Impact of Long‐Term Alcohol Consumption and Relapse on Genome‐Wide DNA Methylation Changes in Alcohol‐Dependent Subjects: A Longitudinal Study

Background: Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks. Methods: Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent. Results: Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample. Conclusion: Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders