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

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 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 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 and R. Thomas Lumbers ()
Additional contact information
Sonia Shah: The University of Queensland
Albert Henry: University College London
Carolina Roselli: The Broad Institute of MIT and Harvard
Honghuang Lin: Boston University School of Medicine
Garðar Sveinbjörnsson: deCODE genetics/Amgen Inc.
Ghazaleh Fatemifar: University College London
Åsa K. Hedman: Karolinska Institute
Jemma B. Wilk: Pfizer Worldwide Research & Development
Michael P. Morley: University of Pennsylvania
Mark D. Chaffin: The Broad Institute of MIT and Harvard
Anna Helgadottir: deCODE genetics/Amgen Inc.
Niek Verweij: The Broad Institute of MIT and Harvard
Abbas Dehghan: Imperial College London, St Mary’s Campus
Peter Almgren: Lund University
Charlotte Andersson: Lung, and Blood Institute’s and Boston University’s Framingham Heart Study
Krishna G. Aragam: The Broad Institute of MIT and Harvard
Johan Ärnlöv: Karolinska Institutet
Joshua D. Backman: Regeneron Genetics Center
Mary L. Biggs: University of Washington
Heather L. Bloom: Emory University Medical Center
Jeffrey Brandimarto: University of Pennsylvania
Michael R. Brown: The University of Texas School of Public Health
Leonard Buckbinder: Pfizer Worldwide Research & Development
David J. Carey: Geisinger
Daniel I. Chasman: Brigham and Women’s Hospital
Xing Chen: Pfizer Worldwide Research & Development
Xu Chen: Karolinska Institutet
Jonathan Chung: Regeneron Genetics Center
William Chutkow: Novartis Institutes for Biomedical Research
James P. Cook: University of Liverpool
Graciela E. Delgado: University of Heidelberg
Spiros Denaxas: University College London
Alexander S. Doney: University of Dundee, Ninewells Hospital and Medical School
Marcus Dörr: University Medicine Greifswald
Samuel C. Dudley: University of Minnesota
Michael E. Dunn: Regeneron Pharmaceuticals, Cardiovascular Research
Gunnar Engström: Lund University
Tõnu Esko: The Broad Institute of MIT and Harvard
Stephan B. Felix: University Medicine Greifswald
Chris Finan: University College London
Ian Ford: University of Glasgow
Mohsen Ghanbari: Erasmus University Medical Center
Sahar Ghasemi: partner site Greifswald
Vilmantas Giedraitis: Uppsala University
Franco Giulianini: Brigham and Women’s Hospital
John S. Gottdiener: University of Maryland School of Medicine
Stefan Gross: University Medicine Greifswald
Daníel F. Guðbjartsson: deCODE genetics/Amgen Inc.
Rebecca Gutmann: University of Iowa Carver College of Medicine
Christopher M. Haggerty: Geisinger
Pim Harst: University Medical Center Groningen, University of Groningen
Craig L. Hyde: Pfizer Worldwide Research & Development
Erik Ingelsson: Stanford University School of Medicine
J. Wouter Jukema: Leiden University Medical Center
Maryam Kavousi: Erasmus University Medical Center
Kay-Tee Khaw: University of Cambridge
Marcus E. Kleber: University of Heidelberg
Lars Køber: Copenhagen University Hospital Rigshospitalet
Andrea Koekemoer: University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital
Claudia Langenberg: University of Cambridge School of Clinical Medicine
Lars Lind: Uppsala University
Cecilia M. Lindgren: The Broad Institute of MIT and Harvard
Barry London: University of Iowa
Luca A. Lotta: University of Cambridge School of Clinical Medicine
Ruth C. Lovering: University College London
Jian’an Luan: University of Cambridge School of Clinical Medicine
Patrik Magnusson: Karolinska Institutet
Anubha Mahajan: University of Oxford
Kenneth B. Margulies: University of Pennsylvania
Winfried März: University of Liverpool
Olle Melander: Lund University and Skåne University Hospital
Ify R. Mordi: University of Dundee, Ninewells Hospital and Medical School
Thomas Morgan: Novartis Institutes for Biomedical Research
Andrew D. Morris: University of Edinburgh
Andrew P. Morris: University of Liverpool
Alanna C. Morrison: The University of Texas School of Public Health
Michael W. Nagle: Pfizer Worldwide Research & Development
Christopher P. Nelson: University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital
