There is nothing else comparable to the remarkable AHRR–smoking relationship in the rest of the SUD epigenetics literature, but alcohol consumption was also associated with epigenetic changes across hundreds of methylation sites in the human genome136, 137. Longitudinal investigations showed that the majority of these methylation changes are reversible in the context of long-term variation in alcohol consumption138. Chronic alcohol consumption appears to be related to methylation changes leading to neuroadaptations that may underlie some of the mechanisms of dependence risk and persistence139. Across multiple CpG sites associated with AUD, there is a consistent correlation of methylation profiles in buccal cells with putamen brain tissues140, highlighting the possibility to investigate brain-related epigenetic changes in peripheral tissues. In a cross-tissue and cross-phenotypic analysis of AUD-induced genome-wide methylomic variation, epigenetic changes in PCSK9 (proprotein convertase subtilisin/kexin type 9) were a possible contributor of the effect of alcohol on lipid metabolism and cardiovascular risk141. A methylome-wide analysis of 1,287 adolescents showed that methylation of the SPDEF (E-twenty-six transcription factor) gene moderated the association of psychosocial stress with alcohol and tobacco abuse142. Epigenetic dysregulation
