Delirium is a complex pathophysiological process, and multiple contributing mechanisms have been identified. However, it is largely unclear how the genes associated with delirium contribute and which of them play key roles. In this study, the genes associated with delirium were retrieved from the Comparative Toxicogenomics Database (CTD) and integrated through a protein–protein interaction (PPI) network. Delirium-associated genes formed a highly interconnected PPI subnetwork, indicating a high tendency to interact and agglomerate. Using the Molecular Complex Detection (MCODE) algorithm, we identified the top two delirium-relevant network modules, M1 and M5, that have the most significant enrichments for the delirium-related gene sets. Functional enrichment analysis showed that genes related to neurotransmitter receptor activity were enriched in both modules. Moreover, analyses with genes located in human accelerated regions (HARs) provided evidence that HAR-Brain genes were overrepresented in the delirium-relevant network modules. We found that four of the HAR-Brain genes, namely APP, PLCB1, NPY, and HTR2A, in the M1 module were highly connected and appeared to exhibit hub properties, which might play vital roles in delirium development. Further understanding of the function of the identified modules and member genes could help to identify therapeutic intervention targets and diagnostic biomarkers for delirium.

中文翻译：

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谵妄相关通路和关键基因的系统级分析和鉴定

谵妄是一个复杂的病理生理过程，并且已经确定了多种促成机制。然而，目前尚不清楚与谵妄相关的基因如何起作用以及其中哪些基因起关键作用。在这项研究中，与谵妄相关的基因是从比较毒物基因组学数据库 (CTD) 中检索出来的，并通过蛋白质 - 蛋白质相互作用 (PPI) 网络进行整合。谵妄相关基因形成了一个高度互连的 PPI 子网络，表明相互作用和聚集的趋势很高。使用分子复合物检测 (MCODE) 算法，我们确定了与谵妄相关的前两个网络模块 M1 和 M5，它们对谵妄相关基因集具有最显着的富集。功能富集分析表明，与神经递质受体活性相关的基因在两个模块中都富集。此外，对位于人类加速区 (HAR) 中的基因进行的分析提供了证据，表明 HAR-Brain 基因在与谵妄相关的网络模块中过多。我们发现 M1 模块中的四个 HAR-Brain 基因，即 APP、PLCB1、NPY 和 HTR2A 高度连接，似乎表现出中枢特性，这可能在谵妄发展中发挥重要作用。进一步了解已识别模块和成员基因的功能有助于确定治疗干预目标和谵妄诊断生物标志物。对位于人类加速区 (HAR) 中的基因进行的分析提供了证据，表明 HAR-Brain 基因在谵妄相关网络模块中过多。我们发现 M1 模块中的四个 HAR-Brain 基因，即 APP、PLCB1、NPY 和 HTR2A 高度连接，似乎表现出中枢特性，这可能在谵妄发展中发挥重要作用。进一步了解已识别模块和成员基因的功能有助于确定治疗干预目标和谵妄诊断生物标志物。对位于人类加速区 (HAR) 中的基因进行的分析提供了证据，表明 HAR-Brain 基因在谵妄相关网络模块中过多。我们发现 M1 模块中的四个 HAR-Brain 基因，即 APP、PLCB1、NPY 和 HTR2A 高度连接，似乎表现出中枢特性，这可能在谵妄发展中发挥重要作用。进一步了解已识别模块和成员基因的功能有助于确定治疗干预目标和谵妄诊断生物标志物。