In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits ...may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems.
Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous-unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits.
In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression.
These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The study's findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems.
Abstract It is unclear whether maltreatment types exert common or specific effects on mental health. In the current study, we aimed to systematically characterize the unique, shared and cumulative ...effects of maltreatment types on psychiatric symptoms, using data drawn from a community sample of high-risk youth ( n = 204, M = 18.85). Analyses controlled for a range of potentially confounding variables, including socio-demographic variables, neighbourhood deprivation and levels of community violence exposure. Outcome measures included multi-informant reports of internalizing difficulties, as well as data on externalizing problems and trauma-related symptoms. We found that (i) consistent with previous studies, maltreatment types were highly interrelated and frequently co-occurred; (ii) symptom severity linearly increased with the number of maltreatment types experienced (more so for self-report vs informant ratings); and (iii) while most forms of maltreatment were significantly associated with mental health outcomes when examined individually, few unique effects were observed when modelling maltreatment types simultaneously, pointing to an important role of shared variance in driving maltreatment effects on mental health. Emotional abuse emerged as the main independent predictor of psychiatric symptomatology – over and above other maltreatment types – and this effect was comparable for males and females (i.e. no significant interaction with sex). Findings contribute to a better understanding of heterogeneity in individual responses to maltreatment.
•We review human studies on childhood maltreatment and DNA methylation.•The 72 studies identified were mainly retrospective and candidate-gene focussed.•While studies generally support a ...relationship, evidence to date is inconsistent.•Limitations include a lack of longitudinal data, low replication and confounding.•We provide 12 concrete recommendations for moving the field forward.
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 and concrete recommendations for future research are provided to move the field forward.
Background
DNA methylation (DNAm) is a potential mechanism for propagating the effects of environmental exposures on child and adolescent mental health. In recent years, this field has experienced ...steady growth.
Methods
We provide a strategic review of the current child and adolescent literature to evaluate evidence for a mediating role of DNAm in the link between environmental risks and psychopathological outcomes, with a focus on internalising and externalising difficulties.
Results
Based on the studies presented, we conclude that there is preliminary evidence to support that (a) environmental factors, such as diet, neurotoxic exposures and stress, influence offspring DNAm, and that (b) variability in DNAm, in turn, is associated with child and adolescent psychopathology. Overall, very few studies have examined DNAm in relation to both exposures and outcomes, and almost all analyses have been correlational in nature.
Conclusions
DNAm holds potential as a biomarker indexing both environmental risk exposure and vulnerability for child psychopathology. However, the extent to which it may represent a causal mediator is not clear. In future, collection of prospective risk exposure, DNAm and outcomes – as well as functional characterisation of epigenetic findings – will assist in determining the role of DNAm in the link between risk exposure and psychopathology.
Read the Commentary on this article at doi: 10.1111/jcpp.12906
Background
Childhood maltreatment is a key risk factor for maladjustment and psychopathology. Although maltreated youth are more likely to experience community violence, both forms of adversity are ...generally examined separately. Consequently, little is known about the unique and interactive effects that characterize maltreatment and community violence exposure (CVE) on mental health.
Methods
Latent Profile Analysis (LPA) was applied to data from a community sample of high‐risk adolescents and young adults (n = 204, M = 18.85) to categorize groups of participants with similar patterns of childhood (i.e. past) maltreatment exposure. Associations between childhood maltreatment, CVE and mental health outcomes were then explored using multivariate regression and moderation analyses.
Results
Latent Profile Analysis identified three groups of individuals with low, moderate and severe levels of childhood maltreatment. Maltreatment was associated with more internalizing, externalizing, and trauma‐related symptoms. By contrast, CVE showed independent associations with only externalizing and trauma‐related symptoms. Typically, childhood maltreatment and CVE exerted additive effects; however, these forms of adversity interacted to predict levels of anger.
Conclusions
Exposure to maltreatment and community violence is associated with increased levels of clinical symptoms. However, while maltreatment is associated with increased symptoms across a broad range of mental health domains, the impact of community violence is more constrained, suggesting that these environmental risk factors differentially impact mental health functioning.
Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU ...(genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.
Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of ...multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74-2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.
Epigenetic mechanisms, such as DNA methylation (DNAm), have gained increasing attention as potential biomarkers and mechanisms underlying risk for neurodevelopmental, psychiatric and other ...brain-based disorders. Yet, surprisingly little is known about the extent to which DNAm is linked to individual differences in the brain itself, and how these associations may unfold across development - a time of life when many of these disorders emerge. Here, we systematically review evidence from the nascent field of Neuroimaging Epigenetics, combining structural or functional neuroimaging measures with DNAm, and the extent to which the developmental period (birth to adolescence) is represented in these studies. We identified 111 articles published between 2011-2021, out of which only a minority (21%) included samples under 18 years of age. Most studies were cross-sectional (85%), employed a candidate-gene approach (67%), and examined DNAm-brain associations in the context of health and behavioral outcomes (75%). Nearly half incorporated genetic data, and a fourth investigated environmental influences. Overall, studies support a link between peripheral DNAm and brain imaging measures, but there is little consistency in specific findings and it remains unclear whether DNAm markers present a cause, correlate or consequence of brain alterations. Overall, there is large heterogeneity in sample characteristics, peripheral tissue and brain outcome examined as well as the methods used. Sample sizes were generally low to moderate (median n
= 98, n
= 80), and attempts at replication or meta-analysis were rare. Based on the strengths and weaknesses of existing studies, we propose three recommendations on how advance the field of Neuroimaging Epigenetics. We advocate for: (1) a greater focus on developmentally oriented research (i.e. pre-birth to adolescence); (2) the analysis of large, prospective, pediatric cohorts with repeated measures of DNAm and imaging to assess directionality; and (3) collaborative, interdisciplinary science to identify robust signals, triangulate findings and enhance translational potential.
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is ...implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)-specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)-that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7-15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.
Abstract Childhood maltreatment is a key risk factor for poor mental and physical health. Recently, variation in epigenetic processes, such as DNA methylation, has emerged as a potential pathway ...mediating this association; yet, the extent to which different forms of maltreatment may be characterized by unique vs shared epigenetic signatures is currently unknown. In this study, we quantified DNA methylation across the genome in buccal epithelial cell samples from a high-risk sample of inner-city youth (n = 124; age = 16–24; 53% female), 68% of whom reported experiencing at least one form of maltreatment while growing up. Our analyses aimed to identify methylomic variation associated with exposure to five major types of childhood maltreatment. We found that: (i) maltreatment types differ in the extent to which they associate with methylomic variation, with physical exposures showing the strongest associations; (ii) many of the identified loci are annotated to genes previously implicated in stress-related outcomes, including psychiatric and physical disorders (e.g. GABBR1, GRIN2D, CACNA2D4 , PSEN2) ; and (iii) based on gene ontology analyses, maltreatment types not only show unique methylation patterns enriched for specific biological processes (e.g. physical abuse and cardiovascular function), but also share a ‘ common’ epigenetic signature enriched for biological processes related to neural development and organismal growth. A stringent set of sensitivity analyses were also run to identify high-confidence associations. Together, findings lend novel insights into epigenetic signatures of childhood abuse and neglect, point to novel potential biomarkers for future investigation and support a molecular link between maltreatment and poor health outcomes. Nevertheless, it will be important in future to replicate findings, as the use of cross-sectional data and high rates of polyvictimization in our study make it difficult to fully disentangle the shared vs unique epigenetic signatures of maltreatment types. Furthermore, studies will be needed to test the role of potential moderators in the identified associations, including age of onset and chronicity of maltreatment exposure.
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