Alexander Niessner: Medical University of Vienna
Teemu Niiranen: National Institute for Health and Welfare
Michelle L. O’Donoghue: TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital
Anjali T. Owens: University of Pennsylvania
Colin N. A. Palmer: University of Dundee, Ninewells Hospital and Medical School
Helen M. Parry: University of Dundee, Ninewells Hospital and Medical School
Markus Perola: National Institute for Health and Welfare
Eliana Portilla-Fernandez: Erasmus University Medical Center
Bruce M. Psaty: University of Washington
Kenneth M. Rice: University of Washington
Paul M. Ridker: Brigham and Women’s Hospital
Simon P. R. Romaine: University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital
Jerome I. Rotter: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Perttu Salo: National Institute for Health and Welfare
Veikko Salomaa: National Institute for Health and Welfare
Jessica Setten: University Medical Center Utrecht, University of Utrecht
Alaa A. Shalaby: University of Pittsburgh Medical Center and VA Pittsburgh HCS
Diane T. Smelser: Geisinger
Nicholas L. Smith: Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington
Steen Stender: Copenhagen University Hospital, Herlev and Gentofte
David J. Stott: University of Glasgow
Per Svensson: Södersjukhuset, Karolinska Institutet
Mari-Liis Tammesoo: University of Tartu
Kent D. Taylor: Institute for Translational Genomics and Population Sciences, LABiomed and Departments of Pediatrics at Harbor-UCLA Medical Center
Maris Teder-Laving: University of Tartu
Alexander Teumer: partner site Greifswald
Guðmundur Thorgeirsson: deCODE genetics/Amgen Inc.
Unnur Thorsteinsdottir: deCODE genetics/Amgen Inc.
Christian Torp-Pedersen: Aalborg University Hospital
Stella Trompet: Leiden University Medical Center
Benoit Tyl: Translational and Clinical Research, Servier Cardiovascular Center for Therapeutic Innovation, 50 rue Carnot
Andre G. Uitterlinden: Erasmus University Medical Center
Abirami Veluchamy: University of Dundee, Ninewells Hospital and Medical School
Uwe Völker: partner site Greifswald
Adriaan A. Voors: Boston University School of Medicine
Xiaosong Wang: Novartis Institutes for Biomedical Research
Nicholas J. Wareham: University of Cambridge School of Clinical Medicine
Dawn Waterworth: Human Genetics, GlaxoSmithKline
Peter E. Weeke: Copenhagen University Hospital Rigshospitalet
Raul Weiss: The Ohio State University Medical Center
Kerri L. Wiggins: Department of Medicine, University of Washington
Heming Xing: Novartis Institutes for Biomedical Research
Laura M. Yerges-Armstrong: Human Genetics, GlaxoSmithKline
Bing Yu: The University of Texas School of Public Health
Faiez Zannad: Université de Lorraine, CHU de Nancy, Inserm and INI-CRCT (F-CRIN), Institut Lorrain du Coeur et des Vaisseaux
Jing Hua Zhao: University of Cambridge School of Clinical Medicine
Harry Hemingway: University College London
Nilesh J. Samani: University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital
John J. V. McMurray: University of Glasgow
Jian Yang: The University of Queensland
Peter M. Visscher: The University of Queensland
Christopher Newton-Cheh: The Broad Institute of MIT and Harvard
Anders Malarstig: Karolinska Institute
Hilma Holm: deCODE genetics/Amgen Inc.
Steven A. Lubitz: The Broad Institute of MIT and Harvard
Naveed Sattar: University of Glasgow
Michael V. Holmes: Medical Research Council Population Health Research Unit at the University of Oxford
Thomas P. Cappola: University of Pennsylvania
Folkert W. Asselbergs: University College London
Aroon D. Hingorani: University College London
Karoline Kuchenbaecker: University College of London
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Chim C. Lang: University of Dundee, Ninewells Hospital and Medical School
Kari Stefansson: deCODE genetics/Amgen Inc.
J. Gustav Smith: The Broad Institute of MIT and Harvard
Ramachandran S. Vasan: Lung, and Blood Institute’s and Boston University’s Framingham Heart Study
Daniel I. Swerdlow: University College London
R. Thomas Lumbers: University College London

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13690-5

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