Atherosclerosis and depression contribute to each other; however, mechanisms linking them at the genetic level remain unexplored. This study aimed to identify shared gene signatures and related pathways between these comorbidities.Atherosclerosis-related datasets were downloaded from the Gene Expression Omnibus database. Differential and weighted gene co-expression network analyses were employed to identify atherosclerosis-related genes. Depression-related genes were downloaded from the DisGeNET database, and the overlaps between atherosclerosis-related genes and depression-related genes were characterized as crosstalk genes. The functional enrichment analysis and protein-protein interaction network were performed in these gene sets. Subsequently, the Boruta algorithm and Recursive Feature Elimination algorithm were performed to identify feature-selection genes. A support vector machine was constructed to measure the accuracy of calculations, and two external validation sets were included to verify the results.Based on two atherosclerosis-related datasets (GSE28829 and GSE43292), 165 genes were determined as atherosclerosis-related genes. Meanwhile, 1478 depression-related genes were obtained. After intersecting, 24 crosstalk genes were identified, and two pathways, "lipid and atherosclerosis" and "tryptophan metabolism," were revealed as mutual pathways according to the enrichment analysis results. Through the protein-protein interaction network, Molecular Complex Detection plugin, and cytoHubba plugin, PTPRC and MMP9 were identified as the hub gene. Moreover, SLC22A3, CASP1, AMPD3, and PIK3CG were recognized as feature-selection genes. Based on two external validation sets, CASP1 and MMP9 were finally determined as the critical crosstalk genes."Lipid and atherosclerosis" and "tryptophan metabolism" were possibly the pathways of atherosclerosis secondary to depression and depression due to atherosclerosis, respectively. CASP1 and MMP9 were revealed as the most pivotal candidates linking atherosclerosis and depression by mediating these two pathways. Further experimentation is needed to confirm these conclusions.Copyright © 2022 Elsevier Ltd. All rights reserved.