Abstract
Alcohol Use Disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation using Illumina HM450 and EPIC chip arrays in AUD samples from 3 discovery, 4 replication, and 2 translational cohorts. The discovery samples consisted of postmortem brain tissues (n=46), bloods form a resting-state functional connectivity imaging endophenotypes (n=68) and postmortem brain tissues sorted into neuronal and non-neuronal cells (n=58). Overrepresentation analyses identified 68 significant CpG probes of which the most significantly associated probe cg01444643 was in in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene (p=0.002). Biological validation showed that PCSK9 promoter methylation is conserved across tissues (brain-blood-liver) and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation (n=392, p<0.05) and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 mRNA and protein downregulation (p<0.0001). Postmortem human liver tissue analyses in control (n=47) and liver transplant cases due to alcohol cirrhosis (n=50) showed marked increase of methylation at cg01444643 (P<0.0001) and significantly decreased PCSK9 expression (p<0.01). 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.
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