Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum

Abstract

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.

DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex

“…Further, integration of epigenome-wide methylation data with other omics data such as transcriptomics or proteomics is necessary to prioritize and substantiate findings from the EWAS. Such multi-omics studies depict promising approaches for deeper profiling of altered biological processes in SUDs as recently shown for AUD ( 64 ) and OUD ( 65 ). To address the temporal dynamics of molecular changes in the disease course of CUD, a longitudinal study assessing different stages of CUD within the same individuals should be performed.…”

DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

“…Further, integration of epigenome-wide methylation data with other omics data such as transcriptomics or proteomics is necessary to prioritize and substantiate findings from the EWAS. Such multi-omics studies depict promising approaches for deeper profiling of altered biological processes in SUDs as recently shown for AUD [63] and opioid use disorder [64]. To address the temporal dynamics of molecular changes in the disease course of CUD, a longitudinal study assessing different stages of CUD within the same individuals should be performed.…”

Is DNA methylation in the brain a mechanism of alcohol use disorder?

“…Further analysis of gene ontologies allowed to indicate “homophilic cell adhesion via plasma-membrane adhesion molecules” and “cell-cell adhesion via plasma-membrane adhesion molecules” as the most overrepresented in the CN, and “Lsm1-7-Pat1 complex” in VS. ( Zillich et al, 2021 ). In the following study the same group focused on the CN, VS, and putamen (PUT) ( Zillich et al, 2022 ). The authors analyzed not only DNA methylation but also compared the methylation data with mRNA expression.…”