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Nat Commun. 2020 Jan 9;11(1):163. doi: 10.1038/s41467-019-13690-5.

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

Shah S1,2,3, Henry A2,3,4, Roselli C5,6, Lin H7,8, Sveinbjörnsson G9, Fatemifar G3,4,10, Hedman ÅK11, Wilk JB12, Morley MP13, Chaffin MD5, Helgadottir A9, Verweij N5,6, Dehghan A14,15, Almgren P16, Andersson C8,17, Aragam KG5,18,19, Ärnlöv J20,21, Backman JD22, Biggs ML23,24, Bloom HL25, Brandimarto J13, Brown MR26, Buckbinder L12, Carey DJ27, Chasman DI28,29, Chen X12, Chen X30, Chung J22, Chutkow W31, Cook JP32, Delgado GE33, Denaxas S3,4,10,34,35, Doney AS36, Dörr M37,38, Dudley SC39, Dunn ME40, Engström G16, Esko T5,41, Felix SB37,38, Finan C2,3, Ford I42, Ghanbari M43, Ghasemi S38,44, Giedraitis V45, Giulianini F28, Gottdiener JS46, Gross S37,38, Guðbjartsson DF9,47, Gutmann R48, Haggerty CM27, van der Harst P6,49,50, Hyde CL12, Ingelsson E51,52,53,54, Jukema JW55,56, Kavousi M43, Khaw KT57, Kleber ME33, Køber L58, Koekemoer A59, Langenberg C60, Lind L61, Lindgren CM5,62,63, London B64, Lotta LA60, Lovering RC2,3, Luan J60, Magnusson P30, Mahajan A63, Margulies KB13, März W32,65,66, Melander O67, Mordi IR36, Morgan T31,68, Morris AD69, Morris AP32,63, Morrison AC26, Nagle MW12, Nelson CP59, Niessner A70, Niiranen T71,72, O'Donoghue ML73, Owens AT13, Palmer CNA36, Parry HM36, Perola M71, Portilla-Fernandez E43,74, Psaty BM75,76; Regeneron Genetics Center, Rice KM23, Ridker PM28,29, Romaine SPR59, Rotter JI77, Salo P71, Salomaa V71, van Setten J78, Shalaby AA79, Smelser DT27, Smith NL76,80,81, Stender S82, Stott DJ83, Svensson P84,85, Tammesoo ML41, Taylor KD86, Teder-Laving M41, Teumer A38,44, Thorgeirsson G9,87, Thorsteinsdottir U9,88, Torp-Pedersen C89,90,91, Trompet S55,92, Tyl B93, Uitterlinden AG43,94, Veluchamy A36, Völker U38,95, Voors AA7, Wang X31, Wareham NJ60, Waterworth D96, Weeke PE58, Weiss R97, Wiggins KL24, Xing H31, Yerges-Armstrong LM96, Yu B26, Zannad F98, Zhao JH60, Hemingway H3,4,10,99, Samani NJ59, McMurray JJV99, Yang J1,100, Visscher PM1,100, Newton-Cheh C5,19,101, Malarstig A11,12, Holm H9, Lubitz SA5,102, Sattar N99, Holmes MV103,104,105, Cappola TP13, Asselbergs FW2,3,78, Hingorani AD2,3, Kuchenbaecker K106,107, Ellinor PT5,102, Lang CC36, Stefansson K9,88, Smith JG5,108,109, Vasan RS8,110, Swerdlow DI2, Lumbers RT111,112,113,114.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
2
Institute of Cardiovascular Science, University College London, London, UK.
3
British Heart Foundation Research Accelerator, University College London, London, UK.
4
Institute of Health Informatics, University College London, London, UK.
5
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
7
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
8
National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
9
deCODE genetics/Amgen Inc., Sturlugata 8, 101, Reykjavik, Iceland.
10
Health Data Research UK London, University College London, London, UK.
11
Cardiovascular Medicine unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
12
Pfizer Worldwide Research & Development, 1 Portland St, Cambridge, MA, USA.
13
Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
14
Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, UK.
15
MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, UK.
16
Department of Clinical Sciences, Lund University, Malmö, Sweden.
17
Department of Cardiology, Herlev Gentofte Hospital, Herlev Ringvej 57, 2650, Herlev, Denmark.
18
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
19
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
20
Department of Neurobiology, Care Sciences and Society/ Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
21
School of Health and Social Sciences, Dalarna University, Falun, Sweden.
22
Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
23
Department of Biostatistics, University of Washington, Seattle, WA, USA.
24
Department of Medicine, University of Washington, Seattle, WA, USA.
25
Division of Cardiology, Department of Medicine, Emory University Medical Center, Atlanta, GA, USA.
26
Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, Texas, USA.
27
Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA.
28
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
29
Harvard Medical School, Boston, MA, 02115, USA.
30
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
31
Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
32
Department of Biostatistics, University of Liverpool, Liverpool, UK.
33
Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany.
34
The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.
35
The Alan Turing Institute, London, United Kingdom.
36
Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.
37
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
38
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
39
Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
40
Regeneron Pharmaceuticals, Cardiovascular Research, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
41
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.
42
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
43
