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.

Fig. 1. Analysis Workflow.

Analysis workflow of the present study.

Fig. 2. Venn Diagrams of Gene Overlap and Network Plots of WGCNA Module Hub Genes.

Venn Diagrams of gene overlap of A DE genes at FDR < 0.25 in caudate nucleus (CN), putamen (PUT), and ventral striatum (VS), B genes forming WGCNA expression-modules showing the strongest association with AUD status for CN, PUT, and VS, C genes forming WGCNA expression-module “e-CN-magenta” and those forming the methylation-modules “m-CN-red” and “m-CN-midnightblue”. Network plots depicting the WGCNA gene expression module hub genes showing the strongest association with AUD: D module magenta from caudate nucleus, E module black from putamen, and F module pink from ventral striatum.

Fig. 3. Network Plot of Co-Expressed Genes in AUD-associated Modules.

Network plot of genes, co-expressed between the WGCNA modules e-CN-magenta, e-PUT-black and e-VS-pink.