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J Am Coll Cardiol. 2016 Sep 27;68(13):1435-1448. doi: 10.1016/j.jacc.2016.07.729.

52 Genetic Loci Influencing Myocardial Mass.

van der Harst P1, van Setten J2, Verweij N3, Vogler G4, Franke L5, Maurano MT6, Wang X7, Mateo Leach I3, Eijgelsheim M8, Sotoodehnia N9, Hayward C10, Sorice R11, Meirelles O12, Lyytikäinen LP13, Polašek O14, Tanaka T15, Arking DE16, Ulivi S17, Trompet S18, Müller-Nurasyid M19, Smith AV20, Dörr M21, Kerr KF22, Magnani JW23, Del Greco M F24, Zhang W25, Nolte IM26, Silva CT27, Padmanabhan S28, Tragante V2, Esko T29, Abecasis GR30, Adriaens ME31, Andersen K32, Barnett P33, Bis JC34, Bodmer R4, Buckley BM35, Campbell H36, Cannon MV3, Chakravarti A16, Chen LY37, Delitala A38, Devereux RB39, Doevendans PA40, Dominiczak AF28, Ferrucci L15, Ford I41, Gieger C42, Harris TB43, Haugen E44, Heinig M45, Hernandez DG46, Hillege HL3, Hirschhorn JN47, Hofman A8, Hubner N48, Hwang SJ49, Iorio A50, Kähönen M51, Kellis M52, Kolcic I53, Kooner IK54, Kooner JS55, Kors JA56, Lakatta EG57, Lage K58, Launer LJ43, Levy D59, Lundby A60, Macfarlane PW61, May D62, Meitinger T63, Metspalu A64, Nappo S11, Naitza S38, Neph S44, Nord AS65, Nutile T11, Okin PM39, Olsen JV66, Oostra BA67, Penninger JM68, Pennacchio LA69, Pers TH70, Perz S71, Peters A72, Pinto YM73, Pfeufer A74, Pilia MG38, Pramstaller PP75, Prins BP76, Raitakari OT77, Raychaudhuri S78, Rice KM22, Rossin EJ79, Rotter JI80, Schafer S81, Schlessinger D12, Schmidt CO82, Sehmi J55, Silljé HHW3, Sinagra G50, Sinner MF83, Slowikowski K84, Soliman EZ85, Spector TD86, Spiering W87, Stamatoyannopoulos JA44, Stolk RP26, Strauch K88, Tan ST55, Tarasov KV57, Trinh B4, Uitterlinden AG8, van den Boogaard M33, van Duijn CM67, van Gilst WH3, Viikari JS89, Visscher PM90, Vitart V10, Völker U91, Waldenberger M92, Weichenberger CX24, Westra HJ93, Wijmenga C5, Wolffenbuttel BH94, Yang J95, Bezzina CR73, Munroe PB96, Snieder H26, Wright AF10, Rudan I36, Boyer LA7, Asselbergs FW97, van Veldhuisen DJ3, Stricker BH8, Psaty BM98, Ciullo M99, Sanna S38, Lehtimäki T13, Wilson JF100, Bandinelli S101, Alonso A102, Gasparini P103, Jukema JW104, Kääb S105, Gudnason V20, Felix SB21, Heckbert SR106, de Boer RA3, Newton-Cheh C107, Hicks AA24, Chambers JC25, Jamshidi Y76, Visel A108, Christoffels VM33, Isaacs A109, Samani NJ110, de Bakker PIW111.

