SCIENTIFIC REPORTS | (2018) 8:3434 | DOI:10.1038/s41598-018-20721-6
Network analysis of coronary
artery disease risk genes elucidates
disease mechanisms and druggable
, Ingrid Brænne
, Tom Michoel
, Vinicius Tragante
, Baiba Vilne
Tom R. Webb
, Theodosios Kyriakou
, Johannes Eichner
, Lingyao Zeng
, Oscar Franzen
, Arno Ruusalepp
, Anuj Goel
, Sander W. van der Laan
, Stephen Hamby
, Husain A. Talukdar
, Hassan Foroughi Asl
, Gerard Pasterkamp
, Hugh Watkins
, Nilesh J. Samani
, Jeanette Erdmann
, Heribert Schunkert
, Folkert W. Asselbergs
Johan L. M. Björkegren
Genome-wide association studies (GWAS) have identied over two hundred chromosomal loci that
modulate risk of coronary artery disease (CAD). The genes aected 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 signicant loci identied 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-dened gene–protein interactions directly aected by genetic variance in CAD risk loci.
Genome-wide association studies (GWAS) have identied over 200 genome-wide signicant and suggestive risk
loci for coronary artery disease (CAD)
. Most of the CAD associated variants are in non-coding regions and
likely aect disease development by regulating gene expression
. Several candidate genes regulated by lead risk
Genedata AG, Basel, Switzerland.
Institute for Cardiogenetics, Lübeck, Germany.
Division of Genetics and
Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
Clinical Gene Networks
AB, Stockholm, Sweden.
Department of Cardiology, Division Heart and Lungs, University Medical Center
Utrecht, University of Utrecht, Utrecht, The Netherlands.
Deutsches Herzzentrum München, Klinik für Herz-
und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
DZHK (German Centre for
Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
Department of Cardiovascular Sciences,
University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom.
Cardiovascular Medicine, Radclie Department of Medicine, John Radclie Hospital, Oxford, United Kingdom.
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn
School of Medicine at Mount Sinai, New York, USA.
Laboratory of Experimental Cardiology, Department of
Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska
Universitetssjukhuset, Huddinge, Sweden.
Laboratory of Clinical Chemistry and Hematology, Division Laboratories
and Pharmacy, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United
Kingdom. Ingrid Brænne, Tom Michoel, Vinicius Tragante, Baiba Vilne and Tom R. Webb contributed equally to this
work. *A comprehensive list of consortium members appears at the end of the paper. Correspondence and requests
for materials should be addressed to H.L. (email: firstname.lastname@example.org) or J.L.M.B. (email: johan.
Received: 8 August 2017
Accepted: 6 December 2017
Published: xx xx xxxx