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Arterioscler Thromb Vasc Biol. 2015 Oct;35(10):2207-17. doi: 10.1161/ATVBAHA.115.306108. Epub 2015 Aug 20.

Prediction of Causal Candidate Genes in Coronary Artery Disease Loci.

Author information

1
From the Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (I.B., B.R., J.E.); DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany (I.B., B.R., J.E.); University Heart Center Lübeck, Lübeck, Germany (I.B., B.R., J.E.); Departments of Medicine (M.C., A.J.L.) and Integrative Biology and Physiology (Y.Z., X.Y.), University of California, Los Angeles; Deutsches Herzzentrum München, Klinik für Herz-und Kreislauferkrankungen, Technische Universität München, Munich, Germany (B.V., L.Z., H.S.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (A.D.N., K.H., E.E.S., J.L.M.B.); Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (A.D.N., K.H., E.E.S., J.L.M.B.); Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA (A.D.J.); Unité Mixte de Recherche en Santé (UMR_S) 1166, Institut National pour la Santé et la Recherche Médicale (INSERM), Paris, France (V.C., D.-A.T.); UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris, France (V.C., D.-A.T.); Institute for Cardiometabolism and Nutrition (ICAN), Paris, France (V.C., D.-A.T.); Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Cardiovascular Biomedical Research Unit, BHF Cardiovascular Research Centre, Leicester, United Kingdom (T.R.W., S.E.H., N.J.S.); Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.F.A., J.L.M.B.); and Department of Molecular and Experimental Medicine, Scripps Translational Science Institute, La Jolla, CA (E.J.T.).
2
From the Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (I.B., B.R., J.E.); DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany (I.B., B.R., J.E.); University Heart Center Lübeck, Lübeck, Germany (I.B., B.R., J.E.); Departments of Medicine (M.C., A.J.L.) and Integrative Biology and Physiology (Y.Z., X.Y.), University of California, Los Angeles; Deutsches Herzzentrum München, Klinik für Herz-und Kreislauferkrankungen, Technische Universität München, Munich, Germany (B.V., L.Z., H.S.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (A.D.N., K.H., E.E.S., J.L.M.B.); Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (A.D.N., K.H., E.E.S., J.L.M.B.); Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA (A.D.J.); Unité Mixte de Recherche en Santé (UMR_S) 1166, Institut National pour la Santé et la Recherche Médicale (INSERM), Paris, France (V.C., D.-A.T.); UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris, France (V.C., D.-A.T.); Institute for Cardiometabolism and Nutrition (ICAN), Paris, France (V.C., D.-A.T.); Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Cardiovascular Biomedical Research Unit, BHF Cardiovascular Research Centre, Leicester, United Kingdom (T.R.W., S.E.H., N.J.S.); Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.F.A., J.L.M.B.); and Department of Molecular and Experimental Medicine, Scripps Translational Science Institute, La Jolla, CA (E.J.T.). jlusis@mednet.ucla.edu.

Abstract

OBJECTIVE:

Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes.

APPROACH AND RESULTS:

All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously.

CONCLUSIONS:

Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses.

KEYWORDS:

coronary artery disease; genome-wide association study; microRNAs; single-nucleotide polymorphism; systems biology

PMID:
26293461
PMCID:
PMC4583353
DOI:
10.1161/ATVBAHA.115.306108
[Indexed for MEDLINE]
Free PMC Article

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