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dc.contributor.authorvan der Harst, Pim
dc.contributor.authorvan Setten, Jessica
dc.contributor.authorVerweij, Niek
dc.contributor.authorVogler, Georg
dc.contributor.authorFranke, Lude
dc.contributor.authorMaurano, Matthew T
dc.contributor.authorWang, Xinchen
dc.contributor.authorMateo Leach, Irene
dc.contributor.authorEijgelsheim, Mark
dc.contributor.authorSotoodehnia, Nona
dc.contributor.authorHayward, Caroline
dc.contributor.authorDel Greco M, Fabiola
dc.contributor.authorLevy, Daniel
dc.contributor.authorZhang, Weihua
dc.contributor.authorKellis, Manolis
dc.contributor.authorNolte, Ilja M
dc.contributor.authorSilva, Claudia T
dc.contributor.authorPadmanabhan, Sandosh
dc.contributor.authorTragante, Vinicius
dc.contributor.authorDoevendans, Pieter A
dc.contributor.authorEsko, Tõnu
dc.contributor.authorPers, Tune H
dc.contributor.authorBis, Joshua C
dc.contributor.authorBodmer, Rolf
dc.contributor.authorBuckley, Brendan M
dc.contributor.authorCampbell, Harry
dc.contributor.authorRaychaudhuri, Soumya
dc.contributor.authorCannon, Megan V
dc.contributor.authorPrins, Bram P
dc.contributor.authorDominiczak, Anna F
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorFord, Ian
dc.contributor.authorBezzina, Connie R
dc.contributor.authorGieger, Christian
dc.contributor.authorSinagra, Gianfranco
dc.contributor.authorHarris, Tamara B
dc.contributor.authorSehmi, Jobanpreet
dc.contributor.authorHaugen, Eric
dc.contributor.authorKolcic, Ivana
dc.contributor.authorHeinig, Matthias
dc.contributor.authorHernandez, Dena G
dc.contributor.authorRaitakari, Olli T
dc.contributor.authorHillege, Hans L
dc.contributor.authorPerz, Siegfried
dc.contributor.authorHirschhorn, Joel N
dc.contributor.authorHofman, Albert
dc.contributor.authorHubner, Norbert
dc.contributor.authorHwang, Shih-Jen
dc.contributor.authorMacfarlane, Peter W
dc.contributor.authorIorio, Annamaria
dc.contributor.authorKooner, Ishminder K
dc.contributor.authorKooner, Jaspal S
dc.contributor.authorKors, Jan A
dc.contributor.authorLakatta, Edward G
dc.contributor.authorVitart, Veronique
dc.contributor.authorLage, Kasper
dc.contributor.authorVisscher, Peter M
dc.contributor.authorMay, Dalit
dc.contributor.authorMeitinger, Thomas
dc.contributor.authorMetspalu, Andres
dc.contributor.authorNappo, Stefania
dc.contributor.authorMunroe, Patricia B
dc.contributor.authorNaitza, Silvia
dc.contributor.authorYang, Jian
dc.contributor.authorNeph, Shane
dc.contributor.authorPeters, Annette
dc.contributor.authorNord, Alex S
dc.contributor.authorNutile, Teresa
dc.contributor.authorMeirelles, Osorio
dc.contributor.authorOkin, Peter M
dc.contributor.authorSinner, Moritz F
dc.contributor.authorOlsen, Jesper V
dc.contributor.authorOostra, Ben A
dc.contributor.authorPenninger, Josef M
dc.contributor.authorRice, Ken M
dc.contributor.authorPennacchio, Len A
dc.contributor.authorPinto, Yigal M
dc.contributor.authorPfeufer, Arne
dc.contributor.authorPilia, Maria Grazia
dc.contributor.authorSlowikowski, Kamil
dc.contributor.authorPramstaller, Peter P
dc.contributor.authorGasparini, Paolo
dc.contributor.authorRossin, Elizabeth J
dc.contributor.authorRotter, Jerome I
dc.contributor.authorSchafer, Sebastian
dc.contributor.authorSchlessinger, David
dc.contributor.authorChambers, John C
dc.contributor.authorSchmidt, Carsten O
dc.contributor.authorNewton-Cheh, Christopher
dc.contributor.authorSoliman, Elsayed Z
dc.contributor.authorSpector, Timothy D
dc.contributor.authorSpiering, Wilko
dc.contributor.authorChen, Lin Y
dc.contributor.authorStamatoyannopoulos, John A
dc.contributor.authorLyytikäinen, Leo-Pekka
dc.contributor.authorStolk, Ronald P
dc.contributor.authorSorice, Rossella
dc.contributor.authorStrauch, Konstantin
dc.contributor.authorVölker, Uwe
dc.contributor.authorTan, Sian-Tsung
dc.contributor.authorTarasov, Kirill V
dc.contributor.authorHicks, Andrew A
dc.contributor.authorTrinh, Bosco
dc.contributor.authorJukema, J Wouter
dc.contributor.authorUitterlinden, Andre G
dc.contributor.authorvan den Boogaard, Malou
dc.contributor.authorvan Duijn, Cornelia M
dc.contributor.authorvan Gilst, Wiek H
dc.contributor.authorSnieder, Harold
dc.contributor.authorViikari, Jorma S
dc.contributor.authorWaldenberger, Melanie
dc.contributor.authorWeichenberger, Christian X
dc.contributor.authorWestra, Harm-Jan
dc.contributor.authorWijmenga, Cisca
dc.contributor.authorAndersen, Karl
dc.contributor.authorWolffenbuttel, Bruce H
dc.contributor.authorAbecasis, Gonçalo R
dc.contributor.authorWright, Alan F
dc.contributor.authorRudan, Igor
dc.contributor.authorBoyer, Laurie A
dc.contributor.authorAsselbergs, Folkert W
dc.contributor.authorDelitala, Alessandro
dc.contributor.authorvan Veldhuisen, Dirk J
dc.contributor.authorChakravarti, Aravinda
dc.contributor.authorStricker, Bruno H
dc.contributor.authorKääb, Stefan
dc.contributor.authorPsaty, Bruce M
dc.contributor.authorCiullo, Marina
dc.contributor.authorAdriaens, Michiel E
dc.contributor.authorSanna, Serena
dc.contributor.authorPolašek, Ozren
dc.contributor.authorLehtimäki, Terho
dc.contributor.authorWilson, James F
dc.contributor.authorBandinelli, Stefania
dc.contributor.authorJamshidi, Yalda
dc.contributor.authorAlonso, Alvaro
dc.contributor.authorGudnason, Vilmundur
dc.contributor.authorFelix, Stephan B
dc.contributor.authorHeckbert, Susan R
dc.contributor.authorTanaka, Toshiko
dc.contributor.authorde Boer, Rudolf A
dc.contributor.authorKähönen, Mika
dc.contributor.authorVisel, Axel
dc.contributor.authorChristoffels, Vincent M
