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

TitleExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.
Publication TypeJournal Article
Year of Publication2018
AuthorsBihlmeyer NA, Brody JA, Smith A V, Warren HR, Lin H, Isaacs A, Liu C-T, Marten J, Radmanesh F, Hall LM, Grarup N, Mei H, Müller-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, Lyytikäinen L-P, Li M, Alonso A, Soliman EZ, Bis JC, Austin T, Chen Y-D I, 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, J Jukema W, Maan AC, Stricker BHC, Rivadeneira F, Uitterlinden A, Völker U, Homuth G, Völzke H, Felix SB, Mangino M, Spector TD, Bots ML, Perez M, Raitakari OT, Kähönen 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, Kääb S, Polasek O, van der Harst P, Heckbert SR, Rotter JI, Mook-Kanamori DO, Eijgelsheim M, Dörr M, Jamshidi Y, Asselbergs FW, Kooperberg C, Lehtimäki T, Arking DE
Secondary AuthorsSotoodehnia N
JournalCirc Genom Precis Med
Date Published2018 01
KeywordsAntiporters, DNA-Binding Proteins, Electrocardiography, Exome, Genome-Wide Association Study, Humans, Long QT Syndrome, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Calcium-Sensing, Transcription Factors

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.

Alternate JournalCirc Genom Precis Med
PubMed ID29874175
PubMed Central IDPMC5992491
Grant ListT32 GM007814 / GM / NIGMS NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
MR/M004422/1 / / Medical Research Council / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
R01 HL111089 / HL / NHLBI NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States