Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN—cg10888111—in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.

Alcohol use disorder (AUD) contributes significantly to the global burden of disease. The susceptibility for AUD is mediated through an interaction of genetic risk factors and environmental influences. These gene × environment (G × E) interactions manifest as epigenetic regulations of gene expression, among other things. Previous research suggests an association between Ganglioside Induced Differentiation Associated Protein 1 (GDAP1) DNA methylation and AUD. Here, we investigate the epigenetic dysregulation of GDAP1 in AUD through comparing DNA methylation in whole blood and saliva, as well as H3K4-trimethylation (H3K4me3) in PBMC (Peripheral Blood Mononuclear Cell) samples of AUD patients and healthy control individuals. Additionally, the effect of abstinence-based therapy was investigated. AUD patients before treatment exhibit significantly lower promoter DNA methylation levels in whole blood and saliva, as well as lower H3K4me3 near the transcription start site. GDAP1 gene expression was not significantly altered. Following treatment, H3K4me3 was significantly increased in patients and no longer differed from control individuals. There was no significant effect of treatment on DNA methylation. We conclude that GDAP1 is epigenetically dysregulated in AUD patients, and is responsive to abstinence-based therapy at the level of H3K4me3. It should be investigated further to establish its potential as a diagnostic biomarker.

Background: Borderline Personality Disorder (BPD) is a complex psychiatric condition with multifactorial origins, with a high proportion of patients reporting early trauma. Stressors such as adverse childhood experiences (ACEs) can shape the epigenetic landscape including DNA methylation (DNAm) and act on gene expression. DNAm is increasingly being investigated as a molecular link between environmental exposures such as ACE and psychiatric outcomes. Differential DNAm of the gene PR domain zinc finger protein 8 (PRDM8), a histone methyltransferase, has recently been reported to be sensitive to early life trauma. Its role in BPD, especially in the context of ACE, remains to be elucidated. Methods: This study investigated DNAm patterns of PRDM8 in peripheral blood and saliva obtained from BPD patients undergoing Dialectic Behavioral Therapy (DBT) compared to healthy control (HC) participants. Associations with ACE and BPD symptom severity were assessed, and therapy-related changes in DNAm were examined. Results: At baseline, BPD patients demonstrated significant hypomethylation of PRDM8 in blood relative to the HC group. Following DBT, a nominally significant increase in DNAm was observed, aligning with inversely correlated symptom severity. No significant differences in saliva were detected. ACE was not associated with PRDM8 DNAm. Conclusions: Our findings suggest that PRDM8 DNAm might be associated with BPD and therapeutic intervention but not with ACE. Together with prior research, the results underscore the importance of future investigation of gene–environment interactions and the functional significance of PRDM8 regulation in the pathophysiology of BPD.

Adult mental disorders (aMD), including borderline personality disorder (BPD), major depressive disorder (MDD), and social anxiety disorder (SAD), share adverse childhood experiences (ACEs) as an environmental risk factor. Epigenetic mechanisms, including DNA methylation (DNAm), may mediate the biological link between early adversity and psychiatric risk. SIAH3, implicated in stress-related and mitochondrial pathways, has been previously associated with both ACE and aMD. This study examined SIAH3 DNAm in adults with BPD, MDD, or SAD, relative to healthy control participants (HC), testing effects of diagnosis, ACE exposure, and their interaction across the pooled sample and within each diagnostic group. Both aMD diagnosis and high ACE exposure showed trends toward SIAH3 hypomethylation, and a significant diagnosis × ACE interaction emerged, with inconclusive post-hoc tests. Disorder-specific analyses revealed heterogeneous patterns: in BPD, high ACE showed a trend toward hypermethylation in unadjusted models; in MDD, interaction effects were marginal and not robust to covariate adjustment; in SAD, significant main effects and a diagnosis × ACE interaction were observed, with high ACE associated with lower DNAm exclusively in HC. These findings suggest disorder-specific epigenetic responses to ACE, positioning SIAH3 as a potential molecular link between early life stress, mitochondrial function, and aMD.