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
44
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
45
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, 75185, Sweden.
46
Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA.
47
School of Engineering and Natural Sciences, University of Iceland, 101, Reykjavik, Iceland.
48
Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
49
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
50
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
51
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
52
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA.
53
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
54
Stanford Diabetes Research Center, Stanford University, Stanford, CA, 94305, USA.
55
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
56
Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
57
Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB2 0QQ, UK.
58
Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
59
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
60
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
61
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
62
Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
63
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
64
Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA.
65
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
66
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
67
Department of Internal Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden.
68
Vanderbilt University School of Medicine, Nashville, TN, USA.
69
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.
70
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
71
National Institute for Health and Welfare, Helsinki, Finland.
72
Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland.
73
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
74
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
75
Department of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
76
Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
77
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.
78
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
79
Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center and VA Pittsburgh HCS, Pittsburgh, PA, USA.
80
Department of Epidemiology, University of Washington, Seattle, WA, USA.
81
Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research & Development, Seattle, WA, USA.
82
Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte, København, Denmark.
83
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
84
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
85
Department of Cardiology, Södersjukhuset, Stockholm, Sweden.
86
Institute for Translational Genomics and Population Sciences, LABiomed and Departments of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
87
Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland.
88
Faculty of Medicine, Department of Medicine, University of Iceland, Saemundargata 2, 101, Reykjavik, Iceland.
89
Department of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.
90
Department of Health, Science and Technology, Aalborg University Hospital, Aalborg, Denmark.
91
Departments of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
92
Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
93
Translational and Clinical Research, Servier Cardiovascular Center for Therapeutic Innovation, 50 rue Carnot, 92284, Suresnes, France.
94
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
95
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
96
Human Genetics, GlaxoSmithKline, Collegeville, PA, USA.
97
Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
98
Université de Lorraine, CHU de Nancy, Inserm and INI-CRCT (F-CRIN), Institut Lorrain du Coeur et des Vaisseaux, 54500, Vandoeuvre Lès, Nancy, France.
99
BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
100
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
101
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
102
Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
103
Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.
104
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, UK.
105
National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
106
Division of Psychiatry, University College of London, London, W1T 7NF, UK.
107
UCL Genetics Institute, University College London, London, WC1E 6BT, UK.
108
Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
109
Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden.
110
Sections of Cardiology, Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
111
British Heart Foundation Research Accelerator, University College London, London, UK. t.lumbers@ucl.ac.uk.
112
Institute of Health Informatics, University College London, London, UK. t.lumbers@ucl.ac.uk.
113
Health Data Research UK London, University College London, London, UK. t.lumbers@ucl.ac.uk.
114
Bart's Heart Centre, St. Bartholomew's Hospital, London, UK. t.lumbers@ucl.ac.uk.

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.

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