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

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Exomechip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated with QT and JT Intervals 1 humans ◼ Circulation: Dan E. January 2018 Creative Commons Creative genome arrhythmias, cardiac arrhythmias, cardiac ◼ License, which permits PhD et al death, sudden, cardiac death, sudden, cardiac genetics The full author list is available on page 7. to: Correspondence Arking, PhD, Johns Hopkins School of Medicine, 733 N. Broadway, MD 21205. MRB 459, Baltimore, E-mail [email protected] Key Words: ◼ ◼ © 2018 The Authors. Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., Kluwer Health, Inc. This by Wolters is an open access article under the terms of the Attribution Non-Commercial- NoDerivs use, distribution, and reproduction that the in any medium, provided cited, original work is properly and no the use is noncommercial, modifications or adaptations are made. Nathan A. Bihlmeyer, Nathan A. Bihlmeyer, 626 626 individuals 626 individuals 449 variants, both common 449 variants, both common 884 European ancestry individuals, 884 European We performed an ExomeChip-wide analysis performed an ExomeChip-wide analysis We Editorial by Bos and Pereira See 2018;11:e001758. DOI: 10.1161/CIRCGEN.117.001758 QT interval, measured through a standard ECG, captures ECG, captures a standard through QT interval, measured Our analyses show a role for myocyte internal Our analyses show a role structure 341 genes from the Illumina Infinium HumanExome 341 genes from e, in 17 om 23 cohorts (comprised 83 Circ Genom Precis Med. and rar CONCLUSIONS: in modulating QT interval duration, adding to and interconnections of potassium, sodium, and calcium ion regulation, known roles previous anticipate that these discoveries will We as well as autonomic control. for the prevention open new paths to the goal of making novel remedies arrest. of lethal ventricular arrhythmias and sudden cardiac BeadChip. We identified 10 loci that modulate QT and JT interval identified 10 loci that modulate QT and JT interval BeadChip. We using in the literature reported duration that have not been previously single-variant statistical models in a meta-analysis of 95 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total associated loci to 45. In addition, number of ventricular repolarization of 17 of using coding variants has highlighted the role our approach repolarization, 7 of which specific genes for involvement in ventricular in novel loci. are METHODS AND RESULTS: for both QT and JT intervals, including 209 BACKGROUND: ventricles to depolarize and repolarize. the time it takes for the cardiac ventricular JT interval is the component of the QT interval that reflects QT interval has been linked to higher risk alone. Prolonged repolarization arrest. of sudden cardiac Associated With QT and JT Intervals Individuals Identifies 10 Novel Loci fr ExomeChip-Wide Analysis of 95 ORIGINAL ARTICLE Downloaded from http://circgenetics.ahajournals.org/ by guest on June 8, 2018 Bihlmeyer et al; ExomeChip Identifies 10 Novel QT Loci individuals and are caused by variants in ion chan- Clinical Perspective nels or their interacting proteins.4 Previous candidate gene and genome-wide association studies (GWAS), Prolonged QT interval has been associated with largely screening common noncoding variants, have increased risk of sudden cardiac arrest, a major identified 35 loci containing variants that modestly cause of mortality, with between 180 000 and influence QT interval, the largest of these studies, the 450 000 cases of sudden cardiac arrest in the QT Interval International GWAS Consortium (QT-IGC),5 United States of America annually. Because the included a discovery population of 76 061 European vast majority of sudden cardiac arrest occurs in ancestry individuals. the absence of clinical features that would bring In this study, we conduct ExomeChip-wide analyses a victim to medical attention, identifying addi- in population-based samples to interrogate the role of a tional risk factors and dissecting the pathogen- largely unstudied class of variation on ventricular repo- esis of disease are of high importance. In this larization in the population—coding single nucleotide study, we conduct ExomeChip-wide analyses in variants (SNVs). These variants fill in the gap between 95 626 population-based multiethnic individu- the extremely rare large-effect coding variants that als to interrogate the role of a largely unstudied result in the Mendelian long- and short-QT syndromes class of variation on ventricular repolarization in and the common small-effect largely noncoding varia- Downloaded from the population—coding single nucleotide vari- tion identified through GWAS. The focus on exons and ants. These variants fill in the gap between the coding variants has an added benefit of directly impli- extremely rare large-effect coding variants that cating genes. By contrast, noncoding variation typically result in the Mendelian long- and short-QT syn- implicates a region of the genome, often containing dromes and the common small-effect largely multiple genes, and therefore requiring extensive func- http://circgenetics.ahajournals.org/ noncoding variation identified through genome- tional experiments to implicate a specific gene. Further- wide association studies. The focus on exons and more, in this study, we examine both QT and JT interval coding variants has an added benefit of directly to more comprehensively examine ventricular repolar- implicating genes. Our approach of focusing on ization. We have previously observed that variation in coding variants and both QT and JT intervals specific loci can influence ventricular depolarization and measures has identified 10 novel loci associated repolarization in a concordant fashion.5,6 with ventricular repolarization and has implicated We performed a meta-analysis of 23 cohorts includ- 17 specific genes, 7 of which are in novel loci. ing 95 626 multiethnic individuals comprised 83 884 Our analyses show a role for myocyte internal European ancestry individuals, 9610 blacks, 1382 His- by guest on June 8, 2018 structure and interconnections in modulating QT panics, and 750 Asian individuals (Table I in the in the interval duration, adding to previous known roles Data Supplement). Each individual was genotyped for of potassium, sodium, and calcium ion regula- 191 740 coding SNVs in 17 341 genes using the Illu- tion, as well as autonomic control. We anticipate mina Infinium HumanExome BeadChip (ExomeChip), that these discoveries will open new paths to the along with 17 709 noncoding SNVs of known impor- goal of making novel remedies for the prevention tance from previous GWAS and variants tiling across of lethal ventricular arrhythmias and sudden car- the genome. These variants were chosen by evaluat- diac arrest. ing ≈12 000 exome sequences for coding variants that appeared in at least 3 individuals. rolonged QT interval has been associated with in- creased risk of sudden cardiac arrest (SCA), a ma- METHODS jor cause of mortality, with between 180 000 and The data, analytic methods, and study materials will be made P available to other researchers for purposes of reproducing 450 000 cases of SCA in the United States of America 1 the results, subject to Data Use/Sharing Agreements adopted annually. Because the vast majority of SCA occurs in by individual participating cohorts. GWAS summary results the absence of clinical features that would bring a vic- will be available through the CHARGE Consortium Summary 2 tim to medical attention, identifying additional risk fac- Results webpage available at dbGaP (phs000930). tors and dissecting the pathogenesis of disease are of This study was approved by local institutional review high importance. boards, and all participating subjects gave informed consent Heritability estimates of QT interval are between (detailed ethics statements in the Data Supplement). 30% and 40%, indicating that genetic variants play a large role in modulating QT interval in the general pop- SNV Association Tests and Meta-Analysis ulation.3 Mendelian syndromes of QT interval (long- Detailed methods are provided in the Data Supplement. and short-QT syndrome), which lead to increased risk Briefly, all cohorts excluded individuals with QRS intervals of cardiac arrhythmias and SCA, occur in ≈1 in 2000 ≥120 ms, heart rate <40 beats per minute or >120 beats per Circ Genom Precis Med. 2018;11:e001758. DOI: 10.1161/CIRCGEN.117.001758 January 2018 2 Bihlmeyer et al; ExomeChip Identifies 10 Novel QT Loci minute , left or right bundle branch block, atrial fibrillation on RESULTS baseline ECG, Wolff–Parkinson–White syndrome, pacemaