Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes
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Published:2022-02-17
Issue:1
Volume:117
Page:
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ISSN:0300-8428
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Container-title:Basic Research in Cardiology
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language:en
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Short-container-title:Basic Res Cardiol
Author:
Li Ling,Chen Zhifen,von Scheidt Moritz,Li Shuangyue,Steiner Andrea,Güldener Ulrich,Koplev Simon,Ma Angela,Hao Ke,Pan Calvin,Lusis Aldons J.,Pang Shichao,Kessler Thorsten,Ermel Raili,Sukhavasi Katyayani,Ruusalepp Arno,Gagneur Julien,Erdmann Jeanette,Kovacic Jason C.,Björkegren Johan L. M.,Schunkert Heribert
Abstract
AbstractThe 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.
Funder
Bundesministerium für Bildung und Forschung Deutsches Zentrum für Herz-Kreislaufforschung Fondation Leducq Deutsche Forschungsgemeinschaft Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst Deutsches Herzzentrum München
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
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