horvath clock robustly predicted depressive and anxiety symptom severity across multiple modeling scenarios. Our findings advance existing research suggesting EAA, as estimated with the Horvath clock, may be a promising biomarker for identifying children at greatest risk for more severe depressive and anxiety symptoms following maltreatment.
... However, it is possible that evidence of accelerated biological age may have been evident earlier in the lives of the individuals in the current study. In two recent studies of young children who had substantiated cases of child maltreatment prior to study entry (74,75), there was evidence of accelerated aging in relation to anxiety, depression and PTSD. As pointed out by Zannas (76), existing research has "assumed unidirectional causality that stress and mental suffering drive accelerated aging" (page E1). ...
Background: Childhood maltreatment and psychiatric morbidity have each been associated with
accelerated biological aging primarily through cross-sectional studies. Using data from a prospective longitudinal study of individuals with histories of childhood maltreatment and controls followed up into midlife, we test two hypotheses examining whether (1) psychiatric symptoms mediate the relationship between childhood maltreatment and biological aging and (2) psychiatric symptoms of anxiety, depression, or post-traumatic stress disorder act in conjunction with childhood maltreatment to exacerbate the association of child maltreatment to aging. Methods: Children (ages 0-11y) with documented histories of maltreatment and demographically matched controls were followed into adulthood (N = 607) and interviewed over several waves of the study. Depression, anxiety, and post-traumatic stress disorder symptoms were assessed at mean ages 29 (interview 1) and 40 (interview 2). Biological age was measured from blood-chemistries collected later (Mage= 41y) using the Klemera-Doubal method. Hypotheses were tested using linear regressions and path analyses.
Results: Adults with documented histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety at both interviews and more advanced biological aging, compared to controls. PTSD symptoms at both interviews and depression and anxiety symptoms only at interview 2 predicted accelerated biological aging. There was no evidence of mediation; however, anxiety and depression moderated the relationship between childhood maltreatment and biological aging.
Conclusion: These new findings reveal the shorter and longer-term longitudinal impact of PTSD on biological aging and the amplifying effect of anxiety and depression on the relationship between child maltreatment and biological aging.
... A growing body of evidence suggests that such indicators of more rapid epigenetic aging may also be associated with developmental measures in children. Youth with greater EAA are more likely to have experienced stress/adverse childhood experiences 22 with future cognitive impairment 23 and depression and anxiety 24 . Our report adds to the growing body of work that examines EAA with respect to childhood markers of growth and maturation. ...
Using data from a longitudinal cohort of children, we examined whether epigenetic age acceleration (EAA) was associated with pubertal growth and whether these associations were mediated by adiposity. We examined associations between EAA at approximately 10 years of age with pubertal growth metrics, including age at peak height velocity (PHV), PHV, and sex steroid levels and whether these associations were mediated by measures of adiposity including body mass index (BMI) and MRI-assessed visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Children (n = 135) with accelerated EAA had higher PHV (β 0.018, p = 0.0008) although the effect size was small. The association between EAA and age at PHV was not significant (β − 0.0022, p = 0.067). Although EAA was associated with higher BMI (β 0.16, p = 0.0041), VAT (β 0.50, p = 0.037), and SAT (β 3.47, p = 0.0076), BMI and VAT did not mediate associations between EAA and PHV, while SAT explained 8.4% of the association. Boys with higher EAA had lower total testosterone (β − 12.03, p = 0.0014), but associations between EAA and other sex steroids were not significant, and EAA was not associated with sex steroid levels in girls. We conclude that EAA did not have strong associations with either age at onset of puberty or pubertal growth speed, although associations with growth speed were statistically significant. Studies with larger sample sizes are needed to confirm this pattern of associations.
Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation.
Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6–8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15–17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7–11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath’s pan-tissue (Horvath1), Horvath’s Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress).
Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation.
Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.
Objective
Childhood maltreatment is associated with mental health problems, but the extent to which this relationship is causal remains unclear. To strengthen causal inference, we conducted a systematic review and meta-analysis of quasi-experimental studies examining the relationship between childhood maltreatment and mental health problems.
Methods
We searched PubMed, PsycINFO, and Embase for peer-reviewed, English language articles from inception until January 1, 2022. Studies were included if they examined the association between childhood maltreatment and mental health problems using a quasi-experimental method (e.g., twin/sibling differences design, Children of Twins design, adoption design, fixed-effects design, random-intercept cross-lagged panel model, natural experiment, propensity score matching, or inverse probability weighting).
Results
We identified 34 quasi-experimental studies, including 54,646 independent participants. Before quasi-experimental adjustment for confounding, childhood maltreatment was moderately associated with mental health problems (Cohen’s d=0.56, 95% CI=0.41-0.71). Following quasi-experimental adjustment, a small association between childhood maltreatment and mental health problems remained (Cohen’s d=0.31, 95% CI=0.24-0.37). This adjusted association between child maltreatment and mental health was consistent across different quasi-experimental methods, and generalised across different psychiatric disorders.
Conclusion
These findings are consistent with a small, causal contribution of childhood maltreatment to mental health problems. Furthermore, the findings suggest that part of the overall risk of mental health problems in individuals exposed to maltreatment is due to wider genetic and environmental risk factors. Therefore, preventing childhood maltreatment and addressing wider psychiatric risk factors in individuals exposed to maltreatment could help to prevent psychopathology.
