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

Dan E Arking; Sara L Pulit; Lia Crotti; Pim van der Harst; Patricia B Munroe; Tamara T Koopmann; Nona Sotoodehnia; Elizabeth J Rossin; Michael Morley; Xinchen Wang; Andrew D Johnson; Alicia Lundby; Daníel F Gudbjartsson; Peter A Noseworthy; Mark Eijgelsheim; Yuki Bradford; Kirill V Tarasov; Marcus Dörr; Martina Müller-Nurasyid; Annukka M Lahtinen; Ilja M Nolte; Albert Vernon Smith; Joshua C Bis; Aaron Isaacs; Stephen J Newhouse; Daniel S Evans; Wendy S Post; Daryl Waggott; Leo-Pekka Lyytikäinen; Andrew A Hicks; Lewin Eisele; David Ellinghaus; Caroline Hayward; Pau Navarro; Sheila Ulivi; Toshiko Tanaka; David J Tester; Stéphanie Chatel; Stefan Gustafsson; Meena Kumari; Richard W Morris; Åsa T Naluai; Sandosh Padmanabhan; Alexander Kluttig; Bernhard Strohmer; Andrie G Panayiotou; Maria Torres; Michael Knoflach; Jaroslav A Hubacek; Marcel den Hoed; CARe Consortium; Christopher H. Newton-Cheh

doi:10.1038/ng.3014

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

Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daníel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M LahtinenIlja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Åsa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Marcel den Hoed, CARe Consortium, Christopher H. Newton-Cheh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

Original language	English
Pages (from-to)	826-36
Number of pages	11
Journal	Nature Genetics
Volume	46
Issue number	8
DOIs	https://doi.org/10.1038/ng.3014
Publication status	Published - Aug 2014
Externally published	Yes

Keywords

Adult
Aged
Arrhythmias, Cardiac/genetics
Calcium Signaling/genetics
Death, Sudden, Cardiac/etiology
Electrocardiography/methods
Female
Genetic Predisposition to Disease
Genome-Wide Association Study/methods
Genotype
Heart Ventricles/metabolism
Humans
Long QT Syndrome/genetics
Male
Middle Aged
Myocardium/metabolism
Polymorphism, Single Nucleotide

Access to Document

10.1038/ng.3014Licence: Unspecified

Cite this

Arking, D. E., Pulit, S. L., Crotti, L., van der Harst, P., Munroe, P. B., Koopmann, T. T., Sotoodehnia, N., Rossin, E. J., Morley, M., Wang, X., Johnson, A. D., Lundby, A., Gudbjartsson, D. F., Noseworthy, P. A., Eijgelsheim, M., Bradford, Y., Tarasov, K. V., Dörr, M., Müller-Nurasyid, M., ... Newton-Cheh, C. H. (2014). Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature Genetics, 46(8), 826-36. https://doi.org/10.1038/ng.3014

@article{b0372a291a2441c7b1a7bef438544b00,

title = "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization",

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 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. ",

keywords = "Adult, Aged, Arrhythmias, Cardiac/genetics, Calcium Signaling/genetics, Death, Sudden, Cardiac/etiology, Electrocardiography/methods, Female, Genetic Predisposition to Disease, Genome-Wide Association Study/methods, Genotype, Heart Ventricles/metabolism, Humans, Long QT Syndrome/genetics, Male, Middle Aged, Myocardium/metabolism, Polymorphism, Single Nucleotide",

author = "Arking, {Dan E} and Pulit, {Sara L} and Lia Crotti and {van der Harst}, Pim and Munroe, {Patricia B} and Koopmann, {Tamara T} and Nona Sotoodehnia and Rossin, {Elizabeth J} and Michael Morley and Xinchen Wang and Johnson, {Andrew D} and Alicia Lundby and Gudbjartsson, {Dan{\'i}el F} and Noseworthy, {Peter A} and Mark Eijgelsheim and Yuki Bradford and Tarasov, {Kirill V} and Marcus D{\"o}rr and Martina M{\"u}ller-Nurasyid and Lahtinen, {Annukka M} and Nolte, {Ilja M} and Smith, {Albert Vernon} and Bis, {Joshua C} and Aaron Isaacs and Newhouse, {Stephen J} and Evans, {Daniel S} and Post, {Wendy S} and Daryl Waggott and Leo-Pekka Lyytik{\"a}inen and Hicks, {Andrew A} and Lewin Eisele and David Ellinghaus and Caroline Hayward and Pau Navarro and Sheila Ulivi and Toshiko Tanaka and Tester, {David J} and St{\'e}phanie Chatel and Stefan Gustafsson and Meena Kumari and Morris, {Richard W} and Naluai, {{\AA}sa T} and Sandosh Padmanabhan and Alexander Kluttig and Bernhard Strohmer and Panayiotou, {Andrie G} and Maria Torres and Michael Knoflach and Hubacek, {Jaroslav A} and {den Hoed}, Marcel and {CARe Consortium} and Newton-Cheh, {Christopher H.}",

year = "2014",

month = aug,

doi = "10.1038/ng.3014",

language = "English",

volume = "46",

pages = "826--36",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

Arking, DE, Pulit, SL, Crotti, L, van der Harst, P, Munroe, PB, Koopmann, TT, Sotoodehnia, N, Rossin, EJ, Morley, M, Wang, X, Johnson, AD, Lundby, A, Gudbjartsson, DF, Noseworthy, PA, Eijgelsheim, M, Bradford, Y, Tarasov, KV, Dörr, M, Müller-Nurasyid, M, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Isaacs, A, Newhouse, SJ, Evans, DS, Post, WS, Waggott, D, Lyytikäinen, L-P, Hicks, AA, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, DJ, Chatel, S, Gustafsson, S, Kumari, M, Morris, RW, Naluai, ÅT, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, AG, Torres, M, Knoflach, M, Hubacek, JA, den Hoed, M, CARe Consortium & Newton-Cheh, CH 2014, 'Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization', Nature Genetics, vol. 46, no. 8, pp. 826-36. https://doi.org/10.1038/ng.3014

TY - JOUR

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, Åsa T

AU - Padmanabhan, Sandosh

AU - Kluttig, Alexander

AU - Strohmer, Bernhard

AU - Panayiotou, Andrie G

AU - Torres, Maria

AU - Knoflach, Michael

AU - Hubacek, Jaroslav A

AU - den Hoed, Marcel

AU - CARe Consortium

AU - Newton-Cheh, Christopher H.

PY - 2014/8

Y1 - 2014/8

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.

KW - Adult

KW - Aged

KW - Arrhythmias, Cardiac/genetics

KW - Calcium Signaling/genetics

KW - Death, Sudden, Cardiac/etiology

KW - Electrocardiography/methods

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study/methods

KW - Genotype

KW - Heart Ventricles/metabolism

KW - Humans

KW - Long QT Syndrome/genetics

KW - Male

KW - Middle Aged

KW - Myocardium/metabolism

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/ng.3014

DO - 10.1038/ng.3014

M3 - Article

C2 - 24952745

SN - 1061-4036

VL - 46

SP - 826

EP - 836

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -