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Article Dans Une Revue Nature Communications Année : 2020

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

Sonia Shah (1, 2) , Albert Henry (2) , Carolina Roselli (3, 4) , Honghuang Lin (5, 6) , Garðar Sveinbjörnsson (7) , Ghazaleh Fatemifar (2) , Åsa Hedman (8) , Jemma B. Wilk (9) , Michael Morley (10) , Mark Chaffin (3) , Anna Helgadottir (7) , Niek Verweij (3, 11) , Abbas Dehghan (12) , Peter Almgren (13) , Charlotte Andersson (3, 14) , Krishna Aragam (3, 15) , Johan Ärnlöv (16, 17) , Joshua Backman (18) , Mary Biggs (19, 20) , Heather Bloom (21) , Jeffrey Brandimarto (10) , Michael Brown (22) , Leonard Buckbinder (9) , David Carey (23) , Daniel Chasman (24, 25) , Xing Chen (9) , Xu Chen (8) , Jonathan Chung (26) , William Chutkow (27) , James Cook (28) , Graciela Delgado (29, 30) , Spiros Denaxas (2, 31) , Alexander Doney (32) , Marcus Dörr (33, 34) , Samuel Dudley (35) , Michael Dunn (36) , Gunnar Engström (37) , Tonu Esko (38, 3) , Stephan B. Felix (33, 34) , Chris Finan (2) , Ian Ford (39) , Mohsen Ghanbari (40, 41) , Sahar Ghasemi (33, 34) , Vilmantas Giedraitis (42) , Franco Giulianini (43) , John Gottdiener (44) , Stefan Gross (33, 34) , Daníel Guðbjartsson (7, 45) , Rebecca Gutmann (46) , Christopher Haggerty (47) , Pim van Der Harst (48, 4) , Craig Hyde (9) , Erik Ingelsson (49, 50, 51) , J. Wouter Jukema (52, 53) , Maryam Kavousi (41) , Kay-Tee Khaw (54) , Marcus Kleber (29) , Lars Køber (55, 56) , Andrea Koekemoer (57, 58) , Claudia Langenberg (59) , Lars Lind (51) , Cecilia Lindgren (3, 60) , Barry London (61) , Luca Lotta (62) , Ruth Lovering (2) , Jian’an Luan (62) , Patrik K. E. Magnusson (62) , Anubha Mahajan (63) , Kenneth Margulies (10) , Winfried März (64, 28, 65) , Olle Melander (13, 66) , Ify Mordi (32) , Thomas Morgan (67, 27) , Andrew D. Morris (68) , Andrew P. Morris (63, 28) , Alanna C. Morrison (22) , Michael Nagle (9) , Christopher Nelson (58) , Alexander Niessner (69) , Teemu Niiranen (70, 71) , Michelle O’donoghue (72) , Anjali Owens (10) , Colin Palmer (32) , Helen Parry (32) , Markus Perola (70) , Eliana Portilla-Fernandez (41) , Bruce Psaty (20, 73) , Regeneron Genetics Center , Kenneth Rice (20) , Paul Ridker (24, 25) , Simon Romaine (58) , Jerome Rotter (74, 75) , Perttu Salo (70) , Veikko Salomaa (70) , Jessica van Setten (76) , Alaa Shalaby (77) , Diane Smelser (47) , Nicholas Smith (73, 20, 78) , Steen Stender (14) , David Stott (79) , Per Svensson (80, 8) , Mari-Liis Tammesoo (33) , Kent D Taylor (75) , Maris Teder-Laving (81) , Alexander Teumer (33, 34) , Guðmundur Thorgeirsson (7, 82) , Unnur Thorsteinsdóttir (7, 83) , Christian Torp-Pedersen (84) , Stella Trompet (52) , Benoit Tyl (85) , André G. Uitterlinden (41) , Abirami Veluchamy (32) , Uwe Völker (86, 34) , Adriaan Voors (5) , Xiaosong Wang (27) , Nicholas J. Wareham (59) , Dawn Waterworth (87) , Peter Weeke (56) , Raul Weiss (88) , Kerri Wiggins (20) , Heming Xing (27) , Laura Yerges-Armstrong (87) , Bing Yu (22) , Faiez Zannad (89, 90, 91, 92) , Jing Hua Zhao (93) , Harry Hemingway (2, 94) , Nilesh J. Samani (95) , John Mcmurray (94) , Jian Yang (1, 96) , Peter M. Visscher (1, 96) , Christopher Newton-Cheh (97, 98, 3) , Anders Mälarstig (8, 9) , Hilma Holm (7) , Steven Lubitz (3, 15) , Naveed Sattar (94) , Michael C. Holmes (60, 99) , Thomas Cappola (10) , Folkert Asselbergs (2, 76) , Aroon Hingorani (2) , Karoline Kuchenbaecker (2) , Patrick Ellinor (15, 3) , Chim Lang (100) , Kari Stefansson (7, 83) , J. Gustav Smith (3, 13) , Ramachandran S Vasan (101, 102, 5) , Daniel Swerdlow (2) , R. Thomas Lumbers (2)
1 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
2 UCL - University College of London [London]
3 BROAD INSTITUTE - Broad Institute of MIT and Harvard
4 UMCG - University Medical Center Groningen [Groningen]
5 BUSM - Boston University School of Medicine
6 Framingham Heart Study
7 deCODE genetics [Reykjavik]
8 Karolinska Institutet [Stockholm]
9 Pfizer
10 University of Pennsylvania
11 University of Groningen [Groningen]
12 Imperial College London
13 Skane University Hospital [Lund]
14 Herlev and Gentofte Hospital
15 Massachusetts General Hospital [Boston]
16 Division of Family Medicine - Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden]
17 Dalarna University
18 Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown
19 Department of Biostatistics
20 University of Washington [Seattle]
21 Emory University School of Medicine
22 The University of Texas Medical School at Houston
23 Department of Molecular and Functional Genomics, Geisinger, Danville, PA
24 Brigham and Women's Hospital [Boston]
25 HMS - Harvard Medical School [Boston]
26 Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY
27 NIBR - Novartis Institutes for BioMedical Research
28 University of Liverpool
29 Universität Heidelberg [Heidelberg] = Heidelberg University
30 Medizinische Fakultät Mannheim
31 The Alan Turing Institute
32 Ninewells Hospital and Medical School [Dundee]
33 Universität Greifswald - University of Greifswald
34 DZHK - German Center for Cardiovascular Research
35 UMN - University of Minnesota System
36 Regeneron Pharmaceuticals [Tarrytown, NY]
37 Department of Clinical Sciences, Cardiovascular Epidemiology
38 Institute of Genomics [Tartu, Estonia]
39 Robertson Centre for Biostatistics, University of Glasgow
40 Department of Epidemiology, Erasmus University Medical Center, Rotterdam
41 Erasmus MC - Erasmus University Medical Center [Rotterdam]
42 Uppsala University
43 BWH - Brigham & Women’s Hospital [Boston]
44 University of Maryland School of Medicine
45 School of Science and Engineering (Reykjavik University)
46 Carver College of Medicine, University of Iowa
47 Geisinger Health System [Danville, PA, USA]
48 Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht
49 Stanford School of Medicine [Stanford]
50 Stanford Cardiovascular Institute
51 Uppsala Universitet [Uppsala]
52 LUMC - Leiden University Medical Center
53 ELEVM - LEIDEN - Einthoven Laboratory for Experimental Vascular Medicine
54 Department of Public Health and Primary Care
55 Rigshospitalet [Copenhagen]
56 Copenhagen University Hospital
57 Glenfield Hospital
58 University Hospitals Leicester
59 MRC Epidemiology Unit
60 Big Data Institute
61 University of Iowa [Iowa City]
62 CAM - University of Cambridge [UK]
63 The Wellcome Trust Centre for Human Genetics [Oxford]
64 Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim
65 Medical University Graz
66 Skane University Hospital [Malmo]
67 Vanderbilt University School of Medicine [Nashville]
68 Edin. - University of Edinburgh
69 Université médicale de Vienne, Autriche
70 National Institute for Health and Welfare [Helsinki]
71 University of Turku
72 Birmingham Women's and Children's NHS Foundation Trust
73 Kaiser Permanente
74 Harbor UCLA Medical Center [Torrance, Ca.]
75 LA BioMed - Los Angeles Biomedical Research Institute
76 University Medical Center [Utrecht]
77 PITT - University of Pittsburgh
78 Seattle Epidemiologic Research and Information Center [Seattle]
79 Institute of Cardiovascular and Medical Sciences [Glasgow]
80 Department of Cardiology, Södersjukhuset, Stockholm
81 Estonian Genome and Medicine
82 Landspitali National University Hospital of Iceland
83 University of Iceland [Reykjavik]
84 AAU - Aalborg University [Denmark]
85 IRS - Institut de Recherches SERVIER
86 Interfaculty Institute for Genetics and Functional Genomics
87 GlaxoSmithKline
88 NEOMED - Northeastern Ohio Medical University
89 CIC-P - Centre d'investigation clinique plurithématique Pierre Drouin [Nancy]
90 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
91 INI-CRCT - Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy]
92 Cardiovascular & Renal Clinical Trialists - CRCT - French-Clinical Research Infrastructure Network - F-CRIN [Paris]
93 MRC Epidemiology Unit, Institute of Metabolic Science
94 BHF GCRC - British Heart Foundation Glasgow Cardiovascular Research Centre
95 Department of Cardiovascular Sciences [Leicester]
96 Queensland Brain Institute
97 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
98 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
99 University of Oxford
100 University of Dundee
101 BU - Boston University [Boston]
102 NHLI - National Heart and Lung Institute [London]
Albert Henry
Jemma B. Wilk
  • Fonction : Auteur
Leonard Buckbinder
  • Fonction : Auteur
Xing Chen
  • Fonction : Auteur
Xu Chen
  • Fonction : Auteur
  • PersonId : 941200
Craig Hyde
  • Fonction : Auteur
Lars Lind
Michael Nagle
  • Fonction : Auteur
Regeneron Genetics Center
  • Fonction : Auteur
Jessica van Setten
Christian Torp-Pedersen
Adriaan Voors
Dawn Waterworth
  • Fonction : Auteur
Chim Lang
  • Fonction : Auteur

Résumé

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 herit-ability 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.
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Dates et versions

hal-02577541 , version 1 (15-05-2020)

Identifiants

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Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, et al.. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 2020, 11 (1), pp.163. ⟨10.1038/s41467-019-13690-5⟩. ⟨hal-02577541⟩
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