Abstract

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks (“modules”). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene–protein interactions directly affected by genetic variance in CAD risk loci.

Details

Title
Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets
Author
Lempiäinen, Harri 1 ; Brænne, Ingrid 2 ; Michoel, Tom 3   VIAFID ORCID Logo  ; Tragante, Vinicius 4 ; Vilne, Baiba 5 ; Webb, Tom R 6   VIAFID ORCID Logo  ; Kyriakou, Theodosios 7 ; Eichner, Johannes 1 ; Zeng, Lingyao 8 ; Willenborg, Christina 2 ; Franzen, Oscar 9   VIAFID ORCID Logo  ; Ruusalepp, Arno 10 ; Goel, Anuj 7   VIAFID ORCID Logo  ; Sander W van der Laan 11   VIAFID ORCID Logo  ; Biegert, Claudia 1 ; Hamby, Stephen 6 ; Talukdar, Husain A 12 ; Hassan Foroughi Asl 12   VIAFID ORCID Logo  ; Dichgans, Martin 13 ; Dreker, Tobias 14 ; Graettinger, Mira 15 ; Gribbon, Philip 15 ; Kessler, Thorsten 16 ; Malik, Rainer 13 ; Prestel, Matthias 13 ; Stiller, Barbara 16 ; Schofield, Christine 17 ; Pasterkamp, Gerard 18 ; Watkins, Hugh 7 ; Samani, Nilesh J 6 ; Wittenberger, Timo 1   VIAFID ORCID Logo  ; Erdmann, Jeanette 2   VIAFID ORCID Logo  ; Schunkert, Heribert 5 ; Asselbergs, Folkert W 19   VIAFID ORCID Logo  ; Björkegren, Johan L M 20 

1  Genedata AG, Basel, Switzerland 
2  Institute for Cardiogenetics, Lübeck, Germany 
3  Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom; Clinical Gene Networks AB, Stockholm, Sweden 
4  Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands 
5  Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany 
6  Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom 
7  Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom 
8  Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany 
9  Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA 
10  Clinical Gene Networks AB, Stockholm, Sweden 
11  Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands 
12  Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden 
13  Ludwig-Maximilians-Universität, Munich, Germany 
14  4SC Discovery GmbH, Mainz, Germany 
15  Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung Ev, Munich, Germany 
16  Deutsches Herzzentrum München, Munich, Germany 
17  Horizon Discovery Limited, Cambridge, United Kingdom 
18  Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands 
19  Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom 
20  Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA; Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden 
Pages
1-14
Publication year
2018
Publication date
Feb 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-018-20721-6
ProQuest document ID
2007097468
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.