Background
Studies reporting accelerated ageing in children with affective disorders or maltreatment exposure have relied on algorithms for estimating epigenetic age derived from adult samples. These algorithms have limited validity for epigenetic age estimation during early development. We here use a pediatric buccal epigenetic (PedBE) clock to predict DNA methylation-based ageing deviation in children with and without internalizing disorder and assess the moderating effect of maltreatment exposure. We further conduct a gene set enrichment analysis to assess the contribution of glucocorticoid signaling to PedBE clock-based results.
Method
DNA was isolated from saliva of 158 children [73 girls, 85 boys; mean age (SD) = 4.25 (0.8) years] including children with internalizing disorder and maltreatment exposure. Epigenetic age was estimated based on DNA methylation across 94 CpGs of the PedBE clock. Residuals of epigenetic age regressed against chronological age were contrasted between children with and without internalizing disorder. Maltreatment was coded in 3 severity levels and entered in a moderation model. Genome-wide dexamethasone-responsive CpGs were derived from an independent sample and enrichment of these CpGs within the PedBE clock was identified.
Results
Children with internalizing disorder exhibited significant acceleration of epigenetic ageing as compared to children without internalizing disorder (F1,147 = 6.67, p = .011). This association was significantly moderated by maltreatment severity (b = 0.49, 95% CI [0.073, 0.909], t = 2.322, p = .022). Children with internalizing disorder who had experienced maltreatment exhibited ageing acceleration relative to children with no internalizing disorder (1–2 categories: b = 0.50, 95% CI [0.170, 0.821], t = 3.008, p = .003; 3 or more categories: b = 0.99, 95% CI [0.380, 1.593], t = 3.215, p = .002). Children with internalizing disorder who were not exposed to maltreatment did not show epigenetic ageing acceleration. There was significant enrichment of dexamethasone-responsive CpGs within the PedbE clock (OR = 4.36, p = 1.65*10–6). Among the 94 CpGs of the PedBE clock, 18 (19%) were responsive to dexamethasone.
Conclusion
Using the novel PedBE clock, we show that internalizing disorder is associated with accelerated epigenetic ageing in early childhood. This association is moderated by maltreatment severity and may, in part, be driven by glucocorticoids. Identifying developmental drivers of accelerated epigenetic ageing after maltreatment will be critical to devise early targeted interventions.
Childhood maltreatment is a major risk factor for chronic and severe mental and physical health problems across the lifespan. Increasing evidence supports the hypothesis that maltreatment is associated with epigenetic changes that may subsequently serve as mechanisms of disease. The current review uses a systematic approach to identify and summarize the literature related to childhood maltreatment and alterations in DNA methylation in humans. A total of 100 empirical articles were identified in our systematic review of research published prior to or during March 2020, including studies that focused on candidate genes and studies that leveraged epigenome-wide data in both children and adults. Themes arising from the literature, including consistent and inconsistent patterns of results, are presented. Several directions for future research, including important methodological considerations for future study design, are discussed. Taken together, the literature on childhood maltreatment and DNA methylation underscores the complexity of transactions between the environment and biology across development.
Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms at ages 6-10 years. Similar trends for externalizing symptoms did not reach statistical significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.
DNA methylation (DNAm) - an epigenetic process that regulates gene expression - may represent a mechanism for the biological embedding of early traumatic experiences, including childhood maltreatment. Here, we conducted the first systematic review of human studies linking childhood maltreatment to DNAm. In total, 72 studies were included in the review (2008-2018). The majority of extant studies (i) were based on retrospective data in adults, (ii) employed a candidate gene approach (iii) focused on global maltreatment, (iv) were based on easily accessible peripheral tissues, typically blood; and (v) were cross-sectional. Two-thirds of studies (n = 48) also examined maltreatment-related outcomes, such as stress reactivity and psychiatric symptoms. While findings generally support an association between childhood maltreatment and altered patterns of DNAm, factors such as the lack of longitudinal data, low comparability across studies as well as potential genetic and 'pre-exposure' environmental confounding currently limit the conclusions that can be drawn. Key challenges are discussed concrete recommendations for future research are provided to move the field forward.
Objectives:
Exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous physical and mental health problems. In recent years, measures of DNA methylation-based epigenetic age--known as "epigenetic clocks"--have been used to estimate accelerated epigenetic aging. Although a small number of studies have found an effect of adversity exposure on epigenetic age in children, none have investigated if there are "sensitive periods" when adversity is most impactful.
Methods:
Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 973), we tested the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7.5 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated potential sensitive period effects.
Results:
We found that exposure to abuse, financial hardship, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of Hannum-based epigenetic age from chronological age, even after considering the role of adversity accumulation and recency. Secondary sex-stratified analyses identified particularly strong sensitive period effects. These effects were undetected in analyses comparing children "exposed" versus "unexposed" to adversity. We did not identify any associations between adversity and epigenetic age using the Horvath epigenetic clock.
Conclusions:
Our results suggest that adversity may alter methylation processes in ways that either directly or indirectly perturb normal cellular aging and that these effects may be heightened during specific life stages.
Importance
Childhood maltreatment is associated with mental illness. Researchers, clinicians, and public health professionals use prospective or retrospective measures interchangeably to assess childhood maltreatment, assuming that the 2 measures identify the same individuals. However, this assumption has not been comprehensively tested.
Objective
To meta-analyze the agreement between prospective and retrospective measures of childhood maltreatment.
Data Sources
MEDLINE, PsycINFO, Embase, and Sociological Abstracts were searched for peer-reviewed, English-language articles from inception through January 1, 2018. Search terms included child* maltreatment, child* abuse, child* neglect, child bull*, child* trauma, child* advers*, and early life stress combined with prospective* and cohort.
Study Selection
Studies with prospective measures of childhood maltreatment were first selected. Among the selected studies, those with corresponding retrospective measures of maltreatment were identified. Of 450 studies with prospective measures of childhood maltreatment, 16 had paired retrospective data to compute the Cohen κ coefficient.
Data Extraction and Synthesis
Multiple investigators independently extracted data according to PRISMA and MOOSE guidelines. Random-effects meta-analyses were used to pool the results and test predictors of heterogeneity.
Main Outcomes and Measures
The primary outcome was the agreement between prospective and retrospective measures of childhood maltreatment, expressed as a κ coefficient. Moderators of agreement were selected a priori and included the measure used for prospective or retrospective assessment of childhood maltreatment, age at retrospective report, sample size, sex distribution, and study quality.
Results
Sixteen unique studies including 25 471 unique participants (52.4% female [SD, 10.6%]; mean [SD] age, 30.6 [11.6] years) contained data on the agreement between prospective and retrospective measures of childhood maltreatment. The agreement between prospective and retrospective measures of childhood maltreatment was poor, with κ = 0.19 (95% CI, 0.14-0.24; P < .001). Agreement was higher when retrospective measures of childhood maltreatment were based on interviews rather than questionnaires (Q = 4.1521; df = 1; P = .04) and in studies with smaller samples (Q = 4.2251; df = 1; P = .04). Agreement was not affected by the type of prospective measure used, age at retrospective report, sex distribution of the sample, or study quality.
Conclusions and Relevance
Prospective and retrospective measures of childhood maltreatment identify different groups of individuals. Therefore, children identified prospectively as having experienced maltreatment may have different risk pathways to mental illness than adults retrospectively reporting childhood maltreatment. Researchers, clinicians, and public health care professionals should recognize these critical measurement differences when conducting research into childhood maltreatment and developing interventions.
Purpose of review:
DNA methylation-based aging biomarkers are valuable tools for evaluating the aging process from a molecular perspective. These epigenetic aging biomarkers can be evaluated across the lifespan and are tissue specific. This review examines the literature relating environmental exposures to DNA methylation-based aging biomarkers and also the literature evaluating these biomarkers as predictors of health outcomes.
Recent findings:
Multiple studies evaluated the association between air pollution and DNA methylation age and consistently observed that higher exposures are associated with elevated DNA methylation age. Psychosocial exposures, e.g., traumas and adolescent adversity, and infections are also associated with epigenetic aging. DNA methylation age has been repeatedly associated with mortality, cancer, and cognitive impairment. DNA methylation age is responsive to the environment and predictive of health outcomes. Studies are still needed to evaluate whether DNA methylation age acts as a mediator or modifier of environmental health effects and to understand the impact of factors such as race, gender, and genetics.
Background:
Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0-13.2 years-old.
Results:
Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist (p values < 0.045). AA was not significantly associated with cognition.
Conclusions:
Our findings suggest that already in adolescence, AA is associated with physiological age acceleration, which may index risk of earlier aging. AA may identify individuals for preventive interventions decades before aging-related diseases become manifest.
The assumption that early stress leads to dysregulation and impairment is widespread in developmental science and informs prevailing models (e.g., “toxic stress”). An alternative evolutionary-developmental approach, which complements the standard emphasis on dysregulation, proposes that early stress may prompt the development of costly but adaptive strategies that promote survival and reproduction in adverse conditions. Here we survey this growing theoretical and empirical literature, highlighting recent developments and outstanding questions. We review concepts of adaptive plasticity and conditional adaptation, introduce the life history framework and the Adaptive Calibration Model, and consider how physiological stress response systems and related neuroendocrine processes may function as plasticity mechanisms. We then address the evolution of individual differences in susceptibility to the environment, which engenders systematic person-environment interactions in the effects of stress on development. Finally, we discuss stress-mediated regulation of pubertal development as a case study of how an evolutionary-developmental approach can foster theoretical integration.
Background: Recent studies examining the association between posttraumatic stress disorder (PTSD)
and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed
chronological age, have yielded mixed results.
Methods: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity
in association with accelerated DNA methylation age using data from 9 cohorts contributing to the
Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2,186). Associations
between demographic and cellular variables and accelerated DNA methylation age were also examined,
as was the moderating influence of demographic variables.
