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Genome Biol. 2018 Jul 17;19(1):87. doi: 10.1186/s13059-018-1457-6.

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

Prins BP1,2, Mead TJ3, Brody JA4, Sveinbjornsson G5, Ntalla I6,7, Bihlmeyer NA8, van den Berg M9, Bork-Jensen J10, Cappellani S11, Van Duijvenboden S6,12, Klena NT13, Gabriel GC13, Liu X13, Gulec C13, Grarup N10, Haessler J14, Hall LM15,16, Iorio A17, Isaacs A18,19, Li-Gao R20, Lin H21, Liu CT22, Lyytikäinen LP23,24, Marten J25, Mei H26, Müller-Nurasyid M27,28,29, Orini M30,31, Padmanabhan S32, Radmanesh F33,34, Ramirez J6,7, Robino A11, Schwartz M13, van Setten J35, Smith AV36,37, Verweij N34,38,39, Warren HR6,7, Weiss S40,41, Alonso A42, Arnar DO5,43, Bots ML44, de Boer RA38, Dominiczak AF45, Eijgelsheim M46, Ellinor PT47, Guo X48,49, Felix SB41,50, Harris TB51, Hayward C25, Heckbert SR52, Huang PL47, Jukema JW53,54,55, Kähönen M56,57, Kors JA58, Lambiase PD12,31, Launer LJ51, Li M59, Linneberg A60,61,62, Nelson CP15,16, Pedersen O10, Perez M63, Peters A29,64,65, Polasek O66, Psaty BM67,68, Raitakari OT69,70, Rice KM71, Rotter JI72, Sinner MF28,29, Soliman EZ73, Spector TD74, Strauch K27,75, Thorsteinsdottir U5,76, Tinker A6,7, Trompet S53,77, Uitterlinden A78, Vaartjes I44, van der Meer P38, Völker U40,41, Völzke H41,79, Waldenberger M29,64,80, Wilson JG81, Xie Z82, Asselbergs FW35,83,84,85, Dörr M41,50, van Duijn CM19, Gasparini P86,87, Gudbjartsson DF5,88, Gudnason V36,37, Hansen T10, Kääb S28,29, Kanters JK89, Kooperberg C14, Lehtimäki T23,24, Lin HJ48,90, Lubitz SA49, Mook-Kanamori DO20,91, Conti FJ92, Newton-Cheh CH34,93, Rosand J33,34, Rudan I94, Samani NJ15,16, Sinagra G17, Smith BH95, Holm H5, Stricker BH96, Ulivi S11, Sotoodehnia N97, Apte SS3, van der Harst P38,83,98, Stefansson K5,76, Munroe PB6,7, Arking DE99, Lo CW13, Jamshidi Y100,101.

Author information

1
Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
2
Department of Public Health and Primary Care, MRC/BHF Cardiovascular Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Worts' Causeway, Cambridge, CB1 8RN, UK.
3
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
4
Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA.
5
deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland.
6
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
7
NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
8
Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
9
Department of Medical Informatics Erasmus MC - University Medical Center, P.O. Box 2040, Rotterdam, 3000, CA, The Netherlands.
10
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
11
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137, Trieste, Italy.
12
Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK.
13
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA.
14
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
15
Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
16
Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
17
Cardiovascular Department, Ospedali Riuniti and University of Trieste, 34100, Trieste, Italy.
18
CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), and Department of Biochemistry, Maastricht University, Universiteitssingel 60, Maastricht, 6229 ER, The Netherlands.
19
Department of Epidemiology, Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands.
20
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
21
Department of Medicine, Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, 02118, USA.
22
Biostatistics Department, Boston University School of Public Health, Boston, MA, 02118, USA.
23
Department of Clinical Chemistry, Fimlab Laboratories, 33520, Tampere, Finland.
24
Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland.
25
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
26
Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
27
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
28
Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Munich, Germany.
29
German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany.
30
Mechanical Engineering Department, University College London, London, WC1E 6BT, UK.
31
Barts Heart Centre, St Bartholomews Hospital, London, EC1A 7BE, UK.
32
Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, Glasgow, G12 8TA, UK.
33
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.
34
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
35
Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
36
Icelandic Heart Association, 201, Kopavogur, Iceland.
37
Department of Cardiology, Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
38
University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
39
Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 2114.0, USA.
40
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17475, Greifswald, Germany.
41
DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany.
42
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
43
Department of Medicine, Landspitali University Hospital, 101, Reykjavik, Iceland.
44
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
45
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
46
Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.
47
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, 02114, USA.
48
The Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
49
Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
50
Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
51
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, 20892, USA.
52
Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA.
53
Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
54
Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
55
Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.
56
Department of Clinical Physiology, Tampere University Hospital, 33521, Tampere, Finland.
57
Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland.
58
Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
59
Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, 84109, USA.
60
Research Centre for Prevention and Health, Capital Region of Denmark, 2600, Glostrup, Denmark.
61
Department of Clinical Experimental Research, Rigshospitalet, 2600, Glostrup, Denmark.
62
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200.0, Copenhagen, Denmark.
63
Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA.
64
Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
65
German Center for Diabetes Research, Neuherberg, Germany.
66
Faculty of Medicine, University of Split, Split, Croatia.
67
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, 98101, USA.
68
Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
69
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521, Turku, Finland.
70
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20014, Turku, Finland.
71
Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
72
The Institute for Translational Genomics and Population Sciences and Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
73
Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
74
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
75
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
76
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
77
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
78
Human Genotyping Facility Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.
79
Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
80
Research unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
81
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
82
TCM Clinical Basis Institute, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China.
83
Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands.
84
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
85
Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK.
86
Department of Medical, Surgical and Health Sciences, University of Trieste, 34100, Trieste, Italy.
87
Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar.
88
School of Engineering and Natural Sciences, University of Iceland, 101, Reykjavik, Iceland.
89
Laboratory of Experimental Cardiology, University of Copenhagen, 2200, Copenhagen, Denmark.
90
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, 90502, USA.
91
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
92
Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
93
Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
94
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK.
95
Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.
96
Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.
97
Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, 98101, USA.
98
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
99
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
100
Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK. yjamshid@sgul.ac.uk.
101
Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK. yjamshid@sgul.ac.uk.

Abstract

BACKGROUND:

Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS:

Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS:

Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

KEYWORDS:

ADAMTS6; Conduction; Exome chip; Meta-analysis

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