Characterization of novel epigenetic biomarkers of alcohol dependence, therapy outcome and the risk of relapse
Final Report Abstract
Alcohol dependence is a severe mental disorder with high relapse rates and farreaching consequences for affected individuals as well as society. In addition to genetic factors, epigenetic mechanisms play a central role in the development and maintenance of the disease. In our research project, we investigated epigenetic changes in the genes GDAP1, HECW2, and SRPK3, which had previously been identified by our research group as potentially relevant epigenetic markers, in a longitudinal cohort of alcohol-dependent individuals and healthy controls. Furthermore, we included postmortem brain tissue and a rat model of alcohol dependence in our investigations to explore potential links between peripheral and central epigenetic changes. Our key findings show that GDAP1 and HECW2 exhibit significant hypomethylation in blood and saliva samples from alcohol-dependent patients compared to healthy controls. This hypomethylation remained stable throughout the course of withdrawal therapy, suggesting that while both genes could serve as potential epigenetic diagnostic biomarkers for alcohol dependence, they are not suitable as markers for treatment success. In contrast, SRPK3 did not show any relevant DNA methylation differences between patients and controls, leading us to discontinue further analysis of this gene. Additionally, we found reduced H3K4me3 histone modification in GDAP1 in alcohol-dependent patients, which reverted to control levels after therapy. HECW2 showed enhanced H3K4me3 levels, but unlike GDAP1, this modification remained stable throughout therapy. Furthermore, while GDAP1 gene expression was not significantly different between patients and control individuals, HECW2 exhibited significantly reduced gene expression in blood samples from alcohol-dependent patients before therapy, which normalized after withdrawal. In postmortem brain samples from alcohol-dependent individuals, we observed hypermethylation of GDAP1 and HECW2 in the dorsolateral prefrontal cortex (Broadman Area 9) within a small, well-characterized discovery cohort. However, this effect could not be replicated in a larger, more heterogeneous sample. Furthermore, those findings contradict the hypomethylation observed in blood and saliva samples. Interestingly, HECW2 also showed reduced gene expression in patients the brain samples derived from the discovery cohort, whereas GDAP1 did not. Those results could not be replicated in the larger postmortem cohort. Investigations in a rat model of alcohol dependence further supported the role of HECW2 as epigenetic biomarker, as hypomethylation was also observed in the prelimbic cortex of alcohol-dependent animals. However, no clear epigenetic patterns were found for GDAP1 in the rat brain. Our candidate-based miRNA analyses remained unsuccessful, leading us to next plan a hypothesis-free miRNA screening using next-generation sequencing. In summary, our findings suggest that epigenetic modifications could play a promising role in the diagnosis and possibly even in the prognosis of alcohol dependence. In particular, the DNA methylation of GDAP1 and HECW2 appears to be a suitable biomarker in easily accessible samples such as saliva and blood. Further research is needed to determine whether epigenetic markers can be used to predict treatment success or relapse risk.
Link to the final report
https://doi.org/10.4126/FRL01-006526387
Publications
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Mai 2022: Vortrag auf dem Student Symposium on Molecular Medicine „Out of my mind! Molecular Psychology & Psychiatry“. Epigenetics in psychiatry: Towards the discovery of biomarkers for treatment success
Vanessa Nieratschker
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November 2023: Poster auf dem Jahreskongress der DGPPN. SYNGAP1: kein epigenetischer Biomarker für den Schweregrad der Alkoholabhängigkeit oder des Therapieerfolgs
Vanessa Nieratschker
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November 2023: Vortrag im Rahmen der Autumn School "Translational Neuroscience". Epigenetics in Psychiatry: Towards an Individualized Therapy for Mental Disorders
Vanessa Nieratschker
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September 2024: Vortrag auf dem Deutschen Suchtkongress. „H3K4-trimethylierung des Gens GDAP1 in Alkoholabhängigkeit“
Vanessa Nieratschker
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GDAP1 Is Dysregulated at DNA Methylation and H3K4me3 Levels in Alcohol Use Disorder. International Journal of Molecular Sciences, 26(4), 1623.
Kawecka, Emilia; Plättner, Henning; Ederer, Lena; Niemann, Kilian; Pasche, Sarah; Zimmermann, Milan; Edelmann, Susanne & Nieratschker, Vanessa