dc.contributor.authorIsaacs, Aaron
dc.contributor.authorSamani, Nilesh J
dc.contributor.authorLundby, Alicia
dc.contributor.authorde Bakker, Paul I W
dc.contributor.authorLauner, Lenore J
dc.contributor.authorArking, Dan E
dc.contributor.authorUlivi, Sheila
dc.contributor.authorTrompet, Stella
dc.contributor.authorSilljé, Herman H W
dc.contributor.authorMüller-Nurasyid, Martina
dc.contributor.authorDevereux, Richard B
dc.contributor.authorSmith, Albert V
dc.contributor.authorDörr, Marcus
dc.contributor.authorKerr, Kathleen F
dc.contributor.authorBarnett, Phil
dc.contributor.authorMagnani, Jared W
dc.date.accessioned2016-09-29T11:08:28Z
dc.date.available2016-09-29T11:08:28Z
dc.date.issued2016-09-27
dc.date.submitted2016
dc.identifier.citation52 Genetic Loci Influencing Myocardial Mass. 2016, 68 (13):1435-48 J. Am. Coll. Cardiol.en
dc.identifier.issn1558-3597
dc.identifier.pmid27659466
dc.identifier.doi10.1016/j.jacc.2016.07.729
dc.identifier.urihttp://hdl.handle.net/2336/620027
dc.descriptionTo 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. This article is open access.en
dc.description.abstractMyocardial 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.
dc.description.abstractThis meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
dc.description.abstractWe 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.
dc.description.abstractWe 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.
dc.description.abstractTaken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
dc.language.isoenen
dc.publisherElsevier Biomedicalen
dc.relation.urlhttp://dx.doi.org/10.1016/j.jacc.2016.07.729en
dc.rightsArchived with thanks to Journal of the American College of Cardiologyen
dc.subjectHjartasjúkdómaren
dc.subjectArfgengien
dc.subjectCAR12
dc.subject.meshGenetic Loci/geneticsen
dc.subject.meshGenome-Wide Association Studyen
dc.subject.meshElectrocardiographyen
dc.subject.meshChromosomes, Human/geneticsen
dc.subject.meshHeart Conduction Systemen
dc.subject.meshHeart Failureen
dc.subject.meshHypertrophy, Left Ventricularen
dc.title52 Genetic Loci Influencing Myocardial Mass.en
dc.typeArticleen
dc.contributor.departmente a Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; b Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; c Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands; d Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; e Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; f Development, Aging and Regeneration, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; g Department of Genome Sciences, University of Washington, Seattle, Washington; h Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington; i Department of Pathology, New York University Langone Medical Center, New York, New York; j Institute for Systems Genetics, New York University Langone Medical Center, New York, New York; k Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; l Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; mDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; n Division of Cardiology, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; o MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland; p Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy; q Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland; r Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; s Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland; t Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; u Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia; v Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland; wCenter for Complex Disease Genomics, McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; x Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste, Italy; y Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; z Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands; aaDepartment of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; bbInstitute of Medical Informatics, Biometry and Epidemiology, Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; ccInstitute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany; ddDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Icelandic Heart Association, Kópavogur, Iceland; University of Iceland, Reykjavik, Iceland; ggDepartment of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; hhDZHK partner site, Greifswald, Germany; iiDepartment of Biostatistics, University of Washington, Seattle, Washington; jjSection of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; kkCenter for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany); llDepartment of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; mmEaling Hospital NHS Trust, Middlesex, United Kingdom; nnDepartment of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; ooGenetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; ppDoctoral Program in Biomedicalen
dc.identifier.journalJournal of the American College of Cardiologyen
dc.rights.accessOpen Accessen
dc.rights.accessOpen Accessen
refterms.dateFOA2018-09-12T16:16:40Z
html.description.abstractMyocardial 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.
html.description.abstractThis meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
html.description.abstractWe 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.
html.description.abstractWe 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.
html.description.abstractTaken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.


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