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Ghosh S, Vivar J, Nelson CP, et al. Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2015;35(7):1712-22doi: 10.1161/ATVBAHA.115.305513.
Ghosh, S., Vivar, J., Nelson, C. P., Willenborg, C., Segrè, A. V., Mäkinen, V. P., Nikpay, M., Erdmann, J., Blankenberg, S., O'Donnell, C., März, W., Laaksonen, R., Stewart, A. F., Epstein, S. E., Shah, S. H., Granger, C. B., Hazen, S. L., Kathiresan, S., Reilly, M. P., Yang, X., Quertermous, T., Samani, N. J., Schunkert, H., Assimes, T. L., & McPherson, R. (2015). Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. Arteriosclerosis, thrombosis, and vascular biology, 35(7), 1712-22. https://doi.org/10.1161/ATVBAHA.115.305513
Ghosh, Sujoy, et al. "Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease." Arteriosclerosis, thrombosis, and vascular biology vol. 35,7 (2015): 1712-22. doi: https://doi.org/10.1161/ATVBAHA.115.305513
Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen VP, Nikpay M, Erdmann J, Blankenberg S, O'Donnell C, März W, Laaksonen R, Stewart AF, Epstein SE, Shah SH, Granger CB, Hazen SL, Kathiresan S, Reilly MP, Yang X, Quertermous T, Samani NJ, Schunkert H, Assimes TL, McPherson R. Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1712-22. doi: 10.1161/ATVBAHA.115.305513. Epub 2015 May 14. PMID: 25977570; PMCID: PMC4841833.
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Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1712-22. doi: 10.1161/ATVBAHA.115.305513. Epub 2015 May 14.

Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.

Arteriosclerosis, thrombosis, and vascular biology

Sujoy Ghosh, Juan Vivar, Christopher P Nelson, Christina Willenborg, Ayellet V Segrè, Ville-Petteri Mäkinen, Majid Nikpay, Jeannette Erdmann, Stefan Blankenberg, Christopher O'Donnell, Winfried März, Reijo Laaksonen, Alexandre F R Stewart, Stephen E Epstein, Svati H Shah, Christopher B Granger, Stanley L Hazen, Sekar Kathiresan, Muredach P Reilly, Xia Yang, Thomas Quertermous, Nilesh J Samani, Heribert Schunkert, Themistocles L Assimes, Ruth McPherson

PMID: 25977570 PMCID: PMC4841833 DOI: 10.1161/ATVBAHA.115.305513

Abstract

OBJECTIVE: Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks.

APPROACHES AND RESULTS: Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways.

CONCLUSIONS: These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.

© 2015 American Heart Association, Inc.

Keywords: coronary artery disease; pathway analysis

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