Results: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood
trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity
evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps
= .028 and .016, respectively). Sex, CD4 T cell proportions, and natural killer cell proportions were also
significantly associated with accelerated DNA methylation age (all ps < .02). PTSD diagnosis and lifetime
trauma exposure were not associated with advanced DNA methylation age. There was no evidence of
moderation of the trauma or PTSD variables by demographic factors.
Conclusions: Results suggest that traumatic stress is associated with advanced epigenetic age and raise
the possibility that cells integral to immune system maintenance and responsivity play a role in this.
This study highlights the need for additional research into the biological mechanisms linking traumatic
stress to accelerated DNA methylation age and the importance of furthering our understanding of the
neurobiological and health consequences of PTSD.
Both prospective informant-reports and retrospective self-reports may be used to measure childhood maltreatment, though both methods entail potential limitations such as underestimation and memory biases. The validity and utility of standard measures of childhood maltreatment requires clarification in order to inform the design of future studies investigating the mental health consequences of maltreatment. The present study assessed agreement between prospective informant-reports and retrospective self-reports of childhood maltreatment, as well as the comparative utility of both reports for predicting a range of psychiatric problems at age 18. Data were obtained from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative birth cohort of 2232 children followed to 18 years of age (with 93% retention). Childhood maltreatment was assessed in two ways: (i) prospective informant-reports from caregivers, researchers, and clinicians when children were aged 5, 7, 10 and 12; and (ii) retrospective self-reports of maltreatment experiences occurring up to age 12, obtained at age 18 using the Childhood Trauma Questionnaire. Participants were privately interviewed at age 18 concerning several psychiatric problems including depression, anxiety, self-injury, alcohol/cannabis dependence, and conduct disorder. There was only slight to fair agreement between prospective and retrospective reports of childhood maltreatment (all Kappa's ≤ 0.31). Both prospective and retrospective reports of maltreatment were associated with age-18 psychiatric problems, though the strongest associations were found when maltreatment was retrospectively self-reported. These findings indicate that prospective and retrospective reports of childhood maltreatment capture largely non-overlapping groups of individuals. Young adults who recall being maltreated have a particularly elevated risk for psychopathology.
Epigenetic processes, including DNA methylation, change reliably with age across the lifespan, such that DNA methylation can be used as an “epigenetic clock”. This epigenetic clock can be used to predict age and age acceleration, which occurs when methylation-based prediction of age exceeds chronological age and has been associated with increased mortality. In the current study we examined epigenetic age acceleration using saliva samples collected from children between ages 6–13 (N = 101). Children’s exposure to neighborhood violence and heart rate during a stressful task were assessed. Age acceleration was associated with children’s direct experience of violence (p = 0.004) and with decreased heart rate (p = 0.002). Children who were predicted to be older than their chronological age had twice as much violence exposure as other children and their heart rate was similar to that of adults. The results remained significant after controlling for demographic variables, such as sex, income and education. This is the first study to show the effects of direct violence exposure on epigenetic aging in children using salivary DNA. Although longitudinal studies are needed to determine whether accelerated epigenetic aging leads to adverse health outcomes later in life, these data point to DNA methylation during childhood as a putative biological mechanism.
Background:
Statistical models that use an individual's DNA methylation levels to estimate their age (known as epigenetic clocks) have recently been developed, with 96% correlation found between epigenetic and chronological age. We postulate that differences between estimated and actual age [age acceleration (AA)] can be used as a measure of developmental age in early life.
Methods:
We obtained DNA methylation measures at three time points (birth, age 7 years and age 17 years) in 1018 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Using an online calculator, we estimated epigenetic age, and thus AA, for each child at each time point. We then investigated whether AA was prospectively associated with repeated measures of height, weight, body mass index (BMI), bone mineral density, bone mass, fat mass, lean mass and Tanner stage.
Results:
Positive AA at birth was associated with higher average fat mass [1321 g per year of AA, 95% confidence interval (CI) 386, 2256 g] from birth to adolescence (i.e. from age 0-17 years) and AA at age 7 was associated with higher average height (0.23 cm per year of AA, 95% CI 0.04, 0.41 cm). Conflicting evidence for the role of AA (at birth and in childhood) on changes during development was also found, with higher AA being positively associated with changes in weight, BMI and Tanner stage, but negatively with changes in height and fat mass.
Conclusions:
We found evidence that being ahead of one's epigenetic age acceleration is related to developmental characteristics during childhood and adolescence. This demonstrates the potential for using AA as a measure of development in future research.
