title: Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease.
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.
authors.affiliation: 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.
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Qingying
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Candace
authors.initials: C
authors.lastname: Levian
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Huan
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Ayellet V
authors.initials: AV
authors.lastname: Segrè
authors.affiliation: 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.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Vivar
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Nikpay
authors.affiliation: John and Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: 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.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Willenborg
authors.affiliation: Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg, Kiel, Lübeck, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blakenberg
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; Synlab Academy, Mannheim, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.affiliation: Science Center, Tampere University Hospital, Tampere, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.affiliation: Cardiovascular Research Institute, Washington Hospital Center, Washington, D.C., United States of America.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.affiliation: 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.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: 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.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000235:genetics*