Dataset Information

The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors.

ABSTRACT: Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5' of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.

SUBMITTER: Chiocchetti AG

PROVIDER: S-EPMC8797262 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Importance:Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development. Objective:To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder. Design, Setting, and Participants:A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control). Main Outcomes and Measures:We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events. Results:Of the 65 participants (mean [SD] age, 18.9 [2.5] years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score?=?0.23; P?<?.001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score?=?0.24; P?<?.001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18?=?0.48; P?=?.03). Resilient adolescent females had greater connectivity within frontal (z score?=?0.07; P?<?.001) and limbic (z score?=?0.21; P?<?.001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score?=?0.13; P?<?.001) and control (z score?=?0.10; P?<?.001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score?=?0.24; P?<?.001) adolescent females. Conclusions and Relevance:Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.

Project description:ObjectiveRank the importance of potentially modifiable psychosocial, dietary and environmental risk and protective factors for female adolescent obesity in order to target and inform public health prevention efforts. Utilizing the largest dataset available that captures the onset of the adolescent obesity surge in the USA, the study provides a more robust understanding of paediatric obesity risk factors.MethodsData were obtained from an observational, longitudinal study conducted between 1989 and 2001, the NHLBI Growth and Health Study. This study includes girls aged 9-19 years from three urban US locations, with Black and White girls generally represented equally. Data were analysed using multiple regression, random forest and propensity score matching to determine the strongest adiposity risk and protective factors during ages 9-12 predicting adiposity at age 19 with multiple methods to maximize the ability to identify possible public health interventions. Multiple linear regression and random forest analysis identified the strongest associations among 288 risk and protective factors selected from the study's literature review. For the 190 factors associated with follow-up adiposity from the data, propensity score matching was used to control for confounding of these factors.ResultsFindings suggest that highest priority interventional targets across the domains surveyed are lowering specific nutrients; eating meals with others or during activities without skipping; parents fixing evening snacks; improving perceptions of non-extremes as the healthy weight; improving self-worth, physical activity and social competence; and limiting any negative impact of dieting relatives. Similar associations were observed for Black and White girls.ConclusionThe clinical implications of these findings allow health practitioners to target behavioural change efforts and address social and environmental factors that have demonstrated higher prioritization value for early obesity interventional efforts for adolescents.

Project description:CONTEXT:Conduct disorder (CD) is characterized by severe antisocial behavior that emerges in childhood (early-onset CD [EO-CD]) or adolescence (adolescence-onset CD [AO-CD]). Early-onset CD is proposed to have a neurodevelopmental basis, whereas AO-CD is thought to emerge owing to social mimicry of deviant peers. However, this developmental taxonomic theory is debated after reports of neuropsychological impairments in both CD subtypes. A critical, although unaddressed, issue is whether these subtypes present similar or distinct neurophysiological profiles. Hence, we investigated neurophysiological responses to emotional and neutral faces in regions associated with antisocial behavior (ie, the amygdala, ventromedial prefrontal cortex, insula, and orbitofrontal cortex) in individuals with EO-CD and AO-CD and in healthy control subjects. OBJECTIVE:To investigate whether EO-CD and AO-CD subjects show neurophysiological abnormalities. DESIGN:Case-control study. SETTING:Government research institute, university department. PARTICIPANTS:Seventy-five male adolescents and young adults aged 16 to 21 years, including 27 with EO-CD, 25 with AO-CD, and 23 healthy controls. Main Outcome Measure Neural activations measured by functional magnetic resonance imaging while participants viewed angry, sad, and neutral faces. RESULTS:Comparing angry vs neutral faces, participants with both CD subtypes displayed reduced responses in regions associated with antisocial behavior compared with controls; differences between the CD subtypes were not significant. Comparing each expression with fixation baseline revealed an abnormal (increased) amygdala response to neutral but not angry faces in both groups of CD relative to controls. For sad vs neutral faces, reduced amygdala activation was observed in EO-CD relative to AO-CD and control participants. Comparing each expression with fixation revealed hypoactive amygdala responses to sadness in individuals with EO-CD relative to AO-CD participants and controls. These findings were not accounted for by attention-deficit/hyperactivity disorder symptoms. CONCLUSIONS:Neurophysiological abnormalities are observed in both CD subtypes, contrary to the developmental taxonomic theory of CD. Additional amygdala hypofunction in relation to sad expressions might indicate why EO-CD is more severe and persistent than AO-CD.

Project description:Background: A deficit in empathy has repeatedly been described in individuals with conduct disorder (CD), and in particular in those with callous unemotional traits. Until now, little is known about the neural basis of empathy in children and adolescents with early onset conduct disorder. The aim of this study was to examine neural responses during empathizing in children and adolescents with CD with a task that allowed to differentiate between the judgment of the emotional states of other people and the own emotional response to other people's emotional state. Moreover, we investigated associations of callous-unemotional traits and neural activations during empathizing. Methods: Using functional magnetic resonance imaging (fMRI) we investigated 14 boys with early onset CD and 15 typically developing (TDC) age matched controls between 8 and 16 years of age. Happy and sad faces were presented, and participants were asked to either infer the emotional state from the face (other-task) or to judge their own emotional response (self-task). A perceptual decision on faces was used as a control task. Individual empathic abilities and callous unemotional traits were assessed. Results: During the other task, TDC boys showed significantly larger right amygdala responses than CD boys. Higher empathic abilities (as assessed with the Bryant Index of Empathy) were associated with higher responses in the right amygdala within the CD boys and across the entire sample. Moreover, across the entire sample, callous-unemotional traits were negatively related to the BOLD-response in the right amygdala. CD boys showed larger responses in the dorsal and ventral medial prefrontal cortex across tasks and increased activation in dorsal medial prefrontal cortex specifically during the self-conditions, which were also related to empathic abilities within the CD boys. Conclusions: The data emphasize the important role of the amygdala in empathy related emotional processing. Diminished amygdala responses and their association with low empathy suggest a pivotal influence of impaired amygdala processing in early-onset CD, in particular for deficits in empathic behavior and related callous-unemotional-traits. Elevated response in the medial prefrontal cortex in boys with CD point toward increased involvement of brain areas related to self-referential processing and cognitive empathy during empathizing.

Dataset Information

The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets