Excessive alcohol consumption is a leading cause of preventable death worldwide. To improve understanding of neurobiological mechanisms associated with alcohol use disorder (AUD) in humans, we compared gene expression data from deceased individuals with and without AUD across two addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Bulk RNA-seq data from NAc and DLPFC (N ≥50 with AUD, ≥46 non-AUD) were analyzed for differential gene expression using modified negative binomial regression adjusting for technical and biological covariates. The region-level results were meta-analyzed with those from an independent dataset (N_NAc = 28 AUD, 29 non-AUD; N_PFC = 66 AUD, 77 non-AUD). We further tested 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 in NAc only, 86 in DLPFC only) for AUD in our new dataset. After meta-analyzing with published data, we identified 476 AUD DEGs (25 in both regions, 29 in NAc only, 422 in PFC only). Of these DEGs, 17 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 PFC, respectively. This study identified robust AUD-associated DEGs, contributing novel neurobiological insights into AUD and highlighting genes targeted by known drug compounds, generating opportunity for drug repurposing to treat AUD.

过量饮酒是全世界可预防死亡的主要原因。为了提高对与人类酒精使用障碍 （AUD） 相关的神经生物学机制的理解，我们比较了两个与成瘾相关的大脑区域：伏隔核 （NAc） 和背外侧前额叶皮层 （DLPFC） 的有和没有 AUD 的已故个体的基因表达数据。使用校正技术和生物协变量的阴性二项式回归分析来自 NAc 和 DLPFC （N ≥50 with AUD， ≥46 non-AUD） 的大量 RNA-seq 数据的差异基因表达。使用来自独立数据集的结果 （N_NAc = 28 AUD， 29 non-AUD;N_PFC = 66 澳元，77 非澳元）。我们进一步测试了 AUD 相关表型的遗传力富集、基因共表达网络、基因本体富集和药物再利用。在我们的新数据集中，我们确定了 AUD 的 176 个差异表达基因 （DEGs;两个区域 12 个，仅在 NAc 中 78 个，仅在 DLPFC 中 86 个）。在对已发表的数据进行荟萃分析后，我们确定了 476 个 AUD DEGs（两个地区 25 个，仅 NAc 中 29 个，仅 PFC 中 422 个）。在这些 DEG 中，17 个在 GWAS 中查找有问题的酒精使用或每周饮酒时是显著的。基因共表达分析显示跨大脑区域的一致和独特的基因网络。我们还从 NAc 和 PFC 的荟萃分析中分别确定了 29 种和 436 种靶向 DEGs 的药物化合物。本研究确定了稳健的 AUD 相关 DEGs，为 AUD 提供了新的神经生物学见解，并突出了已知药物化合物靶向的基因，为药物再利用治疗 AUD 创造了机会。