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Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease.

Publication ,  Journal Article
Mäkinen, V-P; Civelek, M; Meng, Q; Zhang, B; Zhu, J; Levian, C; Huan, T; Segrè, AV; Ghosh, S; Vivar, J; Nikpay, M; Stewart, AFR; Nelson, CP ...
Published in: PLoS Genet
July 2014

The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.

Duke Scholars

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

July 2014

Volume

10

Issue

7

Start / End Page

e1004502

Location

United States

Related Subject Headings

  • Signal Transduction
  • Mice
  • Humans
  • Genomics
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Regulatory Networks
  • Gene Expression Regulation
  • Developmental Biology
  • Coronary Artery Disease
 

Citation

APA
Chicago
ICMJE
MLA
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Mäkinen, V.-P., Civelek, M., Meng, Q., Zhang, B., Zhu, J., Levian, C., … Assimes, T. L. (2014). Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet, 10(7), e1004502. https://doi.org/10.1371/journal.pgen.1004502
Mäkinen, Ville-Petteri, Mete Civelek, Qingying Meng, Bin Zhang, Jun Zhu, Candace Levian, Tianxiao Huan, et al. “Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease.PLoS Genet 10, no. 7 (July 2014): e1004502. https://doi.org/10.1371/journal.pgen.1004502.
Mäkinen V-P, Civelek M, Meng Q, Zhang B, Zhu J, Levian C, et al. Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet. 2014 Jul;10(7):e1004502.
Mäkinen, Ville-Petteri, et al. “Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease.PLoS Genet, vol. 10, no. 7, July 2014, p. e1004502. Pubmed, doi:10.1371/journal.pgen.1004502.
Mäkinen V-P, Civelek M, Meng Q, Zhang B, Zhu J, Levian C, Huan T, Segrè AV, Ghosh S, Vivar J, Nikpay M, Stewart AFR, Nelson CP, Willenborg C, Erdmann J, Blakenberg S, O’Donnell CJ, März W, Laaksonen R, Epstein SE, Kathiresan S, Shah SH, Hazen SL, Reilly MP, Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Lusis AJ, Samani NJ, Schunkert H, Quertermous T, McPherson R, Yang X, Assimes TL. Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet. 2014 Jul;10(7):e1004502.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

July 2014

Volume

10

Issue

7

Start / End Page

e1004502

Location

United States

Related Subject Headings

  • Signal Transduction
  • Mice
  • Humans
  • Genomics
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Regulatory Networks
  • Gene Expression Regulation
  • Developmental Biology
  • Coronary Artery Disease