Lingyao Zeng1, Husain A Talukdar2, Simon Koplev3, Chiara Giannarelli4, Torbjörn Ivert5, Li-Ming Gan6, Arno Ruusalepp7, Eric E Schadt3, Jason C Kovacic8, Aldons J Lusis9, Tom Michoel10, Heribert Schunkert11, Johan L M Björkegren12. 1. Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. 2. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden. 3. Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York; Cardiovascular Research Centre, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Department of Thoracic Surgery, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 6. Cardiovascular, Renal and Metabolism Translational Medicines Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 7. Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden. 8. Cardiovascular Research Centre, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Departments of Medicine, Cardiology, Human Genetics, Microbiology, Immunology & Molecular Genetics, University of California-Los Angeles, Los Angeles, California. 10. Clinical Gene Networks AB, Stockholm, Sweden; Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom. 11. Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. Electronic address: schunkert@dhm.mhn.de. 12. Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany; Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York; Clinical Gene Networks AB, Stockholm, Sweden. Electronic address: johan.bjorkegren@mssm.edu.
Abstract
BACKGROUND: Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown. OBJECTIVES: This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD. METHODS: Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases). RESULTS: The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene-environmental interactions in CAD. CONCLUSIONS: GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.
BACKGROUND: Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown. OBJECTIVES: This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD. METHODS: Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases). RESULTS: The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene-environmental interactions in CAD. CONCLUSIONS: GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.
Authors: M Ashburner; C A Ball; J A Blake; D Botstein; H Butler; J M Cherry; A P Davis; K Dolinski; S S Dwight; J T Eppig; M A Harris; D P Hill; L Issel-Tarver; A Kasarskis; S Lewis; J C Matese; J E Richardson; M Ringwald; G M Rubin; G Sherlock Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Veronica F Hinman; Albert T Nguyen; R Andrew Cameron; Eric H Davidson Journal: Proc Natl Acad Sci U S A Date: 2003-10-31 Impact factor: 11.205
Authors: Eric E Schadt; John Lamb; Xia Yang; Jun Zhu; Steve Edwards; Debraj Guhathakurta; Solveig K Sieberts; Stephanie Monks; Marc Reitman; Chunsheng Zhang; Pek Yee Lum; Amy Leonardson; Rolf Thieringer; Joseph M Metzger; Liming Yang; John Castle; Haoyuan Zhu; Shera F Kash; Thomas A Drake; Alan Sachs; Aldons J Lusis Journal: Nat Genet Date: 2005-06-19 Impact factor: 38.330
Authors: Kelly A Frazer; Dennis G Ballinger; David R Cox; David A Hinds; Laura L Stuve; Richard A Gibbs; John W Belmont; Andrew Boudreau; Paul Hardenbol; Suzanne M Leal; Shiran Pasternak; David A Wheeler; Thomas D Willis; Fuli Yu; Huanming Yang; Changqing Zeng; Yang Gao; Haoran Hu; Weitao Hu; Chaohua Li; Wei Lin; Siqi Liu; Hao Pan; Xiaoli Tang; Jian Wang; Wei Wang; Jun Yu; Bo Zhang; Qingrun Zhang; Hongbin Zhao; Hui Zhao; Jun Zhou; Stacey B Gabriel; Rachel Barry; Brendan Blumenstiel; Amy Camargo; Matthew Defelice; Maura Faggart; Mary Goyette; Supriya Gupta; Jamie Moore; Huy Nguyen; Robert C Onofrio; Melissa Parkin; Jessica Roy; Erich Stahl; Ellen