Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as SAMHD1, VIPAS39, NUP160 and INO80E were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research.

将蛋白质组学和转录组学数据与有问题的酒精使用和饮酒行为的遗传结构相结合，可以促进我们的理解并帮助确定治疗靶点。我们使用来自 8 种典型脑细胞类型 （N = 722） 中的 ~3,500 种皮质蛋白 （N = 722） 和 ~6,100 个基因的基因组关联研究数据进行了系统筛选，其中 4 个与酒精相关的结果 （N ≤ 537,349），确定了 217 个皮质蛋白和 255 个与这些行为相关的细胞型基因，其中 36 种蛋白质和 37 个细胞型基因是新的。尽管蛋白质组和转录组靶标之间的重叠有限，但下游神经影像学显示共享的神经生理学通路。与独立基因组关联研究数据的共定位进一步优先考虑了 16 种蛋白质，包括 CAB39L 和 NRBP1，以及 12 种细胞型基因，涉及 mTOR 信号传导等机制。此外，SAMHD1 、 VIPAS39 、 NUP160 和 INO80E 等基因被鉴定为具有良好的神经精神病学特征。这些发现为控制有问题的酒精使用和饮酒行为的遗传景观提供了见解，突出了未来研究的有希望的治疗靶点。