Genome-wide methylomics identifies pre-existing DNA methylation signatures in the prefrontal cortex of alcohol-naïve rhesus monkeys defining neural vulnerability for future risky ethanol consumption.

Abstract

Alcohol use disorder (AUD) is a highly prevalent, complex, multifactorial, and heterogeneous disorder. Currently, 11% and 30% of adults meet the criteria for past-year and lifetime AUD, respectively. Identification of the molecular mechanisms underlying risk for AUD would facilitate effective deployment of personalized interventions. Previous studies using rhesus monkeys and rats, have demonstrated that individuals with low cognitive flexibility and a predisposition towards habitual behaviors show an increased risk for future heavy drinking. Further, low cognitive flexibility is associated with reduced dorsolateral prefrontal cortex (dlPFC) function in rhesus monkeys. To explore the underlying unique molecular signatures that increase risk for chronic heavy drinking, a genome-wide DNA methylation (DNAm) analysis of the alcohol-naïve dlPFC-A46 biopsy prior to chronic alcohol self-administration was conducted in 11 male macaques. The DNAm profile provides a molecular snapshot of the alcohol-naïve dlPFC, with mapped genes and associated signaling pathways that vary across individuals. The analysis identified 1,463 differentially methylated regions related to unique genes that were strongly associated with a range of daily voluntary ethanol intakes consumed over 6 months. These findings translate behavioral phenotypes into neural markers of risk for AUD, and therefore hold promise for parallel discoveries in risk for other disorders involving impaired cognitive flexibility.