The relationship of maternal and child methylation of the glucocorticoid receptor NR3C1 during early childhood and subsequent child psychopathology at school-age in the context of maternal interpersonal violence-related post-traumatic stress disorder

Abstract

IntroductionInterpersonal violent (IPV) experiences when they begin in childhood and continue in various forms during adulthood often lead to chronic post-traumatic stress disorder (PTSD) that is associated in multiple studies with hypocortisolism and lower percentage of methylation of the promoter region of the gene coding for the glucocorticoid receptor (NR3C1). This prospective, longitudinal study examined the relationship of NR3C1 methylation among mothers with IPV-related PTSD and their toddlers and then looked at the relationship of maternal NR3C1 methylation and child psychopathology at school age.MethodsForty-eight mothers were evaluated for life-events history and post-traumatic stress disorder via structured clinical interview when their children were ages 12–42 months (mean age 26.7 months, SD 8.8). Their children's psychopathology in terms of internalizing symptoms and externalizing behaviors was evaluated using the Child Behavior Checklist at ages 5–9 years (mean age 7 years, SD 1.1). Percentage of methylation for the NR3C1 gene promoter region was assessed from DNA extracted from maternal and child saliva using bisulfite pyrosequencing. Data analysis involved parametric and non-parametric correlations and multiple linear and logistic regression modeling.ResultsLogistic regression models using child NR3C1 methylation as the dependent variable and maternal NR3C1 methylation and PTSD group status as predictors, as well as the interaction indicated that all three of these significantly predicted child NR3C1 methylation. These findings remained significant when controlling for child age, sex and maternal child abuse history. Overall, maternal NR3C1 methylation when children were toddlers was negatively and significantly associated with child externalizing behavior severity at school age.DiscussionWe found that correlations between mothers and their children of NR3C1 methylation levels overall and at all individual CpG sites of interest were significant only in the IPV-PTSD group. The latter findings support that NR3C1 methylation in mothers positively and statistically significantly correlates with NR3C1 methylation in their children only in presence of IPV-PTSD in the mothers. This maternal epigenetic signature with respect to this glucocorticoid receptor is significantly associated with child behavior that may well pose a risk for intergenerational transmission of violence and related psychopathology.

Advances in the molecular neurobiology of posttraumatic stress disorder from global contexts: A systematic review of longitudinal studies

“…Notably, methylation at cg20509117 in IL-6 was among the 79 sites identified. In a study investing intergenerational effects of intimate partner violence-associated PTSD, Cordero et al ( 2022 ) aimed to assess correlations between maternal and infant site- and region-level glucocorticoid receptor ( NR3C1 ) methylation profiles and to determine whether maternal methylation profiles predicted offspring internalising and externalising behaviours measured 4 years later. The average methylation of 13 glucocorticoid receptor promoter region sites was significantly correlated between mothers and their infants only in the context of PTSD, that is, not in control mother-infant dyads.…”

“…Inflammation is also reciprocally related to the activity of the hypothalamus-pituitary–adrenal axis, which is activated upon threat perception, coordinates the stress response, and may affect cognition and mood (Leistner and Menke, 2020 ). The studies by Pereira et al ( 2021 ) and Cordero et al ( 2022 ) directly assessed components of the stress response system, namely FKBP5 rs1360780 genotype and NR3C1 methylation, respectively. Their findings suggest that the sensitivity and number of glucocorticoid receptors play a role in the pathophysiology of PTSD.…”

“…Several key themes emerge from the study findings. First, converging lines of evidence support the role of inflammatory/immune (Wani et al, 2021;Chen et al, 2022;Hawn et al, 2022;Katrinli et al, 2022;Tamman et al, 2022), stress response (Carleial et al, 2021; Pereira et al, 2021;Schultebraucks et al, 2021;Wani et al, 2021;Cordero et al, 2022;Morris et al, 2022) and learning and memory processes (Carleial et al, 2021;Lori et al, 2021;Wuchty et al, 2021;Tamman et al, 2022) in PTSD pathophysiology with exploratory hypothesis-generating approaches utilising wholegenome transcription, epigenetic and genotype data showing enrichment for these mechanisms. Inflammatory processes may contribute to PTSD symptomology by affecting cognition, stress responding, and the structure and function of brain regions involved in affect, and learning and memory (Kim et al, 2020;Sumner et al, 2020).…”

Mother adversity and co-residence time impact mother–child similarity in genome-wide and gene-specific methylation profiles

“…In parents exposed to the Holocaust and their adult offspring, inversed methylation variations were found on the same sites for the gene FKBP5 [ 15 ], suggesting interrelations far from a replica, between the mother and child epigenetic changes. For NR3C1, a gene associated with stress response, the methylation levels of mothers and children in the Exon 1F Promoter region were positively correlated only in the presence of mothers’ interpersonal violence-related post-traumatic stress disorder [ 16 ]. Positive correlations between mothers and adolescents were identified involving the NR3C1 gene and the serotonin transporter 5HTT gene [ 17 , 18 ].…”

DAT1 5′-Un-Translated-Region Methylation Patterns as Bio-Markers of ADHD Psycho-Pathology: Contribution to Disease Prognosis and to Monitoring of a Successful Therapy

“…Epigenetic changes, particularly DNA methylation, are a promising molecular mechanism for understanding the complex interactions between genes, environment, and brain disease development [ 1 ]. The methylation status of numerous genes, in fact, is involved in the risk of developing psychopathological traits or diseases [ 2 , 3 , 4 , 5 , 6 , 7 ].…”