Gene expression differences associated with alcohol use disorder in human brain

Excessive alcohol consumption is a leading cause of preventable death worldwide. Neurobiological mechanisms associated with alcohol use disorder (AUD) remain poorly understood. To further understand differential gene expression (DGE) associated with AUD, we compared deceased individuals with and without AUD across two human brain regions, nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Bulk RNA-seq data in both NAc and DLPFC from human postmortem brains (N ≥ 50 with AUD and ≥ 46 non-AUD) were analyzed for DGE using negative binomial regression adjusting for technical and biological covariates. The region-level results were meta-analyzed with a previously published, independent dataset (NNAc= 28 AUD, 29 non-AUD; NPFC= 66 AUD, 77 non-AUD). We further utilized these data to test for heritability enrichment of AUD-related phenotypes, gene co-expression networks, gene ontology enrichment, and drug repurposing. We identified 176 differentially expressed genes (DEGs; 12 in both regions, 78 only in NAc, 86 only in DLPFC) for AUD in our new dataset. By meta-analyzing with published data, we identified 476 DEGs (25 in both regions, 29 only in NAc, 422 only in PFC). Of these DEGs, we found 17 genes that were significant when looked up in GWAS of problematic alcohol use or drinks per week. Gene co-expression analysis showed both concordant and unique gene networks across brain regions. We also identified 29 and 436 drug compounds that target DEGs from our meta-analysis in NAc and DLPFC, respectively. This study identified robust AUD-associated DEGs, providing novel neurobiological insights into AUD and highlighting genes targeted by known drug compounds, generating opportunity for drug repurposing to treat AUD. ### Competing Interest Statement The following authors declare no conflict of interest: CDW, JDW, MSM, BCQ, SH, RT, JHS, AD-S, TMH, RDM, BTW, EOJ, and DBH. JEK is a member of a drug monitoring committee for an antipsychotic drug trial for Merck. LBJ is listed as an inventor on U.S. Patent 8,080,371, 'Markers for Addiction' covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. ### Funding Statement This work was supported by the National Institute on Alcohol Abuse and Alcoholism R01 AA027049 (mPI: Hancock & Bierut) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB committee of RTI International waived ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Bulk RNAseq data generated from this study has been deposited on GEO (GSE253155) and summary statistics for all analyses are provided as supplement tables.