Please use this identifier to cite or link to this item:
Title: Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease
Authors: Mäkinen, V. P.
Civelek, M.
Meng, Q.
Zhang, B.
Zhu, J.
Levian, C.
Huan, T.
Segrè, A. V.
Ghosh, S.
Vivar, J.
Nikpay, M.
Stewart, A. F.
Nelson, C. P.
Willenborg, C.
Erdmann, J.
Blakenberg, S.
O'Donnell, C. J.
März, W.
Laaksonen, R.
Epstein, S. E.
Kathiresan, S.
Shah, S. H.
Hazen, S. L.
Reilly, M. P.
Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium
Lusis, A. J.
Samani, N. J.
Schunkert, H.
Quertermous, T.
McPherson, R.
Yang, X.
Assimes, T. L.
First Published: 17-Jul-2014
Publisher: Public Library of Science
Citation: PLoS Genetics, 2014, 10 (7), e1004502
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.
DOI Link: 10.1371/journal.pgen.1004502
ISSN: 1553-7390
eISSN: 1553-7404
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2014 Mäkinen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: PMCID: PMC4102418
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

Files in This Item:
File Description SizeFormat 
Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease..pdfPublished (publisher PDF)1.18 MBAdobe PDFView/Open

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.