Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. / Arking, Dan E; Pulit, Sara L; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B; Koopmann, Tamara T; Sotoodehnia, Nona; Rossin, Elizabeth J; 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, Asa T; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G; Torres, Maria; Knoflach, Michael; Olsen, Jesper V; Hansen, Kasper Lage; CARe Consortium.
I: Nature Genetics, Bind 46, Nr. 8, 22.06.2014, s. 826-838.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
AU - Arking, Dan E
AU - Pulit, Sara L
AU - Crotti, Lia
AU - van der Harst, Pim
AU - Munroe, Patricia B
AU - Koopmann, Tamara T
AU - Sotoodehnia, Nona
AU - Rossin, Elizabeth J
AU - Morley, Michael
AU - Wang, Xinchen
AU - Johnson, Andrew D
AU - Lundby, Alicia
AU - Gudbjartsson, Daníel F
AU - Noseworthy, Peter A
AU - Eijgelsheim, Mark
AU - Bradford, Yuki
AU - Tarasov, Kirill V
AU - Dörr, Marcus
AU - Müller-Nurasyid, Martina
AU - Lahtinen, Annukka M
AU - Nolte, Ilja M
AU - Smith, Albert Vernon
AU - Bis, Joshua C
AU - Isaacs, Aaron
AU - Newhouse, Stephen J
AU - Evans, Daniel S
AU - Post, Wendy S
AU - Waggott, Daryl
AU - Lyytikäinen, Leo-Pekka
AU - Hicks, Andrew A
AU - Eisele, Lewin
AU - Ellinghaus, David
AU - Hayward, Caroline
AU - Navarro, Pau
AU - Ulivi, Sheila
AU - Tanaka, Toshiko
AU - Tester, David J
AU - Chatel, Stéphanie
AU - Gustafsson, Stefan
AU - Kumari, Meena
AU - Morris, Richard W
AU - Naluai, Asa T
AU - Padmanabhan, Sandosh
AU - Kluttig, Alexander
AU - Strohmer, Bernhard
AU - Panayiotou, Andrie G
AU - Torres, Maria
AU - Knoflach, Michael
AU - Olsen, Jesper V
AU - Hansen, Kasper Lage
AU - CARe Consortium
PY - 2014/6/22
Y1 - 2014/6/22
N2 - 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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD.
AB - 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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD.
U2 - 10.1038/ng.3014
DO - 10.1038/ng.3014
M3 - Journal article
C2 - 24952745
VL - 46
SP - 826
EP - 838
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8
ER -
ID: 117861698