Aug 2026· Neurobiology of Stress· Vol 44, pp. 100846· 0 citations· 47 references
Medicine
TL;DR
It is suggested that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.
Abstract
Introduction Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in obsessive-compulsive disorder (OCD), but epigenetic changes in HPA axis-related genes remain poorly understood. We investigated whether DNA methylation of the glucocorticoid receptor gene (NR3C1), particularly within exon 1F, is associated with OCD and examined its relationship with stress resilience and early-life trauma. Methods A total of 275 patients with OCD and 200 healthy controls (aged 19–40 years) were recruited. DNA methylation at three CpG sites within NR3C1 exon 1F was measured using pyrosequencing. Group differences were examined using multivariate analysis of covariance (MANCOVA), and structural equation modeling (SEM) was conducted to evaluate resilience-mediated pathways linking NR3C1 methylation, early-life trauma, and OCD status. Results Compared to healthy controls, DNA methylation at NR3C1 exon 1F was significantly reduced in women with OCD (p < 0.001), which remained significant in a drug-naïve or drug-free subset. No overall multivariate difference was observed in men. SEM revealed that stress resilience partially mediated the association between NR3C1 methylation and OCD status (indirect β = −0.117, p = 0.014). While early-life trauma was associated with lower methylation at a specific CpG site, the mediation effect of DNA methylation between trauma and OCD did not reach statistical significance. Conclusion These findings suggest that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.
AIMS
Epigenetic regulation of the oxytocin receptor gene (OXTR), particularly DNA methylation (DNAm), has been linked to insecure attachment, anxiety-related phenotypes, and suicidality. However, its role in panic disorder (PD) and brain network dysfunction remains unclear. This study examined whether peripheral OXTR DNAm and OXTR DNAm-associated structural connectivity are related to clinical symptoms of PD.
METHODS
We investigated OXTR DNAm and its structural connectivity in 563 patients with PD and 210 healthy controls (HCs). Peripheral blood OXTR promoter (-934) DNAm was quantified by pyrosequencing. In a neuroimaging subset, diffusion MRI tractography reconstructed the structural connectome. Network-based statistics tested the diagnosis-by-OXTR DNAm and diagnosis-by-clinical symptomatology effects using separation-related life events (SLEs), Anxiety Sensitivity Index-Revised (ASI-R), and the Scale for Suicidal Ideation (SSI). A preliminary bagging ensemble regression model was used to evaluate treatment response prediction.
RESULTS
Patients with PD exhibited significantly lower OXTR DNAm levels than HCs, adjusting for age, sex, education, smoking status, and body mass index. Within PD, reduced OXTR DNAm was significantly negatively correlated with elevated SLEs, ASI-R, and SSI scores. Diagnosis-by-OXTR DNAm interactions revealed reduced connectivity across the hippocampus, amygdala, orbitofrontal, and precentral regions converging on the extended fear network. Importantly, OXTR DNAm-associated connectivity in the orbitofrontal and lateral occipital cortices showed a cross-validated association with the 8-week treatment outcomes.
CONCLUSION
Lower peripheral OXTR DNAm was associated with higher PD-related symptomatology and altered extended fear network connectivity. These findings suggest that peripheral OXTR DNAm may index aspects of clinical and neural heterogeneity in PD.
Hyunjung Kim, C. Pae, M. Bang et al.· Journal of Affective Disorde...· 0 citations
This study examined whether saliva-derived DNA methylation in the glucocorticoid receptor (NR3C1) gene was linked to loneliness through dysregulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) in 101 early adolescents (Mage = 11.61 years, SDage = 0.64, 55.45% girls). Using person-centered analyses to account for interindividual differences in adolescents' stress reactivity, we identified three subgroups of cortisol responders to a social evaluative stressor: A hyporesponsive subgroup (30.5%), a moderate-responsive subgroup (44.2%), and a hyperresponsive subgroup (25.3%). Exploratory analyses also identified subgroups for two markers of the autonomous nervous system (ANS), that is, heart rate (HR) and skin conductance (SC). Furthermore, the indirect effects from NR3C1 methylation to early adolescent loneliness via individual differences in stress responses were examined. Results indicated that higher NR3C1 methylation levels were associated with a lower probability of belonging to the most reactive stress response subgroups for cortisol and HR, and to the high mean-level subgroup for SC. Additionally, higher probabilities of belonging to the low mean-level SC subgroup were associated with higher levels of loneliness. However, there was no evidence that NR3C1 methylation was associated with early adolescent loneliness, either directly or indirectly via stress reactivity. These findings highlight significant individual differences in stress reactivity, emphasizing the need to explicitly consider such variability in future research. Moreover, the results suggest that NR3C1 methylation is linked to individual differences in stress responding, warranting further investigation.
Yentl Koopmans, S. Nelemans, Patricia Bijttebier et al.· Developmental Psychobiology· 0 citations
Major depressive disorder (MDD) is a widespread, recurrent, and severely disabling psychiatric disorder that imposes a heavy global health burden. Although genetic factors contribute to disease risk, growing evidence highlights gene-environment interaction as the core driver of MDD pathogenesis. Epigenetic regulation acts as a precisely molecular interface that translates environmental stressors into stable changes in gene expression and long-term behavioral phenotypes. In this review, we provide a comprehensive and up-to-date overview of epigenetic dysregulation in MDD, covering five major regulatory layers: DNA methylation, histone post-translational modifications, non-coding RNA networks, RNA chemical modifications, and ATP-dependent chromatin remodeling. We emphasize the spatiotemporal specificity, brain regional selectivity, and cell-type. dependency of these epigenetic events, and their roles in disrupting neuroplasticity, hypothalamic–pituitary–adrenal (HPA) axis function, neurotransmitter homeostasis, and neuroinflammation. We further evaluate the translational value of peripheral epigenetic markers for early diagnosis, severity monitoring, and prediction of antidepressant treatment responses. We also discuss emerging epigenetic-targeted therapeutic strategies, including small-molecule inhibitors, RNA-based modulators, and brain-targeted delivery systems. Finally, we address key obstacles to clinical translation, such as tissue heterogeneity, unclear causality, limited reproducibility, and lack of standardized protocols. We propose future directions centered on single-cell multi-omics, longitudinal clinical validation, and sex-and ethnicity-stratified research. This review aims to establish an integrated framework for understanding MDD epigenetics and accelerating the development of precision diagnostic and therapeutic approaches.
Jiayu Li, Xuchu Guan, Rui-Gang Zhang et al.· Journal of Translational Med...· 0 citations
Background: Posttraumatic stress disorder (PTSD) has been associated with advanced biological age in DNA methylation data, but results have been inconsistent. This study evaluated PTSD in association with epigenetic age in the largest cohort to date (by about 20 fold). Methods: Participants were 45,091 US Veterans (92.76% male) enrolled in the VA Million Veteran Program, with VA electronic health record (EHR), self-report PTSD severity (n = 22,835), and DNA methylation and genotype data. PTSD diagnoses predated the blood draw for obtaining DNA by > = one year. Results: PTSD diagnosis, severity, and duration were associated with age-adjusted metrics of epigenetic age (age residuals) per the Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE epigenetic age algorithms after multiple testing adjustment. The strongest and most robust effect (to additional covariates) was evident for PTSD severity in association with GrimAge residuals (B = .029, adjusted-p = 2.48e-53, up to 2 years advanced age). The relationships between PTSD severity and GrimAge and PhenoAge residuals were stronger among younger vs. older Veterans. In stratified analyses, all PTSD variables were associated with all epigenetic age residuals in the European ancestry subgroup (n = 27,578), but significant associations only emerged for GrimAge and DunedinPACE in the African ancestry participants (n = 11,690). Conclusions: PTSD was associated with advanced epigenetic aging in the largest study to date to evaluate this question. Effects were generally small in magnitude, though meaningful when considering the personal and healthcare system impact of advanced aging in the large population of VA users with PTSD.
E. Wolf, R. Zhang, X. Zhao et al.· medRxiv· 0 citations
Bipolar disorder (BD) is a severe and recurrent psychiatric disorder characterized by alternating manic, hypomanic, and depressive episodes, frequent comorbidity, high relapse rates, and an increased risk of suicide. Although the pathophysiology of BD remains incompletely understood, increasing evidence suggests that DNA methylation may represent an important epigenetic regulatory layer involved in BD-related biological heterogeneity. DNA methylation alterations have been reported in genes related to dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) systems, suggesting a potential role in neurotransmitter dysregulation. In addition, methylation changes in genes involved in neurotrophic signaling and ion-channel function may contribute to altered neuroplasticity and neuronal excitability. Clinically, candidate methylation signatures, including brain-derived neurotrophic factor (BDNF)-related methylation changes, specific GRIN2B CpG sites, and epigenetic age acceleration (EAA), have attracted attention for their potential relevance to diagnostic differentiation, disease progression, and treatment-response research. However, these signatures have not been clinically validated, and their reproducibility, tissue specificity, and longitudinal stability remain uncertain. Mood stabilizers, including lithium, valproate, and atypical antipsychotics, may partly influence methylation-related pathways, although their epigenetic effects and clinical significance remain incompletely defined. DNA methylation-targeted interventions remain experimental and require further validation regarding specificity, safety, blood–brain barrier delivery, and clinical applicability. This review summarizes current evidence on DNA methylation abnormalities in BD, focusing on neurotransmitter systems, neuroplasticity, ion-channel excitability, circadian rhythm, immune-inflammatory regulation, candidate methylation signatures and translational challenges. We emphasize that most available findings remain associative rather than causal, and future longitudinal, brain-region-specific, cell-type-resolved, and multi-omics studies are needed to clarify the mechanistic and translational relevance of DNA methylation in BD.
Lu Sun, Ying Yang, Tong Liu et al.· Frontiers in Pharmacology· 0 citations
It is suggested that 5-HTTLPR-related differences, when present, may be more detectable in overall post-awakening cortisol output than in baseline-relative increase, which is more detectable in overall post-awakening cortisol output than in baseline-relative increase.
R. Jonassen, Ø. Øverli, E. Hilland et al.· Comprehensive Psychoneuroend...· 0 citations
