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Hum Mol Genet. 2017 Jun 15;26(12):2346-2363. doi: 10.1093/hmg/ddx113.

Discovery of novel heart rate-associated loci using the Exome Chip.

van den Berg ME1, Warren HR2,3, Cabrera CP2,3, Verweij N4, Mifsud B2,3, Haessler J5, Bihlmeyer NA6, Fu YP7, Weiss S8,9, Lin HJ10,11, Grarup N12, Li-Gao R13, Pistis G14,15, Shah N16,17, Brody JA18, Müller-Nurasyid M19,20,21, Lin H22, Mei H23, Smith AV24,25, Lyytikäinen LP26, Hall LM27,28, van Setten J29, Trompet S30,31, Prins BP32,33, Isaacs A34, Radmanesh F35,36, Marten J37, Entwistle A2,3, Kors JA1, Silva CT38,39,40, Alonso A41, Bis JC18, de Boer R4, de Haan HG13, de Mutsert R13, Dedoussis G42, Dominiczak AF43, Doney ASF44, Ellinor PT36,45, Eppinga RN4, Felix SB46, Guo X10, Hagemeijer Y4, Hansen T12, Harris TB47, Heckbert SR48,49, Huang PL45, Hwang SJ50, Kähönen M51, Kanters JK52, Kolcic I53, Launer LJ47, Li M54, Yao J10, Linneberg A55,56,57, Liu S58, Macfarlane PW59, Mangino M60,61, Morris AD62, Mulas A14, Murray AD63, Nelson CP27,28, Orrú M64, Padmanabhan S43,65, Peters A20,66,67, Porteous DJ68, Poulter N69, Psaty BM70,71, Qi L72, Raitakari OT73, Rivadeneira F74, Roselli C75, Rudan I62, Sattar N76, Sever P77, Sinner MF20,21, Soliman EZ78, Spector TD60, Stanton AV79, Stirrups KE2,80, Taylor KD81,82,83, Tobin MD84, Uitterlinden A85, Vaartjes I86, Hoes AW87, van der Meer P4, Völker U8,9, Waldenberger M20,88,66, Xie Z22, Zoledziewska M14, Tinker A2,3, Polasek O53,88, Rosand J35,36, Jamshidi Y89, van Duijn CM38, Zeggini E90, Jukema JW30, Asselbergs FW29,91,92, Samani NJ27,28, Lehtimäki T93, Gudnason V24,25, Wilson J94, Lubitz SA36,45, Kääb S20,21, Sotoodehnia N95, Caulfield MJ2,3, Palmer CNA44, Sanna S14, Mook-Kanamori DO13,96, Deloukas P2, Pedersen O12, Rotter JI97, Dörr M46, O'Donnell CJ98, Hayward C37, Arking DE99, Kooperberg C5, van der Harst P4, Eijgelsheim M100, Stricker BH100, Munroe PB2,3.

Author information

1
Department of Medical Informatics Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
2
Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
3
NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
4
University Medical Center Groningen, University of Groningen, Department of Cardiology, the Netherlands.
5
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
6
Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 21205.
7
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
8
Interfaculty Institute for Genetics and Functional Genomics; University Medicine and Ernst-Moritz-Arndt-University Greifswald; Greifswald, 17475, Germany.
9
DZHK (German Centre for Cardiovascular Research); partner site Greifswald; Greifswald, 17475, Germany.
10
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA.
11
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
12
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
14
Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
15
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
16
Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, DD1 9SY, UK.
17
Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
18
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
19
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
20
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
21
Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-Universität, Munich, Germany.
22
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA.
23
Department of Data Science, University of Mississippi Medical Center, Jackson, MI, USA.
24
Icelandic Heart Association, 201 Kopavogur, Iceland.
25
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
26
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Arvo, D339, P.O. Box 100, FI-33014 Tampere, Finland.
27
Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
28
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
29
Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
30
Department of Cardiology, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands.
31
Department of Gerontology and Geriatrics, Leiden university Medical Center, Leiden, the Netherlands.
32
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom, CB10 1SA.
33
Cardiogenetics Lab, Genetics and Molecular Cell Sciences Research Centre, Cardiovascular and Cell Sciences Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
34
CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), Dept. of Biochemistry, Maastricht University, Universiteitssingel 60, 6229 ER Maastricht, NL.
35
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114.
36
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142.
37
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4?2XU, UK.
38
Genetic Epidemiology Unit, Dept. of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, NL.
39
Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia.
40
GENIUROS Group, Genetics and Genomics Research Center CIGGUR, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.
41
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322.
42
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
43
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
44
Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, DD1?9SY, UK.
45
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
46
Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine; University Medicine Greifswald; Greifswald, 17475, Germany & DZHK (German Centre for Cardiovascular Research); partner site Greifswald; Greifswald, 17475, Germany.
47
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, 20892, USA.
48
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
49
Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1600, Seattle, WA, USA.
50
Population Sciences Branch, Division of Intramural Research, NHLBI, NIH, Bethesda MD, USA.
51
Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Finn-Medi 1, 3th floor, P.O. Box 2000, FI-33521 Tampere, Finland.
52
Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark.
53
Faculty of Medicine, University of Split, Split, Croatia.
54
Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84109, USA.
55
Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.
56
Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
57
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
58
Brown University School of Public Health, Providence, Rhode Island 02912, USA.
59
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
60
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
61
NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London SE1 9RT, UK.
62
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8?9AG, UK.
63
Aberdeen Biomedical Imaging Centre, Lilian Sutton Building, University of Aberdeen, Foresterhill, Aberdeen AB25?2ZD, UK.
64
Unita Operativa Complessa di Cardiologia, Presidio Ospedaliero Oncologico Armando Businco Cagliari , Azienda Ospedaliera Brotzu Cagliari, Caglliari, Italy.
65
Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, Glasgow G12 8TA, UK.
66
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
67
German Center for Diabetes Research, Neuherberg, Germany.
68
Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4?2XU, UK.
69
School of Public Health, Imperial College London, W2?1PG, UK.
70
Cardiovascular Health Research Unit, Department of Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
71
Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
72
University of California Davis, One Shields Ave Ms1c 145, Davis, CA 95616 USA.
73
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, P.O. Box 52, FI-20521 Turku, Finland.
74
Human Genomics Facility Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
75
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
76
Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, Glasgow G12?8TA, UK.
77
National Heart and Lung Institute, Imperial College London, W2?1PG, UK.
78
Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
79
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
80
Department of Haematology, University of Cambridge, Cambridge, UK.
81
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
82
Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
83
Departments of Pediatrics, Medicine, and Human Genetics, UCLA, Los Angeles, CA, USA.
84
Department of Health Sciences, University of Leicester, Leicester LE1?7RH, UK.
85
Human Genotyping Facility Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
86
Julius Center for Health Sciences and Primary Care, University Medical Center, PO Box 85500, 3508 GA Utrecht, the Netherlands.
87
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
88
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK.
89
Cardiogenetics Lab, Genetics and Molecular Cell Sciences Research Centre, Cardiovascular and Cell Sciences Institute, St George's, University of London, Cranmer Terrace, London, SW17?0RE, UK.
90
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom, CB10?1SA.
91
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
92
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
93
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Arvo, D338, P.O. Box 100, FI-33014 Tampere, Finland.
94
Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MI, USA.
95
Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
96
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
97
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA.
98
Boston Veteran's Administration Healthcare, Boston MA, USA.
99
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 21205 and.
100
Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.

Abstract

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

PMID:
28379579
PMCID:
PMC5458336
DOI:
10.1093/hmg/ddx113
[Indexed for MEDLINE]
Free PMC Article

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