Winchester; Liuda Ziaugra; David Altshuler; Yan Shen; Zhijian Yao; Wei Huang; Xun Chu; Yungang He; Li Jin; Yangfan Liu; Yayun Shen; Weiwei Sun; Haifeng Wang; Yi Wang; Ying Wang; Xiaoyan Xiong; Liang Xu; Mary M Y Waye; Stephen K W Tsui; Hong Xue; J Tze-Fei Wong; Luana M Galver; Jian-Bing Fan; Kevin Gunderson; Sarah S Murray; Arnold R Oliphant; Mark S Chee; Alexandre Montpetit; Fanny Chagnon; Vincent Ferretti; Martin Leboeuf; Jean-François Olivier; Michael S Phillips; Stéphanie Roumy; Clémentine Sallée; Andrei Verner; Thomas J Hudson; Pui-Yan Kwok; Dongmei Cai; Daniel C Koboldt; Raymond D Miller; Ludmila Pawlikowska; Patricia Taillon-Miller; Ming Xiao; Lap-Chee Tsui; William Mak; You Qiang Song; Paul K H Tam; Yusuke Nakamura; Takahisa Kawaguchi; Takuya Kitamoto; Takashi Morizono; Atsushi Nagashima; Yozo Ohnishi; Akihiro Sekine; Toshihiro Tanaka; Tatsuhiko Tsunoda; Panos Deloukas; Christine P Bird; Marcos Delgado; Emmanouil T Dermitzakis; Rhian Gwilliam; Sarah Hunt; Jonathan Morrison; Don Powell; Barbara E Stranger; Pamela Whittaker; David R Bentley; Mark J Daly; Paul I W de Bakker; Jeff Barrett; Yves R Chretien; Julian Maller; Steve McCarroll; Nick Patterson; Itsik Pe'er; Alkes Price; Shaun Purcell; Daniel J Richter; Pardis Sabeti; Richa Saxena; Stephen F Schaffner; Pak C Sham; Patrick Varilly; David Altshuler; Lincoln D Stein; Lalitha Krishnan; Albert Vernon Smith; Marcela K Tello-Ruiz; Gudmundur A Thorisson; Aravinda Chakravarti; Peter E Chen; David J Cutler; Carl S Kashuk; Shin Lin; Gonçalo R Abecasis; Weihua Guan; Yun Li; Heather M Munro; Zhaohui Steve Qin; Daryl J Thomas; Gilean McVean; Adam Auton; Leonardo Bottolo; Niall Cardin; Susana Eyheramendy; Colin Freeman; Jonathan Marchini; Simon Myers; Chris Spencer; Matthew Stephens; Peter Donnelly; Lon R Cardon; Geraldine Clarke; David M Evans; Andrew P Morris; Bruce S Weir; Tatsuhiko Tsunoda; James C Mullikin; Stephen T Sherry; Michael Feolo; Andrew Skol; Houcan Zhang; Changqing Zeng; Hui Zhao; Ichiro Matsuda; Yoshimitsu Fukushima; Darryl R Macer; Eiko Suda; Charles N Rotimi; Clement A Adebamowo; Ike Ajayi; Toyin Aniagwu; Patricia A Marshall; Chibuzor Nkwodimmah; Charmaine D M Royal; Mark F Leppert; Missy Dixon; Andy Peiffer; Renzong Qiu; Alastair Kent; Kazuto Kato; Norio Niikawa; Isaac F Adewole; Bartha M Knoppers; Morris W Foster; Ellen Wright Clayton; Jessica Watkin; Richard A Gibbs; John W Belmont; Donna Muzny; Lynne Nazareth; Erica Sodergren; George M Weinstock; David A Wheeler; Imtaz Yakub; Stacey B Gabriel; Robert C Onofrio; Daniel J Richter; Liuda Ziaugra; Bruce W Birren; Mark J Daly; David Altshuler; Richard K Wilson; Lucinda L Fulton; Jane Rogers; John Burton; Nigel P Carter; Christopher M Clee; Mark Griffiths; Matthew C Jones; Kirsten McLay; Robert W Plumb; Mark T Ross; Sarah K Sims; David L Willey; Zhu Chen; Hua Han; Le Kang; Martin Godbout; John C Wallenburg; Paul L'Archevêque; Guy Bellemare; Koji Saeki; Hongguang Wang; Daochang An; Hongbo Fu; Qing Li; Zhen Wang; Renwu Wang; Arthur L Holden; Lisa D Brooks; Jean E McEwen; Mark S Guyer; Vivian Ota Wang; Jane L Peterson; Michael Shi; Jack Spiegel; Lawrence M Sung; Lynn F Zacharia; Francis S Collins; Karen Kennedy; Ruth Jamieson; John Stewart Journal: Nature Date: 2007-10-18 Impact factor: 49.962
