Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-01-09

AUTHORS

Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, R. Thomas Lumbers

ABSTRACT

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. More... »

PAGES

163

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    11

    Author Affiliations

  • British Heart Foundation Research Accelerator, University College London, London, UK
  • Institute of Health Informatics, University College London, London, UK
  • Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA, USA
  • deCODE genetics/Amgen Inc., Sturlugata 8, 101, Reykjavik, Iceland
  • Health Data Research UK London, University College London, London, UK
  • Cardiovascular Medicine unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
  • Pfizer Worldwide Research & Development, 1 Portland St, Cambridge, MA, USA
  • Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary’s Campus, W2 1PG, London, UK
  • Department of Clinical Sciences, Lund University, Malmö, Sweden
  • Department of Cardiology, Herlev Gentofte Hospital, Herlev Ringvej 57, 2650, Herlev, Denmark
  • Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
  • School of Health and Social Sciences, Dalarna University, Falun, Sweden
  • Regeneron Genetics Center, 777 Old Saw Mill River Road, 10591, Tarrytown, NY, USA
  • Department of Medicine, University of Washington, Seattle, WA, USA
  • Division of Cardiology, Department of Medicine, Emory University Medical Center, Atlanta, GA, USA
  • Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, Texas, USA
  • Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
  • Harvard Medical School, 02115, Boston, MA, USA
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • Novartis Institutes for Biomedical Research, Cambridge, MA, USA
  • Department of Biostatistics, University of Liverpool, Liverpool, UK
  • Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany
  • The Alan Turing Institute, London, United Kingdom
  • Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, DD1 9SY, Dundee, UK
  • DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
  • Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
  • Regeneron Pharmaceuticals, Cardiovascular Research, 777 Old Saw Mill River Road, 10591, Tarrytown, NY, USA
  • Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia
  • Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK
  • Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
  • Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  • Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, 75185, Uppsala, Sweden
  • Division of Preventive Medicine, Brigham and Women’s Hospital, 02215, Boston, MA, USA
  • Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA
  • School of Engineering and Natural Sciences, University of Iceland, 101, Reykjavik, Iceland
  • Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
  • Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands
  • Stanford Diabetes Research Center, Stanford University, 94305, Stanford, CA, USA
  • Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands
  • Department of Public Health and Primary Care, University of Cambridge, CB2 0QQ, Cambridge, UK
  • Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  • Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
  • MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, CB2 0QQ, Cambridge, UK
  • Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA
  • Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
  • Department of Internal Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden
  • Vanderbilt University School of Medicine, Nashville, TN, USA
  • Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
  • Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
  • Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland
  • TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA
  • National Institute for Health and Welfare, Helsinki, Finland
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  • Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
  • Department of Biostatistics, University of Washington, Seattle, WA, USA
  • The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
  • Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
  • Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center and VA Pittsburgh HCS, Pittsburgh, PA, USA
  • Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research & Development, Seattle, WA, USA
  • Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte, København, Denmark
  • Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
  • Department of Cardiology, Södersjukhuset, Stockholm, Sweden
  • Institute for Translational Genomics and Population Sciences, LABiomed and Departments of Pediatrics at Harbor-UCLA Medical Center, 90502, Torrance, CA, USA
  • Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland
  • Faculty of Medicine, Department of Medicine, University of Iceland, Saemundargata 2, 101, Reykjavik, Iceland
  • Departments of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  • Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
  • Translational and Clinical Research, Servier Cardiovascular Center for Therapeutic Innovation, 50 rue Carnot, 92284, Suresnes, France
  • Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  • Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
  • Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
  • Human Genetics, GlaxoSmithKline, Collegeville, PA, USA
  • Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA
  • Université de Lorraine, CHU de Nancy, Inserm and INI-CRCT (F-CRIN), Institut Lorrain du Coeur et des Vaisseaux, 54500, Vandoeuvre Lès, Nancy, France
  • BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
  • Queensland Brain Institute, The University of Queensland, 4072, Brisbane, QLD, Australia
  • Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
  • Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
  • National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
  • UCL Genetics Institute, University College London, WC1E 6BT, London, UK
  • Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
  • Sections of Cardiology, Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA
  • Institute of Cardiovascular Science, University College London, London, UK
  • Bart’s Heart Centre, St. Bartholomew’s Hospital, London, UK
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-019-13690-5

    DOI

    http://dx.doi.org/10.1038/s41467-019-13690-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1123951767

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31919418


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