Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

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Author
Arking, Dan E.
Pulit, Sara L.
Crotti, Lia
van der Harst, Pim
Munroe, Patricia B.
Koopmann, Tamara T.
Sotoodehnia, Nona
Morley, Michael
Wang, Xinchen
Johnson, Andrew D.
Lundby, Alicia
Gudbjartsson, Daníel F.
Noseworthy, Peter A.
Eijgelsheim, Mark
Bradford, Yuki
Tarasov, Kirill V.
Dörr, Marcus
Müller-Nurasyid, Martina
Lahtinen, Annukka M.
Nolte, Ilja M.
Smith, Albert Vernon
Bis, Joshua C.
Isaacs, Aaron
Newhouse, Stephen J.
Evans, Daniel S.
Post, Wendy S.
Waggott, Daryl
Lyytikäinen, Leo-Pekka
Hicks, Andrew A.
Eisele, Lewin
Ellinghaus, David
Hayward, Caroline
Navarro, Pau
Ulivi, Sheila
Tanaka, Toshiko
Tester, David J.
Chatel, Stéphanie
Gustafsson, Stefan
Kumari, Meena
Morris, Richard W.
Naluai, Åsa T.
Padmanabhan, Sandosh
Kluttig, Alexander
Strohmer, Bernhard
Panayiotou, Andrie G.
Torres, Maria
Knoflach, Michael
Hubacek, Jaroslav A.
Kumar, Runjun D.
Harris, Tamara B.
Launer, Lenore J.
Shuldiner, Alan R.
Alonso, Alvaro
Bader, Joel S.
Ehret, Georg
Kao, W.H. Linda
Strait, James B.
Macfarlane, Peter W.
Brown, Morris
Caulfield, Mark J.
Samani, Nilesh J.
Kronenberg, Florian
Willeit, Johann
Smith, J. Gustav
Greiser, Karin H.
zu Schwabedissen, Henriette Meyer
Werdan, Karl
Carella, Massimo
Zelante, Leopoldo
Heckbert, Susan R.
Psaty, Bruce M.
Rotter, Jerome I.
Kolcic, Ivana
Polašek, Ozren
Wright, Alan F.
Griffin, Maura
Arnar, David O.
Hólm, Hilma
Thorsteinsdottir, Unnur
Denny, Joshua C.
Roden, Dan M.
Zuvich, Rebecca L.
Emilsson, Valur
Plump, Andrew S.
Larson, Martin G.
Yin, Xiaoyan
Bobbo, Marco
D'Adamo, Adamo P.
Iorio, Annamaria
Sinagra, Gianfranco
Carracedo, Angel
Cummings, Steven R.
Nalls, Michael A.
Jula, Antti
Kontula, Kimmo K.
Marjamaa, Annukka
Oikarinen, Lasse
Perola, Markus
Porthan, Kimmo
Erbel, Raimund
Hoffmann, Per
Jöckel, Karl-Heinz
Kälsch, Hagen
Nöthen, Markus M.
consortium, HRGEN
den Hoed, Marcel
Loos, Ruth J.F.
Thelle, Dag S.
Gieger, Christian
Meitinger, Thomas
Perz, Siegfried
Peters, Annette
Prucha, Hanna
Sinner, Moritz F.
Waldenberger, Melanie
de Boer, Rudolf A.
Franke, Lude
van der Vleuten, Pieter A.
Beckmann, Britt Maria
Martens, Eimo
Bardai, Abdennasser
Hofman, Nynke
Wilde, Arthur A.M.
Behr, Elijah R.
Dalageorgou, Chrysoula
Giudicessi, John R.
Medeiros-Domingo, Argelia
Barc, Julien
Kyndt, Florence
Probst, Vincent
Ghidoni, Alice
Insolia, Roberto
Hamilton, Robert M.
Scherer, Stephen W.
Brandimarto, Jeffrey
Margulies, Kenneth
Moravec, Christine E.
Fabiola Del, Greco M.
Fuchsberger, Christian
O'Connell, Jeffrey R.
Lee, Wai K.
Watt, Graham C.M.
Campbell, Harry
Wild, Sarah H.
El Mokhtari, Nour E.
Frey, Norbert
Asselbergs, Folkert W.
Leach, Irene Mateo
Navis, Gerjan
van den Berg, Maarten P.
van Veldhuisen, Dirk J.
Kellis, Manolis
Krijthe, Bouwe P.
Franco, Oscar H.
Hofman, Albert
Kors, Jan A.
Uitterlinden, André G.
Witteman, Jacqueline C.M.
Kedenko, Lyudmyla
Lamina, Claudia
Oostra, Ben A.
Abecasis, Gonçalo R.
Lakatta, Edward G.
Mulas, Antonella
Orrú, Marco
Schlessinger, David
Uda, Manuela
Markus, Marcello R.P.
Völker, Uwe
Snieder, Harold
Spector, Timothy D.
Ärnlöv, Johan
Lind, Lars
Sundström, Johan
Syvänen, Ann-Christine
Kivimaki, Mika
Kähönen, Mika
Mononen, Nina
Raitakari, Olli T.
Viikari, Jorma S.
Adamkova, Vera
Kiechl, Stefan
Brion, Maria
Nicolaides, Andrew N.
Paulweber, Bernhard
Haerting, Johannes
Dominiczak, Anna F.
Nyberg, Fredrik
Whincup, Peter H.
Hingorani, Aroon
Schott, Jean-Jacques
Bezzina, Connie R.
Ingelsson, Erik
Ferrucci, Luigi
Gasparini, Paolo
Wilson, James F.
Rudan, Igor
Franke, Andre
Mühleisen, Thomas W.
Pramstaller, Peter P.
Lehtimäki, Terho J.
Paterson, Andrew D.
Parsa, Afshin
Liu, Yongmei
van Duijn, Cornelia
Siscovick, David S.
Gudnason, Vilmundur
Jamshidi, Yalda
Salomaa, Veikko
Felix, Stephan B.
Sanna, Serena
Ritchie, Marylyn D.
Stricker, Bruno H.
Stefansson, Kari
Boyer, Laurie A.
Cappola, Thomas P.
Olsen, Jesper V.
Lage, Kasper
Schwartz, Peter J.
Kääb, Stefan
Chakravarti, Aravinda
Ackerman, Michael J.
Pfeufer, Arne
de Bakker, Paul I.W.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ng.3014Metadata
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Arking, D. E., S. L. Pulit, L. Crotti, P. van der Harst, P. B. Munroe, T. T. Koopmann, N. Sotoodehnia, et al. 2014. “Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.” Nature genetics 46 (8): 826-836. doi:10.1038/ng.3014. http://dx.doi.org/10.1038/ng.3014.Abstract
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124521/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065318
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(Nature Publishing Group, 2016)Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular ... -
New genetic loci link adipose and insulin biology to body fat distribution
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Barroso, Inês; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth JF; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L (2014)Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and ...