Multi-omic Data Integration and Translational Insights for Alcohol Use Disorder with and Without Cigarette Smoking

PROJECT SUMMARY The goal of the proposed research is to enable discovery of neurobiological factors underlying alcohol use disorder (AUD) with and without cigarette smoking (CS) by investigating AUD-associated differences in DNA methylation (DNAm) and RNA expression (RNAexp) in human nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC), both key to the addiction cycle. By categorizing AUD-associated genes into those modified and unmodified by comorbid CS, our study is designed to highlight AUD-related genes that are (1) neurobiologically meaningful, by integrating DNAm, RNAexp, and genetic variants with disease status and (2) potentially clinically meaningful, by identifying genes targeted by approved drug compounds, which may inform drug repurposing efforts to treat AUD and comorbid AUD+CS. AUD affected ~28.6 million adults in the United States in 2021. Individuals with AUD are at least twice as likely as the general population to smoke, and both health and treatment outcomes are worse for individuals with comorbid alcohol use and smoking. Treatment options geared toward reduction of both substances simultaneously are limited, and there are no currently approved pharmacotherapies tailored for comorbid AUD+CS. Genome-wide association studies (GWAS) have identified thousands of genomic loci associated with alcohol use and smoking, but there is still much to learn about the gene targets and mechanistic basis of these loci at epigenetic and transcriptional levels. Similarly, neurobiological changes related to AUD in the context of CS are rarely examined, so we have an inadequate understanding of how AUD+CS alters the brain. The proposed study addresses these gaps with innovative analyses of existing alcohol research data, and we will use established and integrative multi-omics methods to achieve the following aims: Aim 1: Identify gene regulatory differences associated with AUD and AUD+CS. Aim 2: Elucidate genetically driven dysregulation influencing AUD risk. Aim 3: Prioritize approved pharmacotherapies targeting AUD and AUD+CS associated genes. Aims 1 and 2 will leverage existing multiple-omics data from postmortem human brain tissues (N = 645 brains of Black, White, and Hispanic decedents uniquely characterized for AUD and CS). Aim 2 will additionally leverage results from the field’s largest addiction GWAS (N ≤ 3 million) to provide insight into the potential neurobiological implications of identified genetic variants. In Aim 3, we will integrate omics-driven evidence with large drug databases to prioritize approved drugs that target genes dysregulated in AUD or AUD+CS. Our integration of epigenomics, transcriptomics, and genomics in human brain and characterization of addiction GWAS loci will greatly improve the likelihood of meaningful discovery by identifying genes and specific variants with high biological relevance, specifically in the brain, and will then use multiple lines of evidence to prioritize drug compounds with potential to be repurposed for treatment of AUD or AUD+CS.