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

Publication ,  Journal Article
Ghosh, S; Vivar, J; Nelson, CP; Willenborg, C; Segrè, AV; Mäkinen, V-P; Nikpay, M; Erdmann, J; Blankenberg, S; O'Donnell, C; März, W; Shah, SH ...
Published in: Arterioscler Thromb Vasc Biol
July 2015

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.

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Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

July 2015

Volume

35

Issue

7

Start / End Page

1712 / 1722

Location

United States

Related Subject Headings

  • Humans
  • Genome-Wide Association Study
  • Coronary Artery Disease
  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Ghosh, S., Vivar, J., Nelson, C. P., Willenborg, C., Segrè, A. V., Mäkinen, V.-P., … McPherson, R. (2015). Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. Arterioscler Thromb Vasc Biol, 35(7), 1712–1722. https://doi.org/10.1161/ATVBAHA.115.305513
Ghosh, Sujoy, Juan Vivar, Christopher P. Nelson, Christina Willenborg, Ayellet V. Segrè, Ville-Petteri Mäkinen, Majid Nikpay, 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 35, no. 7 (July 2015): 1712–22. https://doi.org/10.1161/ATVBAHA.115.305513.
Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen V-P, 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 Jul;35(7):1712–22.
Ghosh, Sujoy, 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, vol. 35, no. 7, July 2015, pp. 1712–22. Pubmed, doi:10.1161/ATVBAHA.115.305513.
Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen V-P, Nikpay M, Erdmann J, Blankenberg S, O’Donnell C, März W, Laaksonen R, Stewart AFR, 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):1712–1722.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

July 2015

Volume

35

Issue

7

Start / End Page

1712 / 1722

Location

United States

Related Subject Headings

  • Humans
  • Genome-Wide Association Study
  • Coronary Artery Disease
  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology