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Journal Article

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

Authors

  1. Dan E. Arking
  2. Sara L. Pulit
  3. Lia Crotti
  4. Pim van der Harst
  5. Patricia B. Munroe
  6. Tamara T. Koopmann
  7. Nona Sotoodehnia
  8. Elizabeth J. Rossin
  9. Michael Morley
  10. Xinchen Wang
  11. Andrew D. Johnson
  12. Alicia Lundby
  13. Daniel F. Gudbjartsson
  14. Peter A. Noseworthy
  15. Mark Eijgelsheim
  16. Yuki Bradford
  17. Kirill V. Tarasov
  18. Marcus Dorr
  19. Martina Muller-Nurasyid
  20. Annukka M. Lahtinen
  21. Ilja M. Nolte
  22. Albert Vernon Smith
  23. Joshua C. Bis
  24. Aaron Isaacs
  25. Stephen J. Newhouse
  26. Daniel S. Evans
  27. Wendy S. Post
  28. Daryl Waggott
  29. Leo-Pekka Lyytikainen
  30. Andrew A. Hicks
  31. Lewin Eisele
  32. David Ellinghaus
  33. Caroline Hayward
  34. Pau Navarro
  35. Sheila Ulivi
  36. Toshiko Tanaka
  37. David J. Tester
  38. Stephanie Chatel
  39. Stefan Gustafsson
  40. Meena Kumari
  41. Richard W. Morris
  42. Asa T. Naluai
  43. Sandosh Padmanabhan
  44. Alexander Kluttig
  45. Bernhard Strohmer
  46. Andrie G. Panayiotou
  47. Maria Torres
  48. Michael Knoflach
  49. Jaroslav A. Hubacek
  50. Kamil Slowikowski
  51. Soumya Raychaudhuri
  52. Runjun D. Kumar
  53. Tamara B. Harris
  54. Lenore J. Launer
  55. Alan R. Shuldiner
  56. Alvaro Alonso
  57. Joel S. Bader
  58. Georg Ehret
  59. Hailiang Huang
  60. W. H. Linda Kao
  61. James B. Strait
  62. Peter W. Macfarlane
  63. Morris Brown
  64. Mark J. Caulfield
  65. Nilesh J. Samani
  66. Florian Kronenberg
  67. Johann Willeit
  68. J. Gustav Smith
  69. Karin H. Greiser
  70. Henriette Meyer zu Schwabedissen
  71. Karl Werdan
  72. Massimo Carella
  73. Leopoldo Zelante
  74. Susan R. Heckbert
  75. Bruce M. Psaty
  76. Jerome I. Rotter
  77. Ivana Kolcic
  78. Ozren Polasek
  79. Alan F. Wright
  80. Maura Griffin
  81. Mark J. Daly
  82. David O. Arnar
  83. Hilma Holm
  84. Unnur Thorsteinsdottir
  85. Joshua C. Denny
  86. Dan M. Roden
  87. Rebecca L. Zuvich
  88. Valur Emilsson
  89. Andrew S. Plump
  90. Martin G. Larson
  91. Christopher J. O'Donnell
  92. Xiaoyan Yin
  93. Marco Bobbo
  94. Adamo P. D'Adamo
  95. Annamaria Iorio
  96. Gianfranco Sinagra
  97. Angel Carracedo
  98. Steven R. Cummings
  99. Michael A. Nalls
  100. Antti Jula
  101. Kimmo K. Kontula
  102. Annukka Marjamaa
  103. Lasse Oikarinen
  104. Markus Perola
  105. Kimmo Porthan
  106. Raimund Erbel
  107. Per Hoffmann
  108. Karl-Heinz Jockel
  109. Hagen Kalsch
  110. Markus M. Nothen
  111. Marcel den Hoed
  112. Ruth J. F. Loos
  113. Dag S. Thelle
  114. Christian Gieger
  115. Thomas Meitinger
  116. Siegfried Perz
  117. Annette Peters
  118. Hanna Prucha
  119. Moritz F. Sinner
  120. Melanie Waldenberger
  121. Rudolf A. de Boer
  122. Lude Franke
  123. Pieter A. van der Vleuten
  124. Britt Maria Beckmann
  125. Eimo Martens
  126. Abdennasser Bardai
  127. Nynke Hofman
