Systems Level Analysis and Identification of Pathways and Key Genes Associated with Delirium

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.