Stress, particularly when experienced early in life, can have profound implications for mental health. Previous research covering various tissues such as the brain, suggests that the detrimental impact of early-life stress (ELS) on mental health is mediated via epigenetic modifications including DNA methylation. Genes of the hypothalamic–pituitary–adrenal axis—in particular, the glucocorticoid receptor (hGR) gene—stand out as key targets for ELS. Even though the link between hGR methylation and either ELS or psychopathology is fairly well established, the mutually dependent relationships between ELS, DNA methylation and psychopathology remain to be uncovered. The specific psychopathology an individual might develop in the aftermath of stressful events can be highly variable, however, most studies investigating hGR methylation and psychopathology suffer from being limited to a single symptom cluster of mental disorders. Here, we screened volunteers for childhood maltreatment and analyzed whether it associates with hGR methylation in lymphocytes and a range of measures of psychological ill-health. hGR methylation in lymphocytes most likely reflects methylation patterns found in the brain and thus provides valuable insights into the etiology of psychopathology. We find the interaction between childhood maltreatment and hGR methylation to be strongly correlated with an increased vulnerability to psychopathology providing evidence of epigenome × environment interactions. Furthermore, our results indicate an additive effect of childhood maltreatment and hGR methylation in predicting borderline personality disorder (BPD)-associated symptoms, suggesting that the combination of both ELS and DNA methylation that possibly represents unfavorable events experienced even earlier in life poses the risk for BPD.
Stress during pregnancy widely associates with epigenetic changes and psychiatric problems during childhood. Animal studies, however, show that under specific postnatal conditions prenatal stress may have other, less detrimental consequences for the offspring. Here, we studied mental health and epigenome-wide DNA methylation in saliva following intimate partner violence (IPV) during pregnancy in São Gonçalo, a Brazilian city with high levels of violence. Not surprisingly, mothers exposed to pregnancy IPV expressed elevated depression, PTSD and anxiety symptoms. Children had similar psychiatric problems when they experienced maternal IPV after being born. More surprisingly, when maternal IPV occurred both during (prenatal) and after pregnancy these problems were absent. Following prenatal IPV, genomic sites in genes encoding the glucocorticoid receptor ( NR3C1 ) and its repressor FKBP51 ( FKBP5 ) were among the most differentially methylated and indicated an enhanced ability to terminate hormonal stress responses in prenatally stressed children. These children also showed more DNA methylation in heterochromatin-like regions, which previously has been associated with stress/disease resilience. A similar relationship was seen in prenatally stressed middle-eastern refugees of the same age as the São Gonçalo children but exposed to postnatal war-related violence. While our study is limited in location and sample size, it provides novel insights on how prenatal stress may epigenetically shape resilience in humans, possibly through interactions with the postnatal environment. This translates animal findings and emphasizes the importance to account for population differences when studying how early life gene–environment interactions affects mental health.
A variety of mental disorders are related to deviant brain activity, but these neural alterations do not validate psychiatric diagnostic categories. High symptom overlap and variable symptom patterns encourage a dimensional approach. Following the logic of the Research Domain Criteria (RDoC), we investigated trauma survivors for symptom clusters that might be associated with characteristics of ERPs, in particular with the early posterior negativity (EPN) elicited during affective picture processing. In rapid serial visual presentation, 90 adolescents (40 male/50 female, age M = 15.0 ± 2.5 years) who had been exposed to varying amounts of traumatic stress passively viewed a stream of high‐arousing positive and low‐arousing neutral pictures taken from the International Affective Picture System (IAPS). Using standardized interviews, symptoms of trauma‐related mental disorders were assessed (including those for PTSD, depression, borderline personality disorder, and behavioral problems). A principal component analysis was performed to derive potential dimensions of psychopathology. Multiple regression analysis confirmed a factor comprising problems concentrating, sleeping difficulties, and mistrust as a predictor of a larger EPN difference between high‐arousing positive and low‐arousing neutral IAPS pictures (β = 0.19, p < 0.05). Sex predicted the magnitude of the EPN (β = 0.45, p < 0.001). Male adolescents displayed a stronger EPN suppression than female adolescents. The result suggests that problems concentrating, sleeping difficulties, and mistrust seem to be trans‐diagnostic elements related to diminished early emotional discrimination represented by the EPN. Furthermore, our findings indicate that the EPN in response to emotional processing is modulated by sex.
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