  128. Arthur A. M. Wilde
  129. Elijah R. Behr
  130. Chrysoula Dalageorgou
  131. John R. Giudicessi
  132. Argelia Medeiros-Domingo
  133. Julien Barc
  134. Florence Kyndt
  135. Vincent Probst
  136. Alice Ghidoni
  137. Roberto Insolia
  138. Robert M. Hamilton
  139. Stephen W. Scherer
  140. Jeffrey Brandimarto
  141. Kenneth Margulies
  142. Christine E. Moravec
  143. Fabiola Del Greco M
  144. Christian Fuchsberger
  145. Jeffrey R. O'Connell
  146. Wai K. Lee
  147. Graham C. M. Watt
  148. Sarah H. Wild
  149. Nour E. El Mokhtari
  150. Norbert Frey
  151. Folkert W. Asselbergs
  152. Irene Mateo Leach
  153. Gerjan Navis
  154. Maarten P. van den Berg
  155. Dirk J. van Veldhuisen
  156. Manolis Kellis
  157. Bouwe P. Krijthe
  158. Oscar H. Franco
  159. Albert Hofman
  160. Jan A. Kors
  161. Andre G. Uitterlinden
  162. Jacqueline C. M. Witteman
  163. Lyudmyla Kedenko
  164. Claudia Lamina
  165. Ben A. Oostra
  166. Goncalo R. Abecasis
  167. Edward G. Lakatta
  168. Antonella Mulas
  169. Marco Orru
  170. David Schlessinger
  171. Manuela Uda
  172. Marcello R. P. Markus
  173. Uwe Völker
  174. Harold Snieder
  175. Timothy D. Spector
  176. Johan Arnlov
  177. Lars Lind
  178. Johan Sundström
  179. Ann-Christine Syvänen
  180. Mika Kivimaki
  181. Mika Kahonen
  182. Nina Mononen
  183. Olli T. Raitakari
  184. Jorma S. Viikari
  185. Vera Adamkova
  186. Stefan Kiechl
  187. Maria Brion
  188. Andrew N. Nicolaides
  189. Bernhard Paulweber
  190. Johannes Haerting
  191. Anna F. Dominiczak
  192. Fredrik Nyberg
  193. Peter H. Whincup
  194. Aroon D. Hingorani
  195. Jean-Jacques Schott
  196. Connie R. Bezzina
  197. Erik Ingelsson
  198. Luigi Ferrucci
  199. Paolo Gasparini
  200. James F. Wilson
  201. Igor Rudan
  202. Andre Franke
  203. Thomas W. Muhleisen
  204. Peter P. Pramstaller
  205. Terho J. Lehtimaki
  206. Andrew D. Paterson
  207. Afshin Parsa
  208. Yongmei Liu
  209. Cornelia M. van Duijn
  210. David S. Siscovick
  211. Vilmundur Gudnason
  212. Yalda Jamshidi
  213. Veikko Salomaa
  214. Stephan B. Felix
  215. Serena Sanna
  216. Marylyn D. Ritchie
  217. Bruno H. Stricker
  218. Kari Stefansson
  219. Laurie A. Boyer
  220. Thomas P. Cappola
  221. Jesper V. Olsen
  222. Kasper Lage
  223. Peter J. Schwartz
  224. Stefan Kaab
  225. Aravinda Chakravarti
  226. Michael J. Ackerman
  227. Arne Pfeufer
  228. Paul I. W. de Bakker
  229. Christopher Newton-Cheh

Publication date

Aug 2014

Summary

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 [sim]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.

Published in

Nature Genetics

Volume and page numbers

46 , 826 -836

DOI

http://dx.doi.org/10.1038/ng.3014

ISSN

16

Subjects

Medicine, Health, and Biology

Links

University of Essex, Albert Sloman Library Periodicals *restricted to University of Essex registered users* - http://serlib0.essex.ac.uk/record=b1680801~S5

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