Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes

Li, Ling and Chen, Zhifen and von Scheidt, Moritz and Li, Shuangyue and Steiner, Andrea and Güldener, Ulrich and Koplev, Simon and Ma, Angela and Hao, Ke and Pan, Calvin and Lusis, Aldons J. and Pang, Shichao and Kessler, Thorsten and Ermel, Raili and Sukhavasi, Katyayani and Ruusalepp, Arno and Gagneur, Julien and Erdmann, Jeanette and Kovacic, Jason C. and Björkegren, Johan L. M. and Schunkert, Heribert (2022) Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes. Basic Research in Cardiology, 117 (1). ISSN 0300-8428

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The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e-6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN, in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 14 Apr 2022 03:41
Last Modified: 14 Apr 2022 06:06

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