In the present investigation, differential methylation analyses of the whole genome were conducted among a sample of 548 school-aged low-income children (47.8% female, 67.7% Black, M age = 9.40 years), 54.4% of whom had a history of child maltreatment. In the context of a summer research camp, DNA samples via saliva were obtained. Using GenomeStudio, Methylation Module, and the Illumina Custom Model, differential methylation analyses revealed a pattern of greater methylation at low methylation sites (n = 197 sites) and medium methylation sites (n = 730 sites) and less methylation at high methylation sites (n = 907 sites) among maltreated children. The mean difference in methylation between the maltreated and nonmaltreated children was 6.2%. The relative risk of maltreatment with known disease biomarkers was also investigated using GenoGo MetaCore Software. A large number of network objects previously associated with mental health, cancer, cardiovascular systems, and immune functioning were identified evidencing differential methylation among maltreated and nonmaltreated children. Site-specific analyses were also conducted for aldehyde dehydrogenase 2 (ALDH2), ankyrin repeat and kinase domain containing 1 (ANKK1), and nuclear receptor subfamily 3, group C, member 1 (NR3C1) genes, and the results highlight the importance of considering gender and the developmental timing of maltreatment. For ALDH2, the results indicated that maltreated girls evidenced significantly lower methylation compared to nonmaltreated girls, and maltreated boys evidenced significantly higher methylation compared to nonmaltreated boys. Moreover, early onset–not recently maltreated boys evidenced significantly higher methylation at ALDH2 compared to nonmaltreated boys. Similarly, children with early onset–nonrecent maltreatment evidenced significantly higher methylation compared to nonmaltreated children at ANKK1. The site-specific results were not altered by controlling for genotypic variation of respective genes. The findings demonstrate increased risk for adverse physical and mental health outcomes associated with differences in methylation in maltreated children and indicate differences among maltreated children related to developmental timing of maltreatment and gender in genes involved in mental health functioning.
The current study evaluated the psychometric properties of The Comprehensive Trauma
Interview PTSD Symptoms Scale (CTI-PSS), a novel method of assessing PTSD symptoms
following exposure to a range of child adversities in the child maltreatment population. A sample
of female adolescents (n = 343) exposed to substantiated child sexual abuse and a non-maltreated
comparison condition completed the CTI-PSS and other established measures to assess internal
consistency, factor structure, test discriminability, as well as convergent, discriminant, and
incremental validities. Results demonstrated that the CTI-PSS is a reliable and valid measure of
PTSD symptoms with good discriminability and a factor structure that fits existing
conceptualizations of the PTSD construct. It also demonstrated strong convergence with an
established measure of PTSD symptoms and explained unique variance in the prediction of child
sexual abuse status. Overall, the CTI-PSS appears to be a useful instrument for assessing PTSD
symptoms in the child maltreatment population
Background
Epigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. Conclusions
Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
Background:
Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.
Results:
We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias.
Conclusions:
Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.
Major depressive disorder (MDD) is a prevalent psychiatric condition in the child maltreatment population. However, not all children who have been maltreated will develop MDD or MDD symptoms, suggesting the presence of unique risk pathways that explain how certain children develop MDD symptoms when others do not. The current study tested several candidate risk pathways to MDD symptoms following child maltreatment: neuroendocrine, autonomic, affective, and emotion regulation. Female adolescents (
N
= 110; age range = 14–19) were recruited into a substantiated child maltreatment or comparison condition and completed a laboratory stressor, saliva samples, and measures of emotion regulation, negative affect, and MDD symptoms. MDD symptoms were reassessed 18 months later. Mediational modeling revealed that emotion regulation was the only significant indirect effect of the relationship between child maltreatment and subsequent MDD symptoms, demonstrating that children exposed to maltreatment had greater difficulties managing affective states that in turn led to more severe MDD symptoms. These results highlight the importance of emotion dysregulation as a central risk pathway to MDD following child maltreatment. Areas of future research and implications for optimizing prevention and clinical intervention through the direct targeting of transdiagnostic risk pathways are discussed.
Background
DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age.
Results
Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43.
Conclusions
DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.
It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure.
I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance.
I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.
The factor structure of the Children's Depression Inventory (CDI; M. Kovacs, 1992) was evaluated in a large community sample of 1,777 children and 924 adolescents. There were 5 first-order factors (Externalizing, Dysphoria, Self-Deprecation, School Problems, and Social Problems) for the child group; the adolescent group yielded the same 5 factors plus a 6th factor (Biological Dysregulation). Confirmatory factor analyses supported the stability and replicability of the obtained factor structures. Both samples yielded 2 higher order factors—Internalizing and Externalizing. The factors were compared with previous CDI factors identified for clinical (B. Weiss et al., 1991) and community (M. Kovacs, 1992) samples. Other notable findings included more boys reporting high scores (17 and above) on the CDI among the child sample, whereas, among adolescents more girls reported high scores (17 and above) on the total CDI as well as higher scores on the biological dysregulation factor. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis, monozygotic twins show indistinguishable childhood methylation, suggesting that DNAm is highly coordinated throughout early development. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from a cross-sectional study of 398 boys, aged 3-17 yr, and find significant age-associated changes in DNAm at 2078 loci. These findings correspond well with pyrosequencing data and replicate in a second pediatric population (N = 78). Moreover, we report a deficit of age-related loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. Meta-analysis (N = 1158) with two adult populations reveals that despite a significant overlap of age-associated loci, most methylation changes do not follow a lifelong linear pattern due to a threefold to fourfold higher rate of change in children compared with adults; consequently, the vast majority of changes are more accurately modeled as a function of logarithmic age. We therefore conclude that age-related DNAm changes in peripheral blood occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies should be matched closely for age.
Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.
