Epigenetic Landscapes of Methamphetamine Addiction: Unravelling the Diagnostic Potential of Gene Methylation

Methamphetamine addiction is a chronic brain disorder involving significant neuroadaptive changes, with recent research emphasizing the role of epigenetic mechanisms, particularly DNA methylation. This study aims to evaluate the diagnostic potential of gene methylation by identifying and validating differentially methylated genes in methamphetamine-dependent individuals versus healthy controls. A genome-wide differentially methylated analysis was conducted using methylation microarray technology. Subsequently, pyrosequencing was employed for validation with an expanded sample size, examining 27 CG sites across eight candidate genes: ATP6V1C1, CES1, USP7, GABRB1, KCNQ2, LIAS, CIZ1 and GNG7. ROC curve analyses and correlation assessments with biochemical markers and drug use patterns were also performed. Significant methylation alterations were observed in GABRB1, CES1, KCNQ2 and USP7 between methamphetamine-dependent individuals and controls. Specifically, GABRB1 and KCNQ2 showed decreased methylation, while CES1 exhibited increased methylation. USP7 displayed site-specific changes. ROC curve analysis showed that a specific site in the GABRB1 gene demonstrated excellent diagnostic accuracy (AUC = 0.902). Methylation levels in CG sites in CES1 showed high diagnostic accuracy (AUC = 0.755) for methamphetamine dependence, while the AUC values for KCNQ2 and USP7 were 0.68 and 0.664, respectively, indicating moderate classification. Besides, the study revealed significant positive correlations between diastolic pressure and both the duration of methamphetamine use and KCNQ2 methylation levels. Additionally, USP7 methylation levels showed a positive correlation with the duration of drug use. These findings provide valuable insights for the development of diagnostic biomarkers and targeted therapeutic interventions. Future research will focus on elucidating the functional roles of these genes in the pathophysiology of methamphetamine addiction and their potential applications in treatment strategies.