Gatta E, et al. - Researchers investigated 25 pairs of control and individuals with alcohol use disorder (AUD) for genome-wide DNA methylation patterns in the prefrontal cortex (PFC, BA10) using the Infinium MethylationEPIC BeadChip. Five thousand two hundred fifty-four differentially methylated CpGs were identified. They noted significantly increased methylation of the NR3C1 exon variant 1_H, with a particular increase in the levels of 5-hydroxymethylcytosine over 5-methylcytosine among cases with chronic alcohol drinking. AUD subjects vs controls showed association of these changes in DNA methylation with reduced NR3C1 mRNA and protein expression levels in PFC, along with other cortico-limbic regions. Additionally, the PFC of AUD subjects showed altered expression of several stress-responsive genes (eg, corticotropin-releasing factor, proopiomelanocortin, and FK506 binding protein 5). The hippocampus, a region very vulnerable to stress, also showed changes in these stress-response genes. These data suggest the possible fundamental value of alcohol-dependent aberrant DNA methylation of NR3C1 and resulting changes in other stress-related genes in the pathophysiology of AUD and could be the basis for therapies that target the epigenetic mechanisms controlling NR3C1 in AUD.