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. 2024 Jul 25:15:1344081.
doi: 10.3389/fgene.2024.1344081. eCollection 2024.

Linking coronary artery disease to neurodegenerative diseases through systems genetics

Martina Vescio  1 , Linda Pattini  1   2
Affiliations

Linking coronary artery disease to neurodegenerative diseases through systems genetics

Martina Vescio et al. Front Genet. .

Abstract

Coronary artery disease (CAD) is still a leading cause of death worldwide despite the extensive research and the considerable progresses made through the years. As other cardiovascular diseases, CAD is the result of the complex interaction between genetic variants and environmental factors. Currently identified genetic loci associated to CAD revealed the contribution of multiple molecular pathways to its pathogenesis, suggesting the need for a systemic approach to understand the role of genetic determinants. In this study we wanted to investigate how GWAS variants associated to CAD interact with each other and with nearby genes in the context of the coronary artery molecular interactome. GWAS variants associated to CAD were selected from GWAS Catalog, then, a tissue-specific interactome was constructed integrating protein-protein interactions (PPI) from multiple public repositories and computationally inferred co-expression relationships. To focus on the part of the network most relevant for CAD, we selected the interactions connecting the genes carrying a variant associated to the disease. A functional enrichment analysis conducted on the subnetwork revealed that genes carrying genetic variants associated to CAD closely interact with genes related to relevant biological processes, such as extracellular matrix organization, lipoprotein clearance, arterial morphology and inflammatory response. These results confirm that the identified subnetwork reflects the molecular pathways altered in CAD and intercepted by the selected variants. Interestingly, the most connected nodes of the network included amyloid beta precursor protein (APP) and huntingtin (HTT), both implicated in neurodegenerative disorders. In recent years the interest in investigating the common processes between cardiovascular diseases and neurodegenerative disorders is increasing, with growing evidence of a link between CAD and Alzheimer's disease. The results obtained in this work support the association between such apparently unrelated diseases and highlight the necessity of a systems biology approach to better elucidate shared pathological mechanisms.

Keywords: Alzheimer’s disease; GWAS; Huntington’s disease; coronary artery disease; genetic variants; network analysis; systems biology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Workflow of the study.
FIGURE 2
FIGURE 2
CAD connected subnetwork including the shortest paths connecting nodes affected by genetic variants associated to CAD (shown in yellow).
FIGURE 3
FIGURE 3
Barplot representation of the statistical significance of terms relevant to CAD pathological mechanisms found significant in the selected subnetwork.
FIGURE 4
FIGURE 4
(A) Scatterplot displaying degree and betweenness centrality for each node of the CAD subnetwork. Hubs in the top 1% connected nodes are shown with color filled circles, yellow if they are part of the CAD GWAS variants, blue otherwise. (B) List of the hubs not included in CAD GWAS variants [blue in (A)].
FIGURE 5
FIGURE 5
Barplot representation of the statistical significance of terms related to neurodegenerative disorders found significant in the selected subnetwork.
See this image and copyright information in PMC

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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This paper is supported by the PNRR-PE-AI FAIR project funded by the Next Generation EU program.

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