A Pathway-Based Genomic Approach to Identify Medications: Application to Alcohol Use Disorder

Abstract

Chronic, excessive alcohol use alters brain gene expression patterns, which could be important for initiating, maintaining, or progressing the addicted state. It has been proposed that pharmaceuticals with opposing effects on gene expression could treat alcohol use disorder (AUD). Computational strategies comparing gene expression signatures of disease to those of pharmaceuticals show promise for nominating novel treatments. We reasoned that it may be sufficient for a treatment to target the biological pathway rather than lists of individual genes perturbed by AUD. We analyzed published and unpublished transcriptomic data using gene set enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to identify biological pathways disrupted in AUD brain and by compounds in the Library of Network-based Cellular Signatures (LINCS L1000) and Connectivity Map (CMap) databases. Several pathways were consistently disrupted in AUD brain, including an up-regulation of genes within the Complement and Coagulation Cascade, Focal Adhesion, Systemic Lupus Erythematosus, and MAPK signaling, and a down-regulation of genes within the Oxidative Phosphorylation pathway, strengthening evidence for their importance in AUD. Over 200 compounds targeted genes within those pathways in an opposing manner, more than twenty of which have already been shown to affect alcohol consumption, providing confidence in our approach. We created a user-friendly web-interface that researchers can use to identify drugs that target pathways of interest or nominate mechanism of action for drugs. This study demonstrates a unique systems pharmacology approach that can nominate pharmaceuticals that target pathways disrupted in disease states such as AUD and identify compounds that could be repurposed for AUD if sufficient evidence is attained in preclinical studies.

Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

“…Many of these genes are expressed in a cell type-specific manner and many of the functional groups represent known functions of specific brain cells, providing a more focused interpretation of the data. The CeA is a key brain region implicated in the regulation of escalated alcohol drinking in alcohol-dependent subjects [ 32 , 64 , 65 , 66 , 67 , 68 ]. It is the major output nucleus of the amygdala, and is connected to other parts of the extended amygdala, as well as other key brain regions involved in the regulation of alcohol effects.…”

“…Not surprisingly, biological functions typically associated with these cell types were also over-represented in the DEG list, including ECM organization, myelination, leukocyte migration, angiogenesis, vasculogenesis and a number of immune functions and molecular pathways. Myelin dysfunction has long been implicated in the effects of alcohol on the brain [ 70 , 71 ] and recent studies have also implicated ECM reorganization and neuroimmune processes in AUD-related conditions including alcohol dependence [ 35 , 64 , 72 , 73 , 74 , 75 ]. Microglia, the resident immune cells of the central nervous system, play an important role in brain normal processes and disease, including AUD.…”

Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use

“…KEGG gene-sets and pathways are created via computational and manual methods, primarily derived from experimental evidence in model organisms (Kanehisa et al, 2017). They have provided a valuable resource to enhance the biological understanding of complex human traits (González-Castro et al, 2019) and inform therapeutic targets for alcohol use disorder (Ferguson et al, 2019), but these pathways are thought to be incomplete and lack both tissue specificity and behavioral nuance (Khatri et al, 2012).…”

Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use

“…KEGG gene-sets and pathways are created via computational and manual methods, primarily derived from experimental evidence in model organisms 9 . They have provided a valuable resource to enhance the biological understanding of complex human traits 10 and inform therapeutic targets for alcohol use disorder 11 , but these pathways are thought to be incomplete and lack both tissue specificity and behavioral nuance 12 .…”