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

Author

Listed:
  • Sonia Shah

    (The University of Queensland
    University College London
    University College London)

  • Albert Henry

    (University College London
    University College London
    University College London)

  • Carolina Roselli

    (The Broad Institute of MIT and Harvard
    University Medical Center Groningen, University of Groningen)

  • Honghuang Lin

    (Boston University School of Medicine
    Lung, and Blood Institute’s and Boston University’s Framingham Heart Study)

  • Garðar Sveinbjörnsson

    (deCODE genetics/Amgen Inc.)

  • Ghazaleh Fatemifar

    (University College London
    University College London
    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
    University Medical Center Groningen, University of Groningen)

  • Abbas Dehghan

    (Imperial College London, St Mary’s Campus
    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
    Herlev Gentofte Hospital)

  • Krishna G. Aragam

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Johan Ärnlöv

    (Karolinska Institutet
    Dalarna University)

  • Joshua D. Backman

    (Regeneron Genetics Center)

  • Mary L. Biggs

    (University of Washington
    Department of Medicine, 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
    Harvard Medical School)

  • 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
    University College London
    University College London
    University College London)

  • Alexander S. Doney

    (University of Dundee, Ninewells Hospital and Medical School)

  • Marcus Dörr

    (University Medicine Greifswald
    partner site 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
    University of Tartu)

  • Stephan B. Felix

    (University Medicine Greifswald
    partner site Greifswald)

  • Chris Finan

    (University College London
    University College London)

  • Ian Ford

    (University of Glasgow)

  • Mohsen Ghanbari

    (Erasmus University Medical Center)

  • Sahar Ghasemi

    (partner site Greifswald
    University Medicine 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
    partner site Greifswald)

  • Daníel F. Guðbjartsson

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • Rebecca Gutmann

    (University of Iowa Carver College of Medicine)

  • Christopher M. Haggerty

    (Geisinger)

  • Pim Harst

    (University Medical Center Groningen, University of Groningen
    University of Groningen
    Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute)

  • Craig L. Hyde

    (Pfizer Worldwide Research & Development)

  • Erik Ingelsson

    (Stanford University School of Medicine
    Stanford University
    Uppsala University
    Stanford University)

  • J. Wouter Jukema

    (Leiden University Medical Center
    LUMC)

  • 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
    University of Oxford
    University of Oxford)

  • Barry London

    (University of Iowa)

  • Luca A. Lotta

    (University of Cambridge School of Clinical Medicine)

  • Ruth C. Lovering

    (University College London
    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
    Synlab Academy, Synlab Holding Deutschland GmbH
    Medical University of Graz)

  • 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
    Vanderbilt University School of Medicine)

  • Andrew D. Morris

    (University of Edinburgh)

  • Andrew P. Morris

    (University of Liverpool
    University of Oxford)

  • 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
    Turku University Hospital and University of Turku)

  • 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
    Erasmus University Medical Center)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington)

  • Kenneth M. Rice

    (University of Washington)

  • Paul M. Ridker

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • 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
    University of Washington
    Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research & Development)

  • Steen Stender

    (Copenhagen University Hospital, Herlev and Gentofte)

  • David J. Stott

    (University of Glasgow)

  • Per Svensson

    (Södersjukhuset, Karolinska Institutet
    Södersjukhuset)

  • 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
    University Medicine Greifswald)

  • Guðmundur Thorgeirsson

    (deCODE genetics/Amgen Inc.
    National University Hospital of Iceland, Hringbraut)

  • Unnur Thorsteinsdottir

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • Christian Torp-Pedersen

    (Aalborg University Hospital
    Aalborg University Hospital
    Aalborg University Hospital)

  • Stella Trompet

    (Leiden University Medical Center
    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
    University Medical Center Rotterdam)

  • Abirami Veluchamy

    (University of Dundee, Ninewells Hospital and Medical School)

  • Uwe Völker

    (partner site Greifswald
    University Medicine 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
    University College London
    University College London
    University of Glasgow)

  • 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
    The University of Queensland)

  • Peter M. Visscher

    (The University of Queensland
    The University of Queensland)

  • Christopher Newton-Cheh

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Center for Human Genetic Research, Massachusetts General Hospital)

  • Anders Malarstig

    (Karolinska Institute
    Pfizer Worldwide Research & Development)

  • Hilma Holm

    (deCODE genetics/Amgen Inc.)

  • Steven A. Lubitz

    (The Broad Institute of MIT and Harvard
    Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital)

  • Naveed Sattar

    (University of Glasgow)

  • Michael V. Holmes

    (Medical Research Council Population Health Research Unit at the University of Oxford
    University of Oxford
    Oxford University Hospital)

  • Thomas P. Cappola

    (University of Pennsylvania)

  • Folkert W. Asselbergs

    (University College London
    University College London
    University Medical Center Utrecht, University of Utrecht)

  • Aroon D. Hingorani

    (University College London
    University College London)

  • Karoline Kuchenbaecker

    (University College of London
    UCL Genetics Institute, University College London)

  • Patrick T. Ellinor

    (The Broad Institute of MIT and Harvard
    Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital)

  • Chim C. Lang

    (University of Dundee, Ninewells Hospital and Medical School)

  • Kari Stefansson

    (deCODE genetics/Amgen Inc.
    University of Iceland)

  • J. Gustav Smith

    (The Broad Institute of MIT and Harvard
    Lund University and Skåne University Hospital
    Lund University)

  • Ramachandran S. Vasan

    (Lung, and Blood Institute’s and Boston University’s Framingham Heart Study
    Boston University Schools of Medicine and Public Health)

  • Daniel I. Swerdlow

    (University College London)

  • R. Thomas Lumbers

    (University College London
    University College London
    University College London
    Bart’s Heart Centre, St. Bartholomew’s Hospital)

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.

Suggested Citation

  • 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 & Nie, 2020. "Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13690-5
    DOI: 10.1038/s41467-019-13690-5
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    Cited by:

    1. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Rosalie B. T. M. Sterenborg & Inga Steinbrenner & Yong Li & Melissa N. Bujnis & Tatsuhiko Naito & Eirini Marouli & Tessel E. Galesloot & Oladapo Babajide & Laura Andreasen & Arne Astrup & Bjørn Olav Å, 2024. "Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Diana Dunca & Sandesh Chopade & María Gordillo-Marañón & Aroon D. Hingorani & Karoline Kuchenbaecker & Chris Finan & Amand F. Schmidt, 2024. "Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    5. Amil M. Shah & Peder L. Myhre & Victoria Arthur & Pranav Dorbala & Humaira Rasheed & Leo F. Buckley & Brian Claggett & Guning Liu & Jianzhong Ma & Ngoc Quynh Nguyen & Kunihiro Matsushita & Chiadi Ndum, 2024. "Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Chamlee Cho & Beomsu Kim & Dan Say Kim & Mi Yeong Hwang & Injeong Shim & Minku Song & Yeong Chan Lee & Sang-Hyuk Jung & Sung Kweon Cho & Woong-Yang Park & Woojae Myung & Bong-Jo Kim & Ron Do & Hyon K., 2024. "Large-scale cross-ancestry genome-wide meta-analysis of serum urate," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Shaan Khurshid & Julieta Lazarte & James P. Pirruccello & Lu-Chen Weng & Seung Hoan Choi & Amelia W. Hall & Xin Wang & Samuel F. Friedman & Victor Nauffal & Kiran J. Biddinger & Krishna G. Aragam & Pu, 2023. "Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Michael G. Levin & Noah L. Tsao & Pankhuri Singhal & Chang Liu & Ha My T. Vy & Ishan Paranjpe & Joshua D. Backman & Tiffany R. Bellomo & William P. Bone & Kiran J. Biddinger & Qin Hui & Ozan Dikilitas, 2022. "Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Joeri Meijsen & Kejia Hu & Morten D. Krebs & Georgios Athanasiadis & Sarah Washbrook & Richard Zetterberg & Raquel Nogueira Avelar e Silva & John R. Shorter & Jesper R. Gådin & Jacob Bergstedt & David, 2024. "Quantifying the relative importance of genetics and environment on the comorbidity between mental and cardiometabolic disorders using 17 million Scandinavians," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    10. Adityanarayanan Radhakrishnan & Sam F. Friedman & Shaan Khurshid & Kenney Ng & Puneet Batra & Steven A. Lubitz & Anthony A. Philippakis & Caroline Uhler, 2023. "Cross-modal autoencoder framework learns holistic representations of cardiovascular state," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
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