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

Title:	Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
Authors:	Prins, Bram P.; Mead, Timothy J.; Brody, Jennifer A.; Sveinbjornsson, Gardar; Ntalla, Ioanna; Bihlmeyer, Nathan A.; van den Berg, Marten; Bork-Jensen, Jette; Cappellani, Stefania; Van Duijvenboden, Stefan; Klena, Nikolai T.; Gabriel, George C.; Liu, Xiaoqin; Gulec, Cagri; Grarup, Niels; Haessler, Jeffrey; Hall, Leanne M.; Iorio, Annamaria; Isaacs, Aaron; Li-Gao, Ruifang; Lin, Honghuang; Liu, Ching-Ti; Lyytikäinen, Leo-Pekka; Marten, Jonathan; Mei, Hao; Müller-Nurasyid, Martina; Orini, Michele; Padmanabhan, Sandosh; Radmanesh, Farid; Ramirez, Julia; Robino, Antonietta; Schwartz, Molly; van Setten, Jessica; Smith, Albert V.; Verweij, Niek; Warren, Helen R.; Weiss, Stefan; Alonso, Alvaro; Arnar, David O.; Bots, Michiel L.; de Boer, Rudolf A.; Dominiczak, Anna F.; Eijgelsheim, Mark; Ellinor, Patrick T.; Guo, Xiuqing; Felix, Stephan B.; Harris, Tamara B.; Hayward, Caroline; Heckbert, Susan R.; Huang, Paul L.; Jukema, J. W.; Kähönen, Mika; Kors, Jan A.; Lambiase, Pier D.; Launer, Lenore J.; Li, Man; Linneberg, Allan; Nelson, Christopher P.; Pedersen, Oluf; Perez, Marco; Peters, Annette; Polasek, Ozren; Psaty, Bruce M.; Raitakari, Olli T.; Rice, Kenneth M.; Rotter, Jerome I.; Sinner, Moritz F.; Soliman, Elsayed Z.; Spector, Tim D.; Strauch, Konstantin; Thorsteinsdottir, Unnur; Tinker, Andrew; Trompet, Stella; Uitterlinden, André; Vaartjes, Ilonca; van der Meer, Peter; Völker, Uwe; Völzke, Henry; Waldenberger, Melanie; Wilson, James G.; Xie, Zhijun; Asselbergs, Folkert W.; Dörr, Marcus; van Duijn, Cornelia M.; Gasparini, Paolo; Gudbjartsson, Daniel F.; Gudnason, Vilmundur; Hansen, Torben; Kääb, Stefan; Kanters, Jørgen K.; Kooperberg, Charles; Lehtimäki, Terho; Lin, Henry J.; Lubitz, Steven A.; Mook-Kanamori, Dennis O.; Conti, Francesco J.; Newton-Cheh, Christopher H.; Rosand, Jonathan; Rudan, Igor; Samani, Nilesh J.; Sinagra, Gianfranco; Smith, Blair H.; Holm, Hilma; Stricker, Bruno H.; Ulivi, Sheila; Sotoodehnia, Nona; Apte, Suneel S.; van der Harst, Pim; Stefansson, Kari; Munroe, Patricia B.; Arking, Dan E.; Lo, Cecilia W.; Jamshidi, Yalda
Contributors:	1 St Georges Univ London, Genet Res Ctr, Mol & Clin Sci Inst, London SW17 0RE, England Show more 2 Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Worts Causeway, Cambridge CB1 8RN, England Show more 3 Cleveland Clin, Dept Biomed Engn, Lerner Res Inst, Cleveland, OH 44195 USA Show more 4 Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA 5 deCODE Genet Amgen Inc, IS-101 Reykjavik, Iceland Show more 6 Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England Show more 7 Queen Mary Univ London, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Biomed Res Ctr, London EC1M 6BQ, England Show more 8 Johns Hopkins Univ, Sch Med, Predoctoral Training Program Human Genet, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA Show more 9 Erasmus MC Univ Med Ctr, Dept Med Informat, POB 2040, NL-3000 CA Rotterdam, Netherlands Show more 10 Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2100 Copenhagen, Denmark Show more 11 IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy Show more 12 UCL, Inst Cardiovasc Sci, London WC1E 6BT, England Show more 13 Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15201 USA Show more 14 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA Show more 15 Univ Leicester, Glenfield Hosp, Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England Show more 16 Leicester NIHR Biomed Res Ctr, Glenfield Hosp, Leicester LE3 9QP, Leics, England 17 Osped Riuniti, Cardiovasc Dept, I-34100 Trieste, Italy Show more 18 Univ Trieste, I-34100 Trieste, Italy Show more 19 Maastricht Univ, CARIM Sch Cardiovasc Dis, Maastricht Ctr Syst Biol MaCSBio, Univ Single 60, NL-6229 ER Maastricht, Netherlands Show more 20 Maastricht Univ, Dept Biochem, Univ Single 60, NL-6229 ER Maastricht, Netherlands Show more 21 Erasmus Univ, Med Ctr, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands Show more 22 Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands Show more 23 Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA Show more 24 Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA 25 Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland Show more 26 Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere 33014, Finland Show more 27 Univ Edinburgh, Inst Genet & Mol Med, Med Res Council, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland Show more 28 Univ Mississippi, Med Ctr, Sch Populat Hlth, Dept Data Sci, Jackson, MS 39216 USA Show more 29 German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany Show more 30 Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany Show more 31 Munich Heart Alliance, Partner Site, German Ctr Cardiovasc Res DZHK, Munich, Germany Show more 32 UCL, Mech Engn Dept, London WC1E 6BT, England Show more 33 St Bartholomews Hosp, Barts Heart Ctr, London EC1A 7BE, England Show more 34 Univ Glasgow, Inst Cardiovasc & Med Sci, BHF GCRC, Glasgow G12 8TA, Lanark, Scotland Show more 35 Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA Show more 36 Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA Show more 37 MIT, Cambridge, MA 02142 USA Show more 38 Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands 39 Iceland Heart Assoc, IS-201 Kopavogur, Iceland Show more 40 Univ Iceland, Fac Med, Dept Cardiol, IS-101 Reykjavik, Iceland Show more 41 Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands Show more 42 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA Show more 43 Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA 44 Univ Med, Interfac Inst Genet & Funct Gen, D-17475 Greifswald, Germany Show more 45 Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany Show more 46 DZHK German Ctr Cardiovasc Res, Partner site Greifswald, D-17475 Greifswald, Germany Show more 47 Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA Show more 48 Landspitali Univ Hosp, Dept Med, IS-101 Reykjavik, Iceland Show more 49 Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands Show more 50 Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland Show more 51 Erasmus MC Univ Med Ctr Rotterdam, POB 2040, NL-3000 CA Rotterdam, Netherlands Show more 52 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02114 USA Show more 53 Harbor UCLA Med Ctr, Translat Genom & Populat Sci, Torrance, CA 90509 USA Show more 54 Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA Show more 55 Harbor UCLA Med Ctr, Dept Pediat, Div Genom Outcomes, Torrance, CA 90502 USA Show more 56 Univ Med Greifswald, Dept Internal Med Cardiol Pneumol Infect Dis Inte, D-17475 Greifswald, Germany Show more 57 NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA Show more 58 Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA Show more 59 Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA Show more 60 Leiden Univ, Dept Cardiol, Med Ctr, NL-2300 RC Leiden, Netherlands 61 Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands Show more 62 Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands Show more 63 Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland Show more 64 Univ Tampere, Fac Med & Life Sci, Dept Clin Physiol, Tampere 33014, Finland Show more 65 Erasmus Univ, Med Ctr, Dept Med Informat, Rotterdam, Netherlands Show more 66 Univ Utah, Sch Med, Div Nephrol & Hypertens Internal Med, Salt Lake City, UT 84109 USA 67 Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark Show more 68 Rigshosp, Dept Clin Expt Res, DK-2600 Glostrup, Denmark Show more 69 Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-22000 Copenhagen, Denmark Show more 70 Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA Show more 71 German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany 72 German Ctr Diabet Res, Neuherberg, Germany Show more 73 Univ Split, Fac Med, Split, Croatia Show more 74 Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA 75 Kaiser Permanente Washington Hlth Res Inst, Seattle, WA 98101 USA Show more 76 Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland Show more 77 Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20014, Finland Show more 78 Univ Washington, Dept Biostat, Seattle, WA 98195 USA Show more 79 Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA Show more 80 Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Torrance, CA 90502 USA Show more 81 Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Med, Torrance, CA 90502 USA Show more 82 Wake Forest Univ, Bowman Gray Sch Med, Epidemiol Cardiol Res Ctr EPICARE, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA Show more 83 Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England Show more 84 Ludwig Maximilians Univ Munchen, Fac Med, IBE, Chair Genet Epidemiol, Munich, Germany Show more 85 Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland Show more 86 Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands Show more 87 Erasmus MC Univ Med Ctr Rotterdam, Human Genotyping Facil, POB 2040, NL-3000 CA Rotterdam, Netherlands Show more 88 Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany Show more 89 German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany Show more 90 Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA Show more 91 Zhejiang Chinese Med Univ, TCM Clin Basis Inst, Hangzhou 310000, Zhejiang, Peoples R China 92 Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands Show more 93 UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England Show more 94 UCL, Farr Inst Hlth Informat Res, London, England Show more 95 UCL, Inst Hlth Informat, London, England Show more 96 Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy Show more 97 Sidra Med & Res Ctr, Div Expt Genet, Doha, Qatar Show more 98 Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Iceland Show more 99 Univ Copenhagen, Lab Expt Cardiol, DK-2200 Copenhagen, Denmark Show more 100 Harbor UCLA Med Ctr, Dept Pediat, Div Med Genet, Torrance, CA 90502 USA Show more 101 Leiden Univ, Dept Publ Hlth & Primary Care, Med Ctr, NL-2300 RC Leiden, Netherlands Show more 102 UCL, Inst Child Hlth, Dubowitz Neuromuscular Ctr, 30 Guilford St, London WC1N 1EH, England Show more 103 Harvard Med Sch, Ctr Human Genet Res, Boston, MA 02114 USA Show more 104 Harvard Med Sch, Cardiovasc Res Ctr, Boston, MA 02114 USA Show more 105 Massachusetts Gen Hosp, Boston, MA 02114 USA Show more 106 Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland Show more 107 Univ Dundee, Div Populat Hlth Sci, Ninewells Hosp, Dundee DD1 9SY, Scotland Show more 108 Univ Dundee, Med Sch, Dundee DD1 9SY, Scotland Show more 109 Erasmus MC Univ Med Ctr, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands Show more 110 Univ Washington, Div Cardiol, Dept Med, Seattle, WA 98101 USA Show more 111 Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA Show more 112 Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands Show more 113 Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA Show more 114 St Georges Univ London, Genet Res Ctr, Mol & Clin Sci Inst, London, England
Publisher Information:	BMC
Publication Year:	2018
Collection:	Hirsla - Landspítali University Hospital research archive
Subject Terms:	Hjartasjúkdómar; Gen; Cardiovascular Diseases; Cardiac Conduction System Disease; Genome-Wide Association Study
Description:	To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files ; 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. ; British Heart Foundation NIH NIA Intramural Research Program Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) National Heart, Lung, and Blood Institute contracts National Human Genome Research Institute National Institutes of Health NIH Roadmap for Medical Research NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) Wellcome Trust Strategic Awards Medical Research Council of Great Britain ...
Document Type:	article in journal/newspaper
Language:	English
ISSN:	1474-760X
Relation:	https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1457-6; Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 2018, 19 (1) Genome Biology; http://hdl.handle.net/2336/620666; Genome Biology
DOI:	10.1186/s13059-018-1457-6
Availability:	http://hdl.handle.net/2336/620666; https://doi.org/10.1186/s13059-018-1457-6
Rights:	Archived with thanks to Genome Biology ; Open Access - Opinn aðgangur
Accession Number:	edsbas.9A5BC75F
Database:	BASE