Non-biological experimental variation or "batch effects" are commonly observed across multiple batches of microarray experiments, often rendering the task of combining data from these batches difficult. The ability to combine microarray data sets is advantageous to researchers to increase statistical power to detect biological phenomena from studies where logistical considerations restrict sample size or in studies that require the sequential hybridization of arrays. In general, it is inappropriate to combine data sets without adjusting for batch effects. Methods have been proposed to filter batch effects from data, but these are often complicated and require large batch sizes ( > 25) to implement. Because the majority of microarray studies are conducted using much smaller sample sizes, existing methods are not sufficient. We propose parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples. We illustrate our methods using two example data sets and show that our methods are justifiable, easy to apply, and useful in practice. Software for our method is freely available at: http://biosun1.harvard.edu/complab/batch/.
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.
The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath’s Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PMabs) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PMabs may accelerate epigenetic aging from an early age.
Objective: Child maltreatment is among the strongest predictors of posttraumatic stress disorder (PTSD). However, less than 40% of children who have been maltreated are ever diagnosed with PTSD, suggesting that exposure to child maltreatment alone is insufficient to explain this risk. This study examined whether epigenetic age acceleration, a stress-sensitive biomarker derived from DNA methylation, explains variation in PTSD diagnostic status subsequent to child maltreatment.
Method: Children and adolescents (N = 70; 65.7% female), 8–15 years of age (M = 12.00, SD = 2.37) and exposed to substantiated child maltreatment within the 12 months prior to study entry, were enrolled. Participants provided epithelial cheek cells via buccal swab for genotyping and quantification of epigenetic age acceleration within a case-control design. PTSD diagnostic status was determined using the Child PTSD Symptoms Scale according to the DSM-IV-TR algorithm.
Results: Epigenetic age acceleration predicted current PTSD status, revealing an effect size magnitude in the moderate range, OR = 2.35, 95% CI: 1.22– 4.51, after adjusting for sample demographics, polygenic risk for PTSD, and lifetime exposure to other childhood adversities. Supplemental analyses demonstrated that epigenetic age acceleration was related to a greater severity of PTSD arousal symptoms (r =.29, p =.015). There were no differential effects for child maltreatment subtype on epigenetic age acceleration or PTSD status.
Conclusions: The biological embedding of child maltreatment may explain variation in PTSD diagnostic status and serve as a novel approach for informing selective prevention or precision-based therapeutics for those at risk for PTSD.
Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.
Significance
DNA methylation is the most studied modification in human population epigenetics. Its information content can be explored in 2 principal ways—epigenome-wide association studies and epigenetic age. The latter likely reflects cellular/biological age and works with impressive accuracy across most tissues. In adults, it associates with various environments and health. However, current epigenetic clocks are not very accurate in the pediatric age range perhaps because DNA methylation changes much faster in children. Addressing this crucial gap, we created a precise tool to estimate DNA methylation age specific to pediatric buccal epithelial cells. This tool has the potential to become the standard reference for epigenetic studies broadly relevant to child development across the spectrum from health to disease.
Background:
Child maltreatment is a global public health issue that encompasses physical abuse, sexual abuse, emotional abuse, neglect, and exposure to intimate partner violence (IPV). This systematic review and meta-analysis summarises the association between these five forms of child maltreatment and depressive and anxiety disorders.
Methods:
Published cohort and case-control studies were included if they reported associations between any form of child maltreatment (and/or a combination of), and depressive and anxiety disorders. A total of 604 studies were assessed for eligibility, 106 met inclusion criteria, and 96 were included in meta-analyses. The data were pooled in random effects meta-analyses, giving odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for each form of child maltreatment.
Results:
All forms of child maltreatment were associated with depressive disorders (any child maltreatment [OR = 2.48, 2.14-2.87]; sexual abuse [OR = 2.11, 1.83-2.44]; physical abuse [OR = 1.78, 1.57-2.01]; emotional abuse [OR = 2.35, 1.74-3.18]; neglect [OR = 1.65, 1.35-2.02]; and exposure to IPV [OR = 1.68, 1.34-2.10]). Several forms of child maltreatment were significantly associated with anxiety disorders ('any child maltreatment' [OR = 1.68, 1.33-2.4]; sexual abuse [OR = 1.90, 1.6-2.25]; physical abuse [OR = 1.56, 1.39-1.76]; and neglect [OR = 1.34, 1.09-1.65]). Significant associations were also found between several forms of child maltreatment and post-traumatic stress disorder (PTSD).
Conclusions:
There is a robust association between five forms of child maltreatment and the development of mental disorders. The Global Burden of Disease Study (GBD) includes only sexual abuse as a risk factor for depressive and anxiety disorders. These findings support the inclusion of additional forms of child maltreatment as risk factors in GBD.
Background:
Recent conceptual models argue that early life adversity (ELA) accelerates development, which may contribute to poor mental and physical health outcomes. Evidence for accelerated development in youths comes from studies of telomere shortening or advanced pubertal development following circumscribed ELA experiences and neuroimaging studies of circuits involved in emotional processing. It is unclear whether all ELA is associated with accelerated development across global metrics of biological aging or whether this pattern emerges following specific adversity types.
Methods:
In 247 children and adolescents 8 to 16 years of age with wide variability in ELA exposure, we evaluated the hypothesis that early environments characterized by threat, but not deprivation, would be associated with accelerated development across two global biological aging metrics: DNA methylation (DNAm) age and pubertal stage relative to chronological age. We also examined whether accelerated development explained associations of ELA with depressive symptoms and externalizing problems.
Results:
Exposure to threat-related ELA (e.g., violence) was associated with accelerated DNAm age and advanced pubertal stage, but exposure to deprivation (e.g., neglect, food insecurity) was not. In models including both ELA types, threat-related ELA was uniquely associated with accelerated DNAm age (β = .18) and advanced pubertal stage (β = .28), whereas deprivation was uniquely associated with delayed pubertal stage (β = -.21). Older DNAm age was related to greater depressive symptoms, and a significant indirect effect of threat exposure on depressive symptoms was observed through DNAm age.
Conclusions:
Early threat-related experiences are particularly associated with accelerated biological aging in youths, which may be a mechanism linking ELA with depressive symptoms.
Child maltreatment has well-documented long-term, adverse effects on mental health, but it is not clear whether there are gender differences in these effects. We conducted a systematic review to investigate whether there are gender differences in the effects of maltreatment on adult depression and anxiety. Medline, PsycINFO, Web of Science, and Lilacs were searched for relevant studies published up to May 2016. Eligible studies included population-based studies (with a cohort, case-control or cross-sectional design) which assessed maltreatment during childhood or adolescence (≤18 years) and its association with major depression or generalized anxiety disorder (DSM/ICD diagnostic criteria) in adulthood (>18 years) separately for females and males. Meta-analysis was performed to estimate the association between each exposure and outcome using fixed and random effects models. Pooled odds ratios (OR) were estimated separately for women and men and compared. Five studies of physical and sexual abuse were included in the meta-analyses. These provided twenty-two effects sizes estimates (11 for men, 11 for women) for associations between physical/sexual abuse and depression/anxiety. Exposure to each kind of abuse increased the odds of depression/anxiety. Associations were larger for women than for men, however, these gender differences were not statistically significant. Physical and sexual abuse in childhood/adolescence are risk factors for depression/anxiety in adulthood and the effect could be larger for women; however, currently there is insufficient evidence to definitively identify gender differences in the effects of maltreatment.
Introduction:
Altered DNA methylation (DNAm) levels of hypothalamic-pituitary-adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study.
Methods:
NR3C1 promoter region DNAm was assessed via pyrosequencing using whole blood-derived DNA. Quantitative RT-PCR assays measured GE from leukocyte-derived RNA. Linear regression models were used to examine the relationship among CM, MDD, and DNAm.
Results:
Both CM and MDD were significant predictors of NR3C1 DNAm: CM was associated with an increase in DNAm in an EGR1 transcription factor binding site (TFBS), whereas MDD was associated with a decrease in DNAm downstream of the TFBS. No significant CM-MDD interactions were observed. CM alone was associated with significantly lower NR3C1 GE.
Limitations:
Our report of CM is a retrospective self-report of abuse, which may introduce recall bias. DNAm was measured in whole blood and may not reflect brain-derived DNAm levels.
Conclusions:
CM and MDD are both associated with altered DNAm levels in the NR3C1 promoter region, however the location and direction of effects differ between the two exposures, and the functional effects, as measured by GE, appear to be limited to CM exposure alone. CM exposure may be biologically embedded in this key HPA axis gene.
This article highlights the defining principles, progress, and future directions in epigenetics research in relation to this Special Issue. Exciting studies in the fields of neuroscience, psychology, and psychiatry have provided new insights into the epigenetic factors (e.g., DNA methylation) that are responsive to environmental input and serve as biological pathways in behavioral development. Here we highlight the experimental evidence, mainly from animal models, that factors such as psychosocial stress and environmental adversity can become encoded within epigenetic factors with functional consequences for brain plasticity and behavior. We also highlight evidence that epigenetic marking of genes in one generation can have consequences for future generations (i.e., inherited), and work with humans linking epigenetics, cognitive dysfunction, and psychiatric disorder. Though epigenetics has offered more of a beginning than an answer to the centuries-old nature–nurture debate, continued research is certain to yield substantial information regarding biological determinants of central nervous system changes and behavior with relevance for the study of developmental psychopathology.
The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) (Nr3c1). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.
Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. DNA methylation (HumanMethylation450 BeadChip) was assessed in saliva and blood samples from 64 adult African Americans. Analyses were conducted using linear regression adjusted for appropriate covariates, including estimated cellular proportions. DNA methylation from brain tissues (cerebellum, frontal cortex, entorhinal cortex, and superior temporal gyrus) was obtained from a publically available dataset. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e., CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Finally, DNA methylation in saliva appeared more similar to patterns from each of the brain regions examined overall than methylation in blood. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits. © 2014 Wiley Periodicals, Inc.
A reliability generalization study for Spielberger’s State-Trait Anxiety Inventory (STAI) was conducted. A total of 816 research articles utilizing the STAI between 1990 and 2000 were reviewed and classified as having (a) ignored reliability (73%), (b) mentioned reliability or reported reliability coefficients from another source (21%), or (c) computed reliability for the data at hand (6%). Articles in medically oriented journals were shorter and somewhat less likely to mention or compute reliability than nonmedically oriented articles, perhaps due to paradigm differences. Average reliability coefficients were acceptable for both internal consistency and test-retest, but variation was present among the estimates. State test-retest coefficients were lower than internal consistency coefficients. Score variability was predictive of internal consistency reliability for scores on both scales. Other predictors were the age of research participants, the form of the STAI, and the type of research design.
