ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Nathan A. Bihlmeyer, Jennifer A. Brody, Albert Vernon Smith, Helen R. Warren, Honghuang Lin, Aaron Isaacs, Ching-Ti Liu, Jonathan Marten, Farid Radmanesh, Leanne M. Hall, Niels Grarup, Hao Mei, Martina Muller-Nurasyid, Jennifer E. Huffman, Niek Verweij, Xiuqing Guo, Jie Yao, Ruifang Li-Gao, Marten van den Berg, Stefan WeissBram P. Prins, Jessica van Setten, Jeffrey Haessler, Leo-Pekka Lyytikainen, Man Li, Alvaro Alonso, Elsayed Z. Soliman, Joshua C. Bis, Tom Austin, Yii-Der Ida Chen, Bruce M. Psaty, Tamara B. Harrris, Lenore J. Launer, Sandosh Padmanabhan, Anna Dominiczak, Paul L. Huang, Zhijun Xie, Patrick T. Ellinor, Jan A. Kors, Archie Campbell, Alison D. Murray, Christopher P. Nelson, Martin D. Tobin, Jette Bork-Jensen, Torben Hansen, Oluf Pedersen, Allan Linneberg, Moritz F. Sinner, Annette Peters, Melanie Waldenberger, Thomas Meitinger, Siegfried Perz, Ivana Kolcic, Igor Rudan, Rudolf A. de Boer, Peter van der Meer, Henry J. Lin, Kent D. Taylor, Renee de Mutsert, Stella Trompet, J. Wouter Jukema, Arie C. Maan, Bruno H. C. Stricker, Fernando Rivadeneira, Andre Uitterlinden, Uwe Volker, Georg Homuth, Henry Volzke, Stephan B. Felix, Massimo Mangino, Timothy D. Spector, Michiel L. Bots, Marco Perez, Olli T. Raitakari, Mika Kahonen, Nina Mononen, Vilmundur Gudnason, Patricia B. Munroe, Steven A. Lubitz, Cornelia M. van Duijn, Christopher H. Newton-Cheh, Caroline Hayward, Jonathan Rosand, Nilesh J. Samani, Jorgen K. Kanters, James G. Wilson, Stefan Kaab, Ozren Polasek, Pim van der Harst, Susan R. Heckbert, Jerome I. Rotter, Dennis O. Mook-Kanamori, Mark Eij-Gelsheim, Marcus Dorr, Yalda Jamshidi, Folkert W. Asselbergs, Charles Kooperberg, Terho Lehtimaki, Dan E. Arking*, Nona Sotoodehnia

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
Original languageEnglish
Article numbere001758
Number of pages63
JournalCirculation : Cardiovascular Genetics
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • arrhythmias, cardiac
  • death, sudden, cardiac
  • genetics
  • genome
  • humans
  • SUDDEN CARDIAC DEATH
  • GENERAL-POPULATION
  • COMMON VARIANTS
  • COHORT PROFILE
  • N-RAP
  • DESIGN
  • HEALTH
  • EPIDEMIOLOGY
  • GENETICS
  • HYPERTENSION

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