Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets
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2018-12-01
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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.
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Funding Information: Several figure elements in Fig. 1B (panels II-IV) have been obtained and adapted from Servier Medical Art (www. servier.com) which are distributed under Creative Commons license (https://creativecommons.org/licenses/ by/3.0/). The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007–2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). Folkert W. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001 – Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. Funding Information: Competing Interests: Harri Lempiäinen is an employee and shareholder of Genedata AG. Johannes Eichner, Claudia Biegert and Timo Wittenberger are employees of Genedata AG. Dr. Bjorkegren and Dr. Michoel are consultants and shareholders in Clinical Gene Networks AB (CGN). Dr. Franzen is part-time employee of CGN. Dr. Björkegren is also chairman of the board of directors in CGN. TRW and NJS are funded by the British Heart Foundation and SEH and NJS by the UK National Institute for Health Research. Publisher Copyright: © 2018 The Author(s). Copyright: Copyright 2018 Elsevier B.V., All rights reserved.
Keywords
3.2 Clinical medicine, 3.1 Basic medicine, 1.1. Scientific article indexed in Web of Science and/or Scopus database, General
Citation
Lempiäinen, H, Brænne, I, Michoel, T, Tragante, V, Vilne, B, Webb, T R, Kyriakou, T, Eichner, J, Zeng, L, Willenborg, C, Franzen, O, Ruusalepp, A, Goel, A, Van Der Laan, S W, Biegert, C, Hamby, S, Talukdar, H A, Foroughi Asl, H, Dichgans, M, Dreker, T, Graettinger, M, Gribbon, P, Kessler, T, Malik, R, Prestel, M, Stiller, B, Schofield, C, Pasterkamp, G, Watkins, H, Samani, N J, Wittenberger, T, Erdmann, J, Schunkert, H, Asselbergs, F W & Björkegren, J L M 2018, 'Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets', Scientific Reports, vol. 8, no. 1, 3434. https://doi.org/10.1038/s41598-018-20721-6