Authors: Jeanette Erdmann; Anika Grosshennig; Peter S Braund; Inke R König; Christian Hengstenberg; Alistair S Hall; Patrick Linsel-Nitschke; Sekar Kathiresan; Ben Wright; David-Alexandre Trégouët; Francois Cambien; Petra Bruse; Zouhair Aherrahrou; Arnika K Wagner; Klaus Stark; Stephen M Schwartz; Veikko Salomaa; Roberto Elosua; Olle Melander; Benjamin F Voight; Christopher J O'Donnell; Leena Peltonen; David S Siscovick; David Altshuler; Piera Angelica Merlini; Flora Peyvandi; Luisa Bernardinelli; Diego Ardissino; Arne Schillert; Stefan Blankenberg; Tanja Zeller; Philipp Wild; Daniel F Schwarz; Laurence Tiret; Claire Perret; Stefan Schreiber; Nour Eddine El Mokhtari; Arne Schäfer; Winfried März; Wilfried Renner; Peter Bugert; Harald Klüter; Jürgen Schrezenmeir; Diana Rubin; Stephen G Ball; Anthony J Balmforth; H-Erich Wichmann; Thomas Meitinger; Marcus Fischer; Christa Meisinger; Jens Baumert; Annette Peters; Willem H Ouwehand; Panos Deloukas; John R Thompson; Andreas Ziegler; Nilesh J Samani; Heribert Schunkert Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Sekar Kathiresan; Benjamin F Voight; Shaun Purcell; Kiran Musunuru; Diego Ardissino; Pier M Mannucci; Sonia Anand; James C Engert; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Muredach P Reilly; Daniel J Rader; Thomas Morgan; John A Spertus; Monika Stoll; Domenico Girelli; Pascal P McKeown; Chris C Patterson; David S Siscovick; Christopher J O'Donnell; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; Olle Melander; David Altshuler; Diego Ardissino; Pier Angelica Merlini; Carlo Berzuini; Luisa Bernardinelli; Flora Peyvandi; Marco Tubaro; Patrizia Celli; Maurizio Ferrario; Raffaela Fetiveau; Nicola Marziliano; Giorgio Casari; Michele Galli; Flavio Ribichini; Marco Rossi; Francesco Bernardi; Pietro Zonzin; Alberto Piazza; Pier M Mannucci; Stephen M Schwartz; David S Siscovick; Jean Yee; Yechiel Friedlander; Roberto Elosua; Jaume Marrugat; Gavin Lucas; Isaac Subirana; Joan Sala; Rafael Ramos; Sekar Kathiresan; James B Meigs; Gordon Williams; David M Nathan; Calum A MacRae; Christopher J O'Donnell; Veikko Salomaa; Aki S Havulinna; Leena Peltonen; Olle Melander; Goran Berglund; Benjamin F Voight; Sekar Kathiresan; Joel N Hirschhorn; Rosanna Asselta; Stefano Duga; Marta Spreafico; Kiran Musunuru; Mark J Daly; Shaun Purcell; Benjamin F Voight; Shaun Purcell; James Nemesh; Joshua M Korn; Steven A McCarroll; Stephen M Schwartz; Jean Yee; Sekar Kathiresan; Gavin Lucas; Isaac Subirana; Roberto Elosua; Aarti Surti; Candace Guiducci; Lauren Gianniny; Daniel Mirel; Melissa Parkin; Noel Burtt; Stacey B Gabriel; Nilesh J Samani; John R Thompson; Peter S Braund; Benjamin J Wright; Anthony J Balmforth; Stephen G Ball; Alistair S Hall; Heribert Schunkert; Jeanette Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Heribert Schunkert; Nilesh J Samani; Jeanette Erdmann; Willem Ouwehand; Christian Hengstenberg; Panos Deloukas; Michael Scholz; Francois Cambien; Muredach P Reilly; Mingyao Li; Zhen Chen; Robert Wilensky; William Matthai; Atif Qasim; Hakon H Hakonarson; Joe Devaney; Mary-Susan Burnett; Augusto D Pichard; Kenneth M Kent; Lowell Satler; Joseph M Lindsay; Ron Waksman; Christopher W Knouff; Dawn M Waterworth; Max C Walker; Vincent Mooser; Stephen E Epstein; Daniel J Rader; Thomas Scheffold; Klaus Berger; Monika Stoll; Andreas Huge; Domenico Girelli; Nicola Martinelli; Oliviero Olivieri; Roberto Corrocher; Thomas Morgan; John A Spertus; Pascal McKeown; Chris C Patterson; Heribert Schunkert; Erdmann Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke R König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Hilma Hólm; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; James C Engert; Ron Do; Changchun Xie; Sonia Anand; Sekar Kathiresan; Diego Ardissino; Pier M Mannucci; David Siscovick; Christopher J O'Donnell; Nilesh J Samani; Olle Melander; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; David Altshuler Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
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