This 15-year prospective, longitudinal study examines adolescent and young-adult female self-reports of traumatic sexual and physical experiences occurring subsequent to substantiated childhood sexual abuse-revictimizations (N=89).
These incidences were contrasted to sexual and physical victimizations reported by a group of non-abused comparison females (N=90).
Abused females were almost twice as likely to have experienced sexual revictimization (odds=1.99+/-2.79, p<.05), and physical revictimization (odds=1.96+/-2.58, p<.05) as compared to victimization rates reported by comparison females. Abused females' revictimizations were also more likely to have been perpetrated by older, non-peers and characterized by physical injury than were victimizations reported by comparison females.
Early childhood sexual abuse may provide information regarding the level of risk for recurrent sexual and physical victimization.
The STAIC was administered to 1,522 third and fourth grade Black disadvantaged children from a large metropolitan school district. Although A-State scores were equivalent to the original normative sample. A-Trait levels for boys and girls were found to be higher. Similar alpha coefficients were observed for the A-State scale; the A-Trait scale yielded slightly lower alpha coefficients than the original sample. Norms for the STAIC scales were extended to the third grade level. The small differences between the present study and the original normative study were attributed to differences in population. The STAIC provides a valid and reliable means to measure trait and state anxiety in children of elementary school age.
The present study was undertaken to examine some of the psychometric properties of the Children's Depression Inventory (CDI), a self-report inventory devised by Kovacs and Beck (1977) to measure depression in children and adolescents. Normative and reliability data were obtained from three independent samples taken from eight public schools in central Pennsylvania. Age- and gender-related differences in reported characteristics of depression were also investigated. The subjects were 594 males and 658 females whose ages ranged from 8 to 16 years and whose combined mean age was 11.67 years (SD = 1.91). The CDI was group-administered to all 1,252 subjects; 155 fifth-grade subjects (77 males and 78 females) were retested after 3 weeks, and 107 seventh- and eight-grade subjects (45 males and 62 females) were retested after 1 year. The distribution statistics for the combined samples yielded an overall CDI mean of 9.09, a standard deviation of 7.04, and a cutoff score of 19 for the upper 10% of the distribution. Reliability assessed through coefficient alpha, item-total score product-moment correlations, and test-retest coefficients proved acceptable. Gender differences were obtained for several item-total score correlations and for test-retest reliability of CDI scores.
Few prospective longitudinal studies have examined the relationship between abuse or neglect in childhood and depression in adulthood.
To determine whether abused and neglected children were at elevated risk of major depressive disorder (MDD) and psychiatric comorbidity, compared with matched control subjects, when followed up into young adulthood.
Prospective cohort design study.
Midwestern metropolitan county area.
Children with substantiated cases of physical and sexual abuse and neglect (before the age of 11 years) from January 1, 1967, to December 31, 1971 (n = 676) were matched based on age, race, sex, and approximate family social class with a group of non-abused and non-neglected children (n = 520) and followed up into young adulthood (mean age, 28.7 years).
Between October 20, 1989, and December 22, 1995, 2-hour in-person interviews were conducted, using the National Institute of Mental Health Diagnostic Interview Schedule, Version III Revised, to determine DSM-III-R MDD and other psychiatric diagnoses.
Child abuse and neglect were associated with an increased risk for current MDD (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.06-2.14; P< or=.05) in young adulthood. Children who were physically abused (OR, 1.59; 95% CI, 1.00-2.52; P< or =.05) or experienced multiple types of abuse (OR, 1.75; 95% CI, 1.01-3.02; P< or =.05) were at increased risk of lifetime MDD, whereas neglect increased risk for current MDD (OR, 1.59; 95% CI, 1.10-2.29; P<.01). Childhood sexual abuse was not associated with elevated risk of MDD. Kaplan-Meier age-of-onset curves (log-rank statistic, 4.03; df = 1; P=.04) showed earlier onset of MDD for abused and neglected children compared with controls. Among those with MDD, comorbidity was higher for abused and neglected individuals than for controls.
These results support the need for clinicians to increase efforts to detect and treat depression in physically abused and neglected children.
Early-onset disorders (e.g., conduct problems, autism) show a marked male preponderance, whereas adolescent-onset disorders (e.g., depression, anxiety) show a marked female preponderance. A developmental psychopathology framework provides a means to investigate complex gender-related etiologies of these different disorders. This review focuses on biological and environmental factors implicated in the development of conduct problems and depression in boys and girls. Boys and girls showed certain differences in types, rates, comorbidities, antecedents, correlates, and trajectories of these problems. Origins of male and female preponderant problems are likely to be rooted, in part, in biological, physical, cognitive, and social-emotional differences in boys and girls that can precede the expression of clinical problems. These male-like and female-like characteristics are considered regarding conduct problems and depression to explore how they inform biological and environmental theories about gender and psychopathology. At the same time, because boys and girls also show many similarities, it is important to avoid sex-stereotyping mental health problems.
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