ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals
Authors: Bihlmeyer Nathan A. , Brody Jennifer A. , Smith Albert Vernon , Warren Helen R. , Lin Honghuang , Isaacs Aaron , Liu Ching-Ti , Marten Jonathan , Radmanesh Farid , Hall Leanne M. , Grarup Niels , Mei Hao , Müller-Nurasyid Martina , Huffman Jennifer E. , Verweij Niek , Guo Xiuqing , Yao Jie , Li-Gao Ruifang , van den Berg Marten , Weiss Stefan , Prins Bram P. , van Setten Jessica , Haessler Jeffrey , Lyytikäinen Leo-Pekka , Li Man , Alonso Alvaro , Soliman Elsayed Z. , Bis Joshua C. , Austin Tom , Chen Yii-Der Ida , Psaty Bruce M. , Harrris Tamara B. , Launer Lenore J. , Padmanabhan Sandosh , Dominiczak Anna , Huang Paul L. , Xie Zhijun , Ellinor Patrick T. , Kors Jan A. , Campbell Archie , Murray Alison D. , Nelson Christopher P. , Tobin Martin D. , Bork-Jensen Jette , Hansen Torben , Pedersen Oluf , Linneberg Allan , Sinner Moritz F. , Peters Annette , Waldenberger Melanie , Meitinger Thomas , Perz Siegfried , Kolcic Ivana , Rudan Igor , de Boer Rudolf A. , van der Meer Peter , Lin Henry J. , Taylor Kent D. , de Mutsert Renée , Trompet Stella , Jukema J. Wouter , Maan Arie C. , Stricker Bruno H.C. , Rivadeneira Fernando , Uitterlinden André , Völker Uwe , Homuth Georg , Völzke Henry , Felix Stephan B. , Mangino Massimo , Spector Timothy D. , Bots Michiel L. , Perez Marco , Raitakari Olli T. , Kähönen Mika , Mononen Nina , Gudnason Vilmundur , Munroe Patricia B. , Lubitz Steven A. , van Duijn Cornelia M. , Newton-Cheh Christopher H. , Hayward Caroline , Rosand Jonathan , Samani Nilesh J. , Kanters Jørgen K. , Wilson James G. , Kääb Stefan , Polasek Ozren , van der Harst Pim , Heckbert Susan R. , Rotter Jerome I. , Mook-Kanamori Dennis O. , Eijgelsheim Mark , Dörr Marcus , Jamshidi Yalda , Asselbergs Folkert W. , Kooperberg Charles , Lehtimäki Terho , Arking Dan E. , Sotoodehnia Nona 
Published: October 2018

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.