An Exploratory Association Study of Alcohol Use Disorder and DNA Methylation

Epigenetic factors, including DNA methylation, play an important role in the etiology of alcohol use disorders (AUDs). Noncandidate-based methylome-wide studies leveraging multiple tissue types are needed in order to identify a set of CpG targets that reliably differentiate AUD patients from controls and strongly correlate across brain tissue and more commonly collected tissue types (e.g., buccal cells).

Postmortem precuneus brain tissue samples were collected from 49 alcohol-dependent (AD) cases and 47 controls (sample I), and DNA was extracted from precuneus and putamen brain tissue and buccal cells in 24 postmortem subjects (sample II). Methylation levels were analyzed at over 450,000 CpG sites in both samples. CpGs that demonstrated significant methylation differences between cases and controls were advanced for further analysis with the goal of identifying CpGs that also demonstrated consistent methylation correlations across tissue type.

In the primary analysis, 244 hypomethylated and 188 hypermethylated CpGs met a priori criteria for both significant methylation differences between cases and controls as well as significant correlation across brain and buccal cell tissue types, employing stringent Bonferroni p-value correction. Many of these CpGs were involved in gene networks related to lipid metabolism, immune response, inflammatory response/disease, and gastro-intestinal disease.

More than 400 CpGs demonstrated differences in methylation between AD cases and controls and showed significant correlation across tissue types. Several genes and pathways (e.g., inflammation and immune functioning) that have been previously associated with AUD were identified in the current analyses.