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PLoS Genet. 2014 Jul 17;10(7):e1004502. doi: 10.1371/journal.pgen.1004502. eCollection 2014 Jul.

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

Author information

1
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
2
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
3
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
5
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
6
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
7
Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States of America; Program in Cardiovascular and Metabolic Disorders and Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
8
Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States of America.
9
Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
10
John and Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
11
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
12
Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany.
13
Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg, Kiel, Lübeck, Germany.
14
Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
15
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
16
Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; Synlab Academy, Mannheim, Germany.
17
Science Center, Tampere University Hospital, Tampere, Finland.
18
Cardiovascular Research Institute, Washington Hospital Center, Washington, D.C., United States of America.
19
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
20
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
21
Cleveland Clinic, Cleveland, Ohio, United States of America.
22
Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
23
DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
24
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.

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.

PMID:
25033284
PMCID:
PMC4102418
DOI:
10.1371/journal.pgen.1004502
[Indexed for MEDLINE]
Free PMC Article

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