Author information

1
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands. Electronic address: p.van.der.harst@umcg.nl.
2
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
3
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
4
Development, Aging and Regeneration, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
5
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
6
Department of Genome Sciences, University of Washington, Seattle, Washington; Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington; Department of Pathology, New York University Langone Medical Center, New York, New York; Institute for Systems Genetics, New York University Langone Medical Center, New York, New York.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
8
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
9
Division of Cardiology, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington.
10
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
11
Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy.
12
Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland.
13
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
14
Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
15
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
16
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
17
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste, Italy.
18
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
19
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
20
Icelandic Heart Association, Kópavogur, Iceland; University of Iceland, Reykjavik, Iceland.
21
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK partner site, Greifswald, Germany.
22
Department of Biostatistics, University of Washington, Seattle, Washington.
23
Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
24
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany).
25
Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; Ealing Hospital NHS Trust, Middlesex, United Kingdom.
26
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
27
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia; Department of Genetics (GENIUROS), Escuela de Medicina y Ciencias de la salud, Universidad del Rosario, Bogotá, Colombia.
28
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
29
Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts.
30
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
31
Department of Experimental Cardiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands; Maastricht Centre for Systems Biology, Maastricht University, Maastricht, the Netherlands.
32
University of Iceland, Reykjavik, Iceland; Landspitali University Hospital, Reykjavik, Iceland.
33
Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
34
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
35
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
36
Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
37
Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota.
38
Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
39
Department of Medicine, Division of Cardiology, Weill Cornell Medicine, New York, New York.
40
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
41
Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
42
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
43
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
44
Department of Genome Sciences, University of Washington, Seattle, Washington.
45
Cardiovascular and Metabolic Diseases, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; Department of Computational Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany; Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
46
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland.
47
Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts; Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts.
48
Cardiovascular and Metabolic Diseases, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; DZHK partner site, Berlin, Germany.
49
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
50
Cardiovascular Department and Postgraduate School of Cardiovascular Disease, University of Trieste, Trieste, Italy.
51
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
52
Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts; Broad Institute, Cambridge, Massachusetts.
53
Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
54
Ealing Hospital NHS Trust, Middlesex, United Kingdom.
55
Ealing Hospital NHS Trust, Middlesex, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
56
Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands.
57
Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland.
58
Broad Institute, Cambridge, Massachusetts; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Harvard University, Boston, Massachusetts.
59
Center for Population Studies, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland.
60
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
61
Electrocardiology Section, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
62
Department of Family Medicine, Clalit Health Services, and The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
63
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
64
Estonian Genome Center, University of Tartu, Tartu, Estonia.
65
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California; Center for Neuroscience, Departments of Neurobiology, Physiology, and Behavior and Psychiatry and Behavioral Sciences, University of California, Davis, California.
66
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
67
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
68
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
69
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California; DOE Joint Genome Institute, Walnut Creek, California.
70
Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts; Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
71
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute for Biological and Medical Imaging, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
72
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
73
Department of Experimental Cardiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
74
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany); Department of Bioinformatics and Systems Biology IBIS, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
75
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany); Department of Neurology, General Central Hospital, Bolzano, Italy; Department of Neurology, University of Lübeck, Lübeck, Germany.
76
Cardiogenetics Lab, Human Genetics Research Centre, St. George's University of London, London, United Kingdom.
77
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
78
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
79
Harvard Medical School, Harvard University, Boston, Massachusetts; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
80
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California.
81
Cardiovascular and Metabolic Diseases, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; DZHK partner site, Berlin, Germany; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
82
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
83
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
84
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts.
85
Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina.
86
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
87
Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
88
Institute of Medical Informatics, Biometry and Epidemiology, Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
89
Division of Medicine, Turku University Hospital, Turku, Finland; Department of Medicine, University of Turku, Turku, Finland.
90
Queensland Brain Institute, University of Queensland, St. Lucia, Australia; University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Australia.
91
DZHK partner site, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
92
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
93
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts.
94
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
95
Queensland Brain Institute, University of Queensland, St. Lucia, Australia.
96
Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Biomedical Research Unit, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
97
Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
98
Departments of Medicine, Epidemiology, and Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
99
Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy; IRCCS Neuromed, Isernia, Italy.
100
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland; Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
101
Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
102
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
103
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste, Italy; University of Trieste, Trieste, Italy; Sidra Medical and Research Center, Doha, Qatar.
104
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands.
105
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
106
Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
107
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
108
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California; DOE Joint Genome Institute, Walnut Creek, California; School of Natural Sciences, University of California, Merced, California.
109
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology, Department of Biochemistry, Maastricht University, Maastricht, the Netherlands.
110
Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
111
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Abstract

BACKGROUND:

Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES:

This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS:

We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS:

We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.

CONCLUSIONS:

Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

KEYWORDS:

QRS; electrocardiogram; genetic association study; heart failure; left ventricular hypertrophy

PMID:
27659466
PMCID:
PMC5478167
DOI:
10.1016/j.jacc.2016.07.729
[Indexed for MEDLINE]
Free PMC Article

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