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

Bihlmeyer, NA; Brody, JA; Smith, AV; Warren, HR; Lin, H; Isaacs, A; Liu, C-T; Marten, J; Radmanesh, F; Hall, LM; et al. Bihlmeyer, NA; Brody, JA; Smith, AV; Warren, HR; Lin, H; Isaacs, A; Liu, C-T; Marten, J; Radmanesh, F; Hall, LM; Grarup, N; Mei, H; Muller-Nurasyid, M; Huffman, JE; Verweij, N; Guo, X; Yao, J; Li-Gao, R; van den Berg, M; Weiss, S; Prins, BP; van Setten, J; Haessler, J; Lyytikainen, L-P; Li, M; Alonso, A; Soliman, EZ; Bis, JC; Austin, T; Chen, Y-DI; Psaty, BM; Harrris, TB; Launer, LJ; Padmanabhan, S; Dominiczak, A; Huang, PL; Xie, Z; Ellinor, PT; Kors, JA; Campbell, A; Murray, AD; Nelson, CP; Tobin, MD; Bork-Jensen, J; Hansen, T; Pedersen, O; Linneberg, A; Sinner, MF; Peters, A; Waldenberger, M; Meitinger, T; Perz, S; Kolcic, I; Rudan, I; de Boer, RA; van der Meer, P; Lin, HJ; Taylor, KD; de Mutsert, R; Trompet, S; Jukema, JW; Maan, AC; Stricker, BHC; Rivadeneira, F; Uitterlinden, A; Volker, U; Homuth, G; Volzke, H; Felix, SB; Mangino, M; Spector, TD; Bots, ML; Perez, M; Raitakari, OT; Kahonen, M; Mononen, N; Gudnason, V; Munroe, PB; Lubitz, SA; van Duijn, CM; Newton-Cheh, CH; Hayward, C; Rosand, J; Samani, NJ; Kanters, JK; Wilson, JG; Kaab, S; Polasek, O; van der Harst, P; Heckbert, SR; Rotter, JI; Mook-Kanamori, DO; Eij-Gelsheim, M; Dorr, M; Jamshidi, Y; Asselbergs, FW; Kooperberg, C; Lehtimaki, T; Arking, DE; Sotoodehnia, N (2018) ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. Circulation: Genomic and Precision Medicine, 11 (1). e001758. ISSN 1942-325X https://doi.org/10.1161/CIRCGEN.117.001758
SGUL Authors: Jamshidi, Yalda

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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.

Item Type: Article
Additional Information: © 2018 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Keywords: arrhythmias, cardiac, death, sudden, cardiac, genetics, genome, humans, Cardiovascular System & Hematology, 0604 Genetics, 1102 Cardiovascular Medicine And Haematology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Circulation: Genomic and Precision Medicine
ISSN: 1942-325X
Dates:
DateEvent
11 January 2018Published
3 October 2017Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
5T32GM07814National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
R01HL116747National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
R01 HL111089National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
DGE-1232825National Science Foundationhttp://dx.doi.org/10.13039/100000001
Web of Science ID: WOS:000428988100003
URI: https://openaccess.sgul.ac.uk/id/eprint/109747
Publisher's version: https://doi.org/10.1161/CIRCGEN.117.001758

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