Project description:Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3’ untranslated regions (3’-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. We identified genes whose 3’-UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells.
Project description:Excessive alcohol consumption is a leading cause of preventable death worldwide. Neurobiological mechanisms associated with alcohol use disorder (AUD) remain insufficiently understood. Here, we provide RNA-sequencing data generated in nucleus accumbent and dorsolateral prefrontal cortex, from 114 deceased individuals: 58 AUD cases, 56 non-AUD controls. DNA methylation data on many of these same individuals is available (see GEO accession number GSE252501).
Project description:The present study utilized patient-derived “cell-line” model systems treated with anti-craving drugs that are used to treat alcohol use disorder (AUD) as “molecular probes” to help identify molecular mechanisms associated with craving and AUD treatment outcomes.
Project description:Alcohol use disorder (AUD) affects transcriptomic, epigenetic and proteomic expression in several organs including the brain. Multi-omic analyses of the brain from individuals with AUD to date lack a comprehensive analysis of protein alterations in the multiple brain regions that underlie neuroadaptations occurring in AUD. We performed quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of human post-mortem tissue from brain regions that play a key role in the development and maintenance of AUD: amygdala (AMG), hippocampus (HIPP), hypothalamus (HYP), nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral tegmental area (VTA). Brain tissues analyzed were from individuals with AUD (n = 11) and matched controls (n = 16).