Alcohol Use Disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health1. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components2. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Key Points Question What changes in circulating lipid and liver function enzyme levels are associated with high-intensity binge drinking? Findings In this cross-sectional study of 1519 participants, high-intensity binge drinking was associated with increased cholesterol, triglyceride, and liver function enzyme levels. Meaning Lipid and liver function enzyme levels demonstrate dose-dependent increases with high-intensity binge drinking, indicating potential adverse health outcomes may be associated with such drinking behavior.

The current study examines associations between neural activation to the receipt of monetary reward in a rewarding game task and bias toward immediate reward measured in a behavioral delay discounting task among early adolescents (N = 58, 12-14 years). As expected, heightened brain activation in reward-related regions were correlated with higher bias toward immediate reward. This suggests that bias toward immediate reward in delay discounting tasks may be linked to heightened activation to reward in reward processing regions. This interplay between neural reward processing and bias toward immediate reward might explain the sharp increases in bias toward immediate reward that occur in early adolescence.