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.

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.