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

Li L, Chen Z, Von Scheidt M, Li S, Steiner A, Gueldener U, Koplev S, Ma A, Hao K, Pan C, Lusis AJ, Pang S, Kessler T, Ermel R, Sukhavasi K, Ruusalepp A, Gagneur J, Erdmann J, Kovacic JC, Bjorkegren JLM, Schunkert H (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Basic Research in Cardiology Springer Verlag (Germany)

Book Volume: 117

Article Number: 6

Journal Issue: 1

DOI: 10.1007/s00395-022-00917-8

Abstract

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.

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Icahn School of Medicine at Mount Sinai US United States (USA) (US) University of California Los Angeles (UCLA) US United States (USA) (US) Tartu University Hospital EE Estonia (EE) Victor Chang Cardiac Research Institute AU Australia (AU) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE)

How to cite

APA:

Li, L., Chen, Z., Von Scheidt, M., Li, S., Steiner, A., Gueldener, U.,... Schunkert, H. (2022). Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes. Basic Research in Cardiology, 117(1). https://dx.doi.org/10.1007/s00395-022-00917-8

MLA:

Li, Ling, et al. "Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes." Basic Research in Cardiology 117.1 (2022).

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