A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder

Alcohol use disorder (AUD) is a complex mental health condition. Currently available clinical treatments exhibit limited efficacy and new druggable targets are required. One promising approach to discover new molecular treatment targets involves the transcriptomic profiling of brain regions within the addiction neurocircuitry, utilizing animal models and post-mortem brain tissue from deceased AUD patients. Unfortunately, such studies suffer from large heterogeneity and small sample sizes. To address these limitations, we conducted a cross-species meta-analysis on transcriptome-wide data obtained from brain tissue of AUD patients and animal models. We integrated 36 cross-species transcriptome-wide RNA-expression datasets with an alcohol-dependent phenotype vs. controls, following the PRISMA guidelines. In total, we meta-analyzed 1,000 samples - 502 samples for the prefrontal cortex (PFC), 318 nucleus accumbens (NAc) samples, and 180 amygdala (AMY) samples. The PFC had the highest number of differentially expressed genes (DEGs) across rodents, monkeys, and humans. Commonly dysregulated DEGs pointed towards enrichment in inflammatory responses and alterations in BBB-regulatory mechanisms in astrocytes, microglia and endothelial cells. Gene set enrichment analysis further showed that MAPK/ERK-signaling plays a critical role in AUD and especially in monkeys Dusp4 as a major inhibitor of the MAPK pathway may be a main driver of these pathway alterations. Our data also suggest that the transcriptomic profile in the NAc is less vulnerable to the maintenance of AUD. Finally, we provide a combination of DEGs that are commonly regulated across different brain tissues as potential biomarker for AUD. In summary, we provide a compendium of genes, signaling pathways, and physiological and cellular processes that are altered in AUD and that require future studies for functional validation.