%0 Generic
%A Zillich, Lea Sigrid Silke
%C Heidelberg
%D 2023
%F heidok:33330
%R 10.11588/heidok.00033330
%T Multi-Omics Analysis of Alcohol Use Disorder   in Postmortem Human Brain Tissue
%U https://archiv.ub.uni-heidelberg.de/volltextserver/33330/
%X Alcohol use disorder is characterized by a loss of control over alcohol intake and contributes to a large number of premature deaths worldwide by representing a strong risk factor for numerous diseases. Despite decade-long research on alcohol use disorder, treatment options are limited and relapse rates following withdrawal treatment are high. Currently, alcohol use disorder is understood as a brain disorder as neuroimaging studies have shown substantial alcohol use disorder-associated connectivity and activity alterations in the human brain. This led to the hypothesis of a neurocircuitry of addiction involving multiple brain regions such as the ventral and dorsal striatum, but also cortical regions that display aberrant functional connectivity patterns in alcohol use disorder. These profound brain changes in alcohol use disorder are assumed to be established by molecular processes such as aberrant DNA methylation and gene expression patterns. To investigate these processes in the human brain, postmortem brain tissue depicts a valuable resource. Previous studies have been published reporting on alcohol use disorder-associated differential methylation or differentially expressed genes mainly in the prefrontal cortex. So far, no analysis has integrated DNA methylation and gene expression data in a multi-Omics approach. Further, it remains unclear how alterations in DNA methylation and gene expression are related to each other in the alcohol use disorder brain. The overall aim of the presented studies was to identify functionally relevant molecular mechanisms of alcohol use disorder in the neurocircuitry of addiction.     To address these points, the first paper aimed to expand the epigenetic characterization of alcohol use disorder to the neurocircuitry of addiction by performing an epigenome-wide association study of DNA methylation in alcohol use disorder in five brain regions: the cortical regions anterior cingulate cortex and Brodmann Area 9, and the striatal regions caudate nucleus, putamen, and ventral striatum. In the second study, the gene expression profile of the striatal brain regions was investigated using RNA-Sequencing enabling the integration of DNA methylation and gene expression data in a multi-omics approach. The biological implication of alcohol use disorder-associated DNA methylation and expression signatures was investigated in both studies using a comprehensive set of bioinformatic tools including Gene Ontology- and gene-set enrichment analyses, weighted correlation network analyses, enrichment analyses of results from genome-wide association studies of substance use disorder phenotypes, and protein-protein interaction networks.     In the epigenome-wide association study of alcohol use disorder in five brain regions, 20 differentially methylated CpG sites were detected, two in caudate nucleus and 18 in the ventral striatum, that were associated with alcohol use disorder at epigenome-wide significance. Alcohol use disorder-associated DNA methylation signatures were strongest in the caudate nucleus, putamen, and ventral striatum and were enriched within immune-related cellular pathways. Gene expression analysis in the second study suggested converging evidence for inflammatory and immunological signaling in alcohol use disorder. While the overlap of differential methylation and differential expression at the gene level was limited, it was evident on the network level. Consistent differential expression of the ARHGEF15 gene was found in the caudate nucleus, putamen, and ventral striatum in alcohol use disorder. Further, the STAT3 gene was identified as a conserved hub node in alcohol use disorder-associated gene networks and might be a promising candidate for further evaluation.     In conclusion, this is the first study that integrated DNA methylation and gene expression data from the same individuals in multiple brain regions in the context of alcohol use disorder. Converging evidence from this study supports the role of (neuro) inflammation in the pathophysiology of alcohol use disorder. Methods for multi-omics integration are rapidly emerging and the integration of multiple omics including epigenome-wide DNA Methylation, transcriptomics, proteomics, and non-coding RNAs enables the complementation, but also the prioritization of findings from single omics layers. In follow-up studies, functional validation of multi-omics-derived candidate genes and pathways should be performed using animal models and patient-derived brain organoids. Conducting such precision medicine approaches might lead to the discovery of novel therapeutic strategies in alcohol use disorder, which are urgently required.