A pilot examination of the genome-wide DNA methylation signatures of subjects entering and exiting short-term alcohol dependence treatment programs

Abstract

Alcoholism has a profound impact on millions of people throughout the world. However, the ability to determine if a patient needs treatment is hindered by reliance on self-reporting and the clinician’s capability to monitor the patient’s response to treatment is challenged by the lack of reliable biomarkers. Using a genome-wide approach, we have previously shown that chronic alcohol use is associated with methylation changes in DNA from human cell lines. In this pilot study, we now examine DNA methylation in peripheral mononuclear cell DNA gathered from subjects as they enter and leave short-term alcohol treatment. When compared with abstinent controls, subjects with heavy alcohol use show widespread changes in DNA methylation that have a tendency to reverse with abstinence. Pathway analysis demonstrates that these changes map to gene networks involved in apoptosis. There is no significant overlap of the alcohol signature with the methylation signature previously derived for smoking. We conclude that DNA methylation may have future clinical utility in assessing acute alcohol use status and monitoring treatment response.

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

“…While the former [54] found no significant differences pre-vs-post treatment, the latter [55] observed a general increase in methylation with alcohol consumption over a 12-year period, particularly in CKM, PHOX2A, and NPDC1. With regard to wider biological pathways, EWAS studies indicated that the most common pathways that were hypermethylated in response to alcohol use were those related to G-protein mediated and GTPase signal transduction processes [51,54,55], whereas pathways associated with stimulus and stress responses, as well as immune and inflammatory processes, where likely to be hypomethylated [51]. Hypomethylation was also observed in long terminal repeat (LTR) regions of retrotransposons in the superior frontal cortex of postmortem alcohol users [56].…”

“…Hypomethylation was also observed in long terminal repeat (LTR) regions of retrotransposons in the superior frontal cortex of postmortem alcohol users [56]. Other important pathways related to apoptosis [52,54,55], metabolism [53], as well as GABA and dopamine systems [40,53].…”

“…Finally, two EWASs measured DNAm at multiple time points: before and after a 25-day treatment programme [54], or a 12-year interim period [55]. While the former [54] found no significant differences pre-vs-post treatment, the latter [55] observed a general increase in methylation with alcohol consumption over a 12-year period, particularly in CKM, PHOX2A, and NPDC1. With regard to wider biological pathways, EWAS studies indicated that the most common pathways that were hypermethylated in response to alcohol use were those related to G-protein mediated and GTPase signal transduction processes [51,54,55], whereas pathways associated with stimulus and stress responses, as well as immune and inflammatory processes, where likely to be hypomethylated [51].…”

“…In another study, alcohol-dependent discordant siblings showed hypomethylation of SSTR4-an important gene for hormonal function-and hypermethylation of the GABA receptor gene GABRP [53]. Finally, two EWASs measured DNAm at multiple time points: before and after a 25-day treatment programme [54], or a 12-year interim period [55]. While the former [54] found no significant differences pre-vs-post treatment, the latter [55] observed a general increase in methylation with alcohol consumption over a 12-year period, particularly in CKM, PHOX2A, and NPDC1.…”

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

“…The epigenetically differentially regulated regions included hyper-as well as hypo-methylated genes in patients. [32][33][34] The most recent study by Clark et al identified CNTN4 as a risk factor for alcohol use by examining the methylation status of approximately 27 million autosomal CpG sites and comparing them to GWAS data. 35 Earlier candidate-gene based studies investigating the influence of therapeutic interventions on DNA methylation reported decreasing homocysteine levels in alcohol dependent patients during alcohol treatment, 20,21,36,37 leading to the hypothesis that DNA methylation levels also decrease during alcohol treatment.…”