EPIGENOME-WIDE ASSOCIATION ANALYSIS AND REPLICATION IMPLICATES DEREGULATION OF PCSK9 IN ALCOHOL USE DISORDER

摘要: Background Alcohol Use Disorder (AUD) is a common and chronic disorder with substantial effects on personal public health. The underlying pathophysiology poorly understood but strong evidence suggests significant roles of both genetic epigenetic components. Methods Given that alcohol affects many organ systems, we performed cross-tissue cross-phenotypic analysis genome-wide methylomic variation using Illumina HM450 EPIC chip arrays in AUD samples from 3 discovery, 4 replication, 2 translational cohorts. discovery consisted postmortem brain tissues (n=46), bloods form resting-state functional connectivity imaging endophenotypes (n=68) sorted into neuronal non-neuronal cells (n=58). Results Overrepresentation analyses identified 68 CpG probes which the most significantly associated probe cg01444643 was promoter proprotein convertase subtilisin/kexin 9 (PCSK9) gene (p=0.002). Biological validation showed PCSK9 methylation conserved across (brain-blood-liver) positively correlated expression. Replication datasets confirmed hypomethylation (n=392, p Discussion Our finding alcohol-induced regulation represents one mechanisms between well-known lipid metabolism cardiovascular risk, light use generally being protective while heavy has detrimental health outcomes.