Transcriptome-wide association study reveals novel susceptibility genes for coronary atherosclerosis

Qiuping Zhao; Rongmei Liu; Hui Chen; Xiaomo Yang; Jiajia Dong; Minfu Bai; Yao Lu; Yiming Leng

doi:10.3389/fcvm.2023.1149113

Transcriptome-wide association study reveals novel susceptibility genes for coronary atherosclerosis

Front Cardiovasc Med. 2023 Jun 7:10:1149113. doi: 10.3389/fcvm.2023.1149113. eCollection 2023.

Authors

Qiuping Zhao¹, Rongmei Liu¹, Hui Chen¹, Xiaomo Yang¹, Jiajia Dong¹, Minfu Bai¹, Yao Lu², Yiming Leng^{3

4}

Affiliations

¹ Heart Center of Henan Provincial People's Hospital, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
² School of Life Course Sciences, King's College London, London, United Kingdom.
³ Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.

Abstract

Background: Genetic risk factors substantially contributed to the development of coronary atherosclerosis. Genome-wide association study (GWAS) has identified many risk loci for coronary atherosclerosis, but the translation of these loci into therapeutic targets is limited for their location in non-coding regions. Here, we aimed to screen the potential coronary atherosclerosis pathogenic genes expressed though TWAS (transcriptome wide association study) and explore the underlying mechanism association.

Methods: Four TWAS approaches (PrediXcan, JTI, UTMOST, and FUSION) were used to screen genes associated with coronary atherosclerosis. Enrichment analysis of TWAS-identified genes was applied through the Metascape website. The summary-data-based Mendelian randomization (SMR) analysis was conducted to provide the evidence of causal relationship between the candidate genes and coronary atherosclerosis. At last, the cell type-specific expression of the intersection genes was examined by using human coronary artery single-cell RNA-seq, interrogating the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.

Results: We identified 19 genes by at least three approaches and 1 gene (NBEAL1) by four approaches. Enrichment analysis enriching the genes identified at least by two TWAS approaches, suggesting that these genes were markedly enriched in asthma and leukocyte mediated immunity reaction. Further, the summary-data-based Mendelian randomization (SMR) analysis provided the evidence of causal relationship between NBEAL1 gene and coronary atherosclerosis, confirming the protecting effects of NBEAL1 gene and coronary atherosclerosis. At last, the single cell cluster analysis demonstrated that NBEAL1 gene has differential expressions in macrophages, plasma cells and endothelial cells.

Conclusion: Our study identified the novel genes associated with coronary atherosclerosis and suggested the potential biological function for these genes, providing insightful guidance for further biological investigation and therapeutic approaches development in atherosclerosis-related diseases.

Keywords: GWAS; TWAS; coronary atherosclerosis; genetic mechanisms; genetic risk factors.

Grants and funding

Henan Provincial Medical Science and Education Research Program project jointly built by the Ministry (SB201903022), Henan Province Key and Joint Construction Project of Medical Science and Technology (LHGJ20210102), Henan Province Key and Joint Construction Project of Medical Science and Technology (LHGJ20220103).