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

Nat Genet
Authors
Dan Arking
Sara Pulit
Lia Crotti
Pim van der Harst
Patricia Munroe
Tamara Koopmann
Nona Sotoodehnia
Elizabeth Rossin
Michael Morley
Xinchen Wang
Andrew Johnson
Alicia Lundby
Daniel Gudbjartsson
Peter Noseworthy
Mark Eijgelsheim
Yuki Bradford
Kirill Tarasov
Marcus Dorr
Martina Müller-Nurasyid
Annukka Lahtinen
Ilja Nolte
Albert Smith
Joshua Bis
Aaron Isaacs
Stephen Newhouse
Daniel Evans
Wendy Post
Daryl Waggott
Leo-Pekka Lyytikäinen
Andrew Hicks
Lewin Eisele
David Ellinghaus
Caroline Hayward
Pau Navarro
Sheila Ulivi
Toshiko Tanaka
David Tester
Stéphanie Chatel
Stefan Gustafsson
Meena Kumari
Richard Morris
Åsa Naluai
Sandosh Padmanabhan
Alexander Kluttig
Bernhard Strohmer
Andrie Panayiotou
Maria Torres
Michael Knoflach
Jaroslav Hubacek
Kamil Slowikowski
Soumya Raychaudhuri
Runjun Kumar
Tamara Harris
Lenore Launer
Alan Shuldiner
Alvaro Alonso
Joel Bader
Georg Ehret
Hailiang Huang
W Kao
James Strait
Peter Macfarlane
Morris Brown
Mark Caulfield
Nilesh Samani
Florian Kronenberg
Johann Willeit
CARe Consortium
COGENT Consortium
J Gustav Smith
Karin Greiser
Henriette Schwabedissen
Karl Werdan
Massimo Carella
Leopoldo Zelante
Susan Heckbert
Bruce Psaty
Jerome Rotter
Ivana Kolcic
Ozren Polasek
Alan Wright
Maura Griffin
Mark Daly
DCCT/EDIC
David Arnar
Hilma Holm
Unnur Thorsteinsdottir
eMERGE Consortium
Joshua Denny
Dan Roden
Rebecca Zuvich
Valur Emilsson
Andrew Plump
Martin Larson
Christopher O'Donnell
Xiaoyan Yin
Marco Bobbo
Adamo D'Adamo
Annamaria Iorio
Gianfranco Sinagra
Ángel Carracedo
Steven Cummings
Michael Nalls
Antti Jula
Kimmo Kontula
Annukka Marjamaa
Lasse Oikarinen
Markus Perola
Kimmo Porthan
Raimund Erbel
Per Hoffmann
Karl-Heinz Jöckel
Hagen Kälsch
Markus Nöthen
HRGEN Consortium
Marcel Hoed
Ruth Loos
Dag Thelle
Christian Gieger
Thomas Meitinger
Siegfried Perz
Annette Peters
Hanna Prucha
Moritz Sinner
Melanie Waldenberger
Rudolf de Boer
Lude Franke
Pieter van der Vleuten
Britt Beckmann
Eimo Martens
Abdennasser Bardai
Nynke Hofman
Arthur Wilde
Elijah Behr
Chrysoula Dalageorgou
John Giudicessi
Argelia Medeiros-Domingo
Julien Barc
Florence Kyndt
Vincent Probst
Alice Ghidoni
Roberto Insolia
Robert Hamilton
Stephen Scherer
Jeffrey Brandimarto
Kenneth Margulies
Christine Moravec
Fabiola M
Christian Fuchsberger
Jeffrey O'Connell
Wai Lee
Graham Watt
Harry Campbell
Sarah Wild
Nour Mokhtari
Norbert Frey
Folkert Asselbergs
Irene Leach
Gerjan Navis
Maarten van den Berg
Dirk van Veldhuisen
Manolis Kellis
Bouwe Krijthe
Oscar Franco
Albert Hofman
Jan Kors
André Uitterlinden
Jacqueline Witteman
Lyudmyla Kedenko
Claudia Lamina
Ben Oostra
Gonçalo Abecasis
Edward Lakatta
Antonella Mulas
Marco Orrú
David Schlessinger
Manuela Uda
Marcello Markus
Uwe Volker
Harold Snieder
Timothy Spector
Johan Ärnlöv
Lars Lind
Johan Sundstrom
Ann-Christine Syvänen
Mika Kivimaki
Mika Kähönen
Nina Mononen
Olli Raitakari
Jorma Viikari
Vera Adamkova
Stefan Kiechl
María Brion
Andrew Nicolaides
Bernhard Paulweber
Johannes Haerting
Anna Dominiczak
Fredrik Nyberg
Peter Whincup
Aroon Hingorani
Jean-Jacques Schott
Connie Bezzina
Erik Ingelsson
Luigi Ferrucci
Paolo Gasparini
James Wilson
Igor Rudan
Andre Franke
Thomas Mühleisen
Peter Pramstaller
Terho Lehtimäki
Andrew Paterson
Afshin Parsa
Yongmei Liu
Cornelia van Duijn
David Siscovick
Vilmundur Gudnason
Yalda Jamshidi
Veikko Salomaa
Stephan Felix
Serena Sanna
Marylyn Ritchie
Bruno Stricker
Kari Stefansson
Laurie Boyer
Thomas Cappola
Jesper Olsen
Kasper Lage
Peter Schwartz
Stefan Kääb
Aravinda Chakravarti
Michael Ackerman
Arne Pfeufer
Paul de Bakker
Christopher Newton-Cheh
Keywords
Female
Humans
Male
Adult
Aged
Genetic Predisposition to Disease
Genotype
Middle Aged
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Heart Ventricles
Calcium Signaling
Myocardium
Arrhythmias, Cardiac
Electrocardiography
Death, Sudden, Cardiac
Long QT Syndrome
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.
Year of Publication
2014
Journal
Nat Genet
Volume
46
Issue
8
Pages
826-36
Date Published
2014 Aug
ISSN
1546-1718
URL
http://dx.doi.org/10.1038/ng.3014
DOI
10.1038/ng.3014
PubMed ID
24952745
PubMed Central ID
PMC4124521
Links
Grant list
CZB/4/710 / Chief Scientist Office / United Kingdom
G9521010 / Medical Research Council / United Kingdom
U01 DK094176 / DK / NIDDK NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HG004037 / HG / NHGRI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 HL098283 / HL / NHLBI NIH HHS / United States
UL1 TR000114 / TR / NCATS NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MC_UU_12015/1 / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_U106179471 / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
MC_PC_U127592696 / Medical Research Council / United Kingdom
G0701863 / Medical Research Council / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
UL1 TR000142 / TR / NCATS NIH HHS / United States
MR/K006584/1 / Medical Research Council / United Kingdom
MR/K013351/1 / Medical Research Council / United Kingdom
RG/13/16/30528 / British Heart Foundation / United Kingdom
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL113933 / HL / NHLBI NIH HHS / United States
K23 HL080025 / HL / NHLBI NIH HHS / United States
PG/12/38/29615 / British Heart Foundation / United Kingdom
R01 HL111267 / HL / NHLBI NIH HHS / United States
RG/10/12/28456 / British Heart Foundation / United Kingdom

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