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

Autor:	Prins BP; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.; Department of Public Health and Primary Care, MRC/BHF Cardiovascular Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Worts' Causeway, Cambridge, CB1 8RN, UK., Mead TJ; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA., Brody JA; Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98101, USA., Sveinbjornsson G; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland., Ntalla I; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK., Bihlmeyer NA; Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., van den Berg M; Department of Medical Informatics Erasmus MC - University Medical Center, P.O. Box 2040, Rotterdam, 3000, CA, The Netherlands., Bork-Jensen J; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark., Cappellani S; Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', 34137, Trieste, Italy., Van Duijvenboden S; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK., Klena NT; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., Gabriel GC; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., Liu X; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., Gulec C; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., Grarup N; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark., Haessler J; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Hall LM; Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.; Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK., Iorio A; Cardiovascular Department, Ospedali Riuniti and University of Trieste, 34100, Trieste, Italy., Isaacs A; CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), and Department of Biochemistry, Maastricht University, Universiteitssingel 60, Maastricht, 6229 ER, The Netherlands.; Department of Epidemiology, Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands., Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands., Lin H; Department of Medicine, Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, 02118, USA., Liu CT; Biostatistics Department, Boston University School of Public Health, Boston, MA, 02118, USA., Lyytikäinen LP; Department of Clinical Chemistry, Fimlab Laboratories, 33520, Tampere, Finland.; Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland., Marten J; Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK., Mei H; Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Müller-Nurasyid M; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Munich, Germany.; German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany., Orini M; Mechanical Engineering Department, University College London, London, WC1E 6BT, UK.; Barts Heart Centre, St Bartholomews Hospital, London, EC1A 7BE, UK., Padmanabhan S; Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, Glasgow, G12 8TA, UK., Radmanesh F; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA., Ramirez J; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK., Robino A; Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', 34137, Trieste, Italy., Schwartz M; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., van Setten J; Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands., Smith AV; Icelandic Heart Association, 201, Kopavogur, Iceland.; Department of Cardiology, Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Verweij N; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.; University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 2114.0, USA., Warren HR; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK., Weiss S; Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17475, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany., Alonso A; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA., Arnar DO; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland.; Department of Medicine, Landspitali University Hospital, 101, Reykjavik, Iceland., Bots ML; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands., de Boer RA; University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Dominiczak AF; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Eijgelsheim M; Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands., Ellinor PT; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, 02114, USA., Guo X; 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.; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA., Felix SB; DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany.; Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, 17475, Greifswald, Germany., Harris TB; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, 20892, USA., Hayward C; Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK., Heckbert SR; Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA., Huang PL; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, 02114, USA., Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.; Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.; Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands., Kähönen M; Department of Clinical Physiology, Tampere University Hospital, 33521, Tampere, Finland.; Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland., Kors JA; Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands., Lambiase PD; Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK.; Barts Heart Centre, St Bartholomews Hospital, London, EC1A 7BE, UK., Launer LJ; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, 20892, USA., Li M; Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, 84109, USA., Linneberg A; Research Centre for Prevention and Health, Capital Region of Denmark, 2600, Glostrup, Denmark.; Department of Clinical Experimental Research, Rigshospitalet, 2600, Glostrup, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200.0, Copenhagen, Denmark., Nelson CP; Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.; Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK., Pedersen O; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark., Perez M; Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA., Peters A; German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany.; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; German Center for Diabetes Research, Neuherberg, Germany., Polasek O; Faculty of Medicine, University of Split, Split, Croatia., Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, 98101, USA.; Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA., Raitakari OT; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521, Turku, Finland.; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20014, Turku, Finland., Rice KM; Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA., Rotter JI; 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., Sinner MF; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Munich, Germany.; German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany., Soliman EZ; Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA., Spector TD; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK., Strauch K; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany., Thorsteinsdottir U; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Tinker A; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK., Trompet S; Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands., Uitterlinden A; Human Genotyping Facility Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands., Vaartjes I; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands., van der Meer P; University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Völker U; Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17475, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany., Völzke H; DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany.; Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany., Waldenberger M; German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany.; Institute of Epidemiology, 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., Wilson JG; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Xie Z; TCM Clinical Basis Institute, Zhejiang Chinese Medical University, Hangzhou, 310000, Zhejiang, China., Asselbergs FW; Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands.; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.; Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK., Dörr M; DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475, Greifswald, Germany.; Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, 17475, Greifswald, Germany., van Duijn CM; Department of Epidemiology, Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands., Gasparini P; Department of Medical, Surgical and Health Sciences, University of Trieste, 34100, Trieste, Italy.; Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar., Gudbjartsson DF; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, 101, Reykjavik, Iceland., Gudnason V; Icelandic Heart Association, 201, Kopavogur, Iceland.; Department of Cardiology, Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Hansen T; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark., Kääb S; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Munich, Germany.; German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany., Kanters JK; Laboratory of Experimental Cardiology, University of Copenhagen, 2200, Copenhagen, Denmark., Kooperberg C; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Lehtimäki T; Department of Clinical Chemistry, Fimlab Laboratories, 33520, Tampere, Finland.; Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland., Lin HJ; 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.; Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, 90502, USA., Lubitz SA; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA., Mook-Kanamori DO; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300RC, The Netherlands., Conti FJ; Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK., Newton-Cheh CH; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.; Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA., Rosand J; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA., Rudan I; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK., Samani NJ; Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.; Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK., Sinagra G; Cardiovascular Department, Ospedali Riuniti and University of Trieste, 34100, Trieste, Italy., Smith BH; Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK., Holm H; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland., Stricker BH; Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands., Ulivi S; Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', 34137, Trieste, Italy., Sotoodehnia N; Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, 98101, USA., Apte SS; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA., van der Harst P; University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands.; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Stefansson K; deCODE genetics/Amgen, Inc., 101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Munroe PB; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK., Arking DE; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Lo CW; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15201, USA., Jamshidi Y; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK. yjamshid@sgul.ac.uk.; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK. yjamshid@sgul.ac.uk.
Jazyk:	angličtina
Zdroj:	Genome biology [Genome Biol] 2018 Jul 17; Vol. 19 (1), pp. 87. Date of Electronic Publication: 2018 Jul 17.
DOI:	10.1186/s13059-018-1457-6
Abstrakt:	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.
Databáze:	MEDLINE
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