DNA methylation signatures in the prefrontal cortex of alcohol-naïve nonhuman primates predict risk for future ethanol drinking.

Abstract

Alcohol use disorder (AUD) is a highly prevalent, complex, multifactorial and heterogeneous disorder, with 11% and 30% of adults meeting criteria for past-year and lifetime AUD, respectively. Early and accurate identification of individuals at risk of developing an AUD would facilitate effective deployment of personalized interventions. Studies using rhesus monkeys1,2 and rats3, 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 monkeys2. To explore the underlying unique molecular signatures that may predict 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. 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 ten DMRs that were strongly predictive of average ethanol intake consumed over 6 months of voluntary self-administration. Importantly, the same set of DMRs was able to predict drinking levels with moderate success in an independent cohort of macaques. These findings translate behavioral phenotypes into neural markers of risk for AUD, and hold promise for parallel discoveries in risk for other disorders involving impaired cognitive flexibility.