Characterization of novel epigenetic biomarkers of alcohol dependence, therapy outcome and the risk of relapse

• Applicant: Professorin Dr. Vanessa Nieratschker
• Subject Area: Biological Psychiatry
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426375552

Alcohol dependence (AD) is a severe disorder which contributes substantially to the global burden of disease. Despite the deleterious effects of alcohol, optimal therapeutic and preventive strategies are lacking, which is especially apparent as the number of patients relapsing after initially successful treatment is as high as 75%. The aetiology of AD is influenced by genetic as well as environmental factors and by an interplay of both. An important molecular mechanism for those G x E interactions is the epigenetic regulation of gene expression. While the contribution of alterations in DNA methylation patterns and of histone modifications in AD is widely established, a validated panel of clinically usable epigenetic biomarkers for chronic AD, treatment success and relapse risk is still missing to date. However, in order to be able to develop better treatment strategies to facilitate long-term abstinence and to prevent relapse, the establishment of such a set of epigenetic biomarkers is mandatory. Also missing is a multi-omics integration of the different layers of epigenetic information. This is necessary as epigenetic modifications do not act in isolation, but interact with each other as well as with underlying genetic factors.The aims of this research proposal are therefore to further investigate the potential of a panel of epigenetic modifications for AD previously identified by our group, as biomarkers for disease severity, treatment success and risk of relapse after initial successful abstinence in a large cohort of AD patients and well matched healthy control individuals. We intend to extent our previous studies on HECW2, SRPK3 and GDAP1 by investigating DNA methylation of those genes in additional tissues (saliva, postmortem brain), by comparing DNA methylation pattern between brain and blood in a rat model of AD to answer the question whether peripheral DNA methylation reflects the situation in the brain, and by including other layers of epigenetic (histone modifications, miRNA effects) as well as genetic information. Furthermore, the effects of those epigenetic modifications on gene expression levels will be studied in peripheral blood (human, rat) and brain (rat) as well as by performing functional in vitro assays. The research project will contribute to a better understanding of the biological mechanisms underlying AD, treatment response and relapse risk. Furthermore, the establishment of a set of epigenetic biomarkers of potential clinical value could prove to be useful in order to be able to develop strategies to facilitate more personalized treatment options to foster long-term abstinence and to prevent relapse. This would be highly valuable for the individual patient because for patients that are most likely not benefiting from the therapy, other treatment options could be considered early and patients at an increased risk to suffer from relapse could be monitored more closely to avoid repeated cycles of withdrawal and relapse

• DFG Programme: Research Grants