Genome‐wide DNA methylation analysis in alcohol dependence

Abstract

Genetic, epigenetic, and environmental factors influence the development of alcohol dependence (AD). Recent studies have shown that DNA methylation markers in peripheral blood may serve as risk markers for AD. Yet a genome-wide epigenomic approach investigating the role of DNA methylation in AD has yet to be performed. We conducted a population-based, case-control study of genome-wide DNA methylation to determine if alterations in gene-specific methylation were associated with AD in a Chinese population. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed gene-specific methylation in over 27 000 CpG sites from DNA isolated from lymphocytes in 63 male AD in-patients and 65 male healthy controls. Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites with the majority of the methylated CpG sites being hypomethylated. Analyses with the online gene set analysis toolkit WebGestalt revealed that the genes of interest were enriched in multiple biological processes involved in AD development. Gene Ontology function annotation showed that stress, immune response and signal transduction were highly associated with AD. Further analysis by the Kyoto Encyclopedia of Genes and Genomes revealed associations with multiple pathways involved in metabolism through cytochrome P450, cytokine-cytokine receptor interaction and calcium signaling. Associations with canonical pathways previously shown to be involved in AD were also observed, such as dehydrogenases 1A (ADH1A), ADH7, aldehyde dehydrogenases 3B2 (ALDH3B2) and cytochrome P450 2A13. We present evidence that alterations in DNA methylation may be associated with AD, which is consistent with epigenetic theory.

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

“…Generally, results were mixed, depending on sample characteristics and methods. In terms of specific genes, two epigenome-wide association studies ( E WA S s ) c o n f i r m e d a s s o c i a t i o n s w i t h a l c o h o l metabolism-related genes, including alcohol and aldehyde dehydrogenases (ADH1A, ADH7, ALDH3B2, ALDH1A2) and cytochrome P450 2A13 [50,51]. In one study [52], the tumour suppressor gene BLCAP and ABR-involved in vestibular morphogenesis-were hypomethylated in heavy alcohol drinkers versus abstinent controls, suggesting one mechanism by which tumour risk may be higher in alcohol drinkers.…”

“…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].…”

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.…”

Understanding genetic variation – the value of systems biology

“…DNA methylation could provide explanations for interindividual variations in drug response in the (many) cases where genetic variation does not offer a coherent picture [48]. The DNA methylation maps becoming available, in particular for clinical cohorts, provide datasets of outstanding importance for systems biology (see, for example, [49]). …”