Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Abstract

Alcohol exposure triggers changes in gene expression and biological pathways in human brain.We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling.Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

Single cell transcriptome profiling of the human alcohol-dependent brain

“…Furthermore, we did not find differences in cell type proportions between alcoholics and controls ( Fig S2 ). This is consistent with previous findings (3) .…”

“…DEGs corresponding to both protein-coding and non-coding transcripts were present in every cell type that had more than two total DEGs ( Fig 3A-B ). Bulk and scRNA-seq studies often exclude non-coding RNAs from their analyses (3,8,35) . However, the importance of ncRNAs is becoming increasingly apparent, not only in alcohol dependence (36) , but in brain physiology in general (37) , and these RNAs were therefore included in our data.…”

“…We next determined which cell types were most similar or dissimilar to bulk data in terms of alcohol-associated expression changes. We compared our DE results to that from a published bulk RNA-seq analysis of the PFC from 65 alcoholics and 73 control donors (3) . Hierarchical clustering revealed that all non-microglia cell types were more similar to bulk than they were to microglia in terms of DE patterns between alcoholics and controls ( Fig 4A ).…”

“…The PFC is involved in executive function and is an important substrate in the reward circuitry associated with development of alcohol dependence (19) . The PFC has also been the focus of many transcriptomic studies (3,4,20,21) and was a logical choice for our initial work. Using the approach presented here, we discovered novel cell type-specific transcriptome changes associated with alcohol abuse in the human PFC.…”

“…Comparison of alcohol dependence-associated differential expression from human bulkRNA-seq and snRNA-seq data. (A) Gene expression changes in alcoholics for each cell type as well as bulkdata from a previous study(3) . Groups were hierarchically clustered using average as the linkage method.…”