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) is associated with widespread epigenetic alterations, including changes in DNA methylation (DNAm). This multi-cohort study validated and extended previous findings on DNAm of HECW2 and GDAP1 in AUD, assessed sex differences, and explored DNAm in blood and brain tissue in humans and rats. DNAm was measured via pyrosequencing in human blood (N_Ctrl = 341, N_AUD = 258), postmortem frontal cortex (Brodmann area 9; discovery cohort: N_Ctrl = 10, N_AUD = 13, replication cohort: N_Ctrl = 64, N_AUD = 55) and rat blood and medial prefrontal cortex (N_Ctrl = 16, N_AUD = 15). Gene expression was assessed in human postmortem brain by quantitative real-time PCR. AUD-associated DNAm differences in HECW2 and GDAP1 were replicated in human blood. While decreased GDAP1 DNAm was only observed in men, HECW2 hypomethylation was present in both sexes. In brain tissue, initial DNAm increases in AUD and HECW2 gene expression decreases were not validated in the replication cohort. In rats, HECW2 hypomethylation appeared in the prelimbic cortex but not in blood. Our findings support the involvement of HECW2 and GDAP1 DNAm in AUD, revealing sex-specific and tissue-dependent epigenetic patterns. The opposing DNAm directionality in blood and brain underscores the complexity of alcohol-related epigenetic modifications and suggests the need for multi-tissue, cross-species, and longitudinal studies to clarify causal mechanisms.

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.