DNA Methylation signatures of alcohol use disorder - a large-scale meta-analysis

• Applicant: Lea Zillich
• Subject Area: Biological Psychiatry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560791125

Little is known about epigenetic changes in alcohol use disorder, although some epigenome-wide association studies (EWAS) have been conducted. Epigenetic changes, such as DNA methylation, are changes in DNA that can affect gene expression without altering the DNA sequence itself. So far, it has been shown that DNA methylation signatures can be used as biomarkers, e.g. for aging or smoking behavior. This proposal details a comprehensive study of the epigenetics of AUD. The aim of the submitted proposal is to identify reliable and valid DNA methylation signatures of alcohol use disorder and possibly derive a biomarker. To this end, a meta-analysis of EWAS with a total sample size of 3857 subjects will be conducted as part of the Epigenetics of Substance Use Disorders working group of the Psychiatric Genomics Consortium. A total of seven cohorts from the US and Europe will participate. EWAS will be calculated locally in each cohort and outcome statistics will be quality-controlled and meta-analyzed. Downstream analysis involves fine-mapping differentially methylated positions (DMPs) to understand their genomic location and regulatory elements. The study will also explore whether individual CpG sites form differentially methylated regions (DMRs) with larger effects on biological processes. The findings from the meta-analysis will be replicated in two independent cohorts, using a two-step approach. First, EWAS will be conducted using the same analysis scripts, followed by correlating effect sizes of significant CpG sites between discovery and replication results. Then, polymethylation scores, aggregating the meta-analysis results, will be generated based on the meta-analysis results to provide weighted sums of DNA methylation profiles. These will be validated in the independent cohorts. The second part of the proposal aims to determine if individuals with AUD exhibit a stronger epigenetic age acceleration compared to those without AUD. Various epigenetic clocks will be calculated, and linear models will predict age acceleration by AUD status, sex, age, and cell type composition. Interaction terms between AUD and sex, as well as between age at onset and AUD, will be explored. Overall, the study is designed to deepen understanding of the epigenetic mechanisms underlying AUD and its relationship with age acceleration, with a rigorous methodology that involves meta-analyses and replication in independent cohorts.

• DFG Programme: WBP Position