Currently available clinical treatments on alcohol use disorder (AUD) 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 postmortem brain tissue from deceased patients with AUD. 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 patients with AUD 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 964 samples – 502 samples from the prefrontal cortex (PFC), 282 nucleus accumbens (NAc) samples, and 180 from amygdala (AMY). The PFC had the highest number of differentially expressed genes (DEGs) across rodents, monkeys, and humans. Commonly dysregulated DEGs suggest conserved cross-species mechanisms for chronic alcohol consumption/AUD comprising MAPKs as well as STAT, IRF7, and TNF. Furthermore, we identified numerous unique gene sets that might contribute individually to these conserved mechanisms and also suggest novel molecular aspects of AUD. Validation of the transcriptomic alterations on the protein level revealed interesting targets for further investigation. Finally, we identified a combination of DEGs that are commonly regulated across different brain tissues as potential biomarkers for AUD. In summary, we provide a compendium of genes that are assessable via a shiny app, and describe signaling pathways, and physiological and cellular processes that are altered in AUD that require future studies for functional validation.

目前可用的酒精使用障碍 （AUD） 临床治疗方法疗效有限，需要新的成药靶点。发现新分子治疗靶点的一种有前途的方法涉及利用动物模型和已故 AUD 患者的死后脑组织，对成瘾神经回路内的大脑区域进行转录组学分析。不幸的是，此类研究存在异质性大和样本量小的问题。为了解决这些限制，我们对从 AUD 患者脑组织和动物模型获得的转录组范围数据进行了跨物种荟萃分析。我们遵循 PRISMA 指南，整合了 36 个跨物种转录组范围的 RNA 表达数据集，这些数据集具有酒精依赖性表型与对照。我们总共对 964 个样本进行了荟萃分析——502 个样本来自前额叶皮层 （PFC），282 个伏隔核 （NAc） 样本，180 个来自杏仁核 （AMY） 样本。PFC 在啮齿动物、猴子和人类中具有最多的差异表达基因 （DEG）。通常失调的 DEG 表明慢性饮酒/AUD 的保守跨物种机制包括 MAPK 以及 STAT、IRF7 和 TNF。此外，我们确定了许多独特的基因集，这些基因集可能单独有助于这些保守机制，并且还表明了 AUD 的新分子方面。在蛋白质水平上验证转录组改变揭示了进一步研究的有趣靶点。最后，我们确定了通常在不同脑组织中调节的 DEGs 组合作为 AUD 的潜在生物标志物。 总之，我们提供了一份可通过闪亮应用程序评估的基因纲要，并描述了在 AUD 中改变的信号通路以及生理和细胞过程，这些需要未来的研究进行功能验证。