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Title: Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease
Authors: M�kinen V.-P.
Civelek M.
Meng Q.
Zhang B.
Zhu J.
Levian C.
Huan T.
Segr� A.V.
Ghosh S. 
Vivar J.
Nikpay M.
Stewart A.F.R.
Nelson C.P.
Willenborg C.
Erdmann J.
Blakenberg S.
O'Donnell C.J.
M�rz W.
Laaksonen R.
Epstein S.E.
Kathiresan S.
Shah S.H.
Hazen S.L.
Reilly M.P.
Lusis A.J.
Samani N.J.
Schunkert H.
Quertermous T.
McPherson R.
Yang X.
Assimes T.L.
Keywords: lactoylglutathione lyase
small interfering RNA
controlled study
coronary artery disease
endothelium cell
gene control
gene expression
gene interaction
gene regulatory network
genetic association
glyoxalase I gene
human cell
human genome
major clinical study
peptidylprolyl isomerase I gene
quantitative trait locus
single nucleotide polymorphism
coronary artery disease
gene expression regulation
gene regulatory network
genetic predisposition
meta analysis
signal transduction
Coronary Artery Disease
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome-Wide Association Study
Signal Transduction
Issue Date: 2014
Citation: M�kinen V.-P., Civelek M., Meng Q., Zhang B., Zhu J., Levian C., Huan T., Segr� A.V., Ghosh S., Vivar J., Nikpay M., Stewart A.F.R., Nelson C.P., Willenborg C., Erdmann J., Blakenberg S., O'Donnell C.J., M�rz W., Laaksonen R., Epstein S.E., Kathiresan S., Shah S.H., Hazen S.L., Reilly M.P., Lusis A.J., Samani N.J., Schunkert H., Quertermous T., McPherson R., Yang X., Assimes T.L. (2014). Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease. PLoS Genetics 10 (7) : e1004502. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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. ? 2014 M�kinen et al.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1004502
Rights: Attribution 4.0 International
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