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[Preprint]. 2023 Sep 20:2023.06.08.544148.
doi: 10.1101/2023.06.08.544148.

Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Zeyneb Kurt  1   2 , Jenny Cheng  1   3 , Caden N McQuillen  1 , Zara Saleem  1 , Neil Hsu  1 , Nuoya Jiang  1 , Rio Barrere-Cain  1 , Calvin Pan  4 , Oscar Franzen  5 , Simon Koplev  5 , Susanna Wang  1 , Johan Bjorkegren  5   6 , Aldons J Lusis  4   7   8 , Montgomery Blencowe  1   3 , Xia Yang  1   3   9   10
Affiliations

Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Zeyneb Kurt et al. bioRxiv. .

Update in

Abstract

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

Keywords: Atherosclerosis; Coronary Artery Disease; Cross-species Comparison; GWAS; Gene Networks; Human; Liver; Mouse; Multiomics; Vascular Tissues.

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Figures

Figure 1:
Figure 1:. Overview of Study.
Figure 2:
Figure 2:. Shared and species-specific biological pathways.
Figure 3:
Figure 3:. Shared Networks between mice and humans.
(A) Vascular (B) Non-vascular. Red border diamonds represent recent CAD GWAS hits and pink border diamonds represent GWAS hits pre-CARDIOGRAM+C4D GWAS hits.
Figure 3:
Figure 3:. Shared Networks between mice and humans.
(A) Vascular (B) Non-vascular. Red border diamonds represent recent CAD GWAS hits and pink border diamonds represent GWAS hits pre-CARDIOGRAM+C4D GWAS hits.
Figure 4:
Figure 4:. Species Specific Networks.
(A) Human Vascular (B) Human Non-vascular (C) Mouse Vascular (D) Mouse Non-vascular. Red border diamonds represent recent CAD GWAS hits and pink border diamonds represent GWAS hits pre-CARDIOGRAM+C4D GWAS hits.
Figure 5:
Figure 5:. In silico validation of KDs and their subnetwork genes and associated cell type.
(A-D) Aorta KDs and subnetwork genes. (E-H) Liver OIT3 and subnetwork genes. Five end genes are randomly selected genes. * indicate p<0.05
See this image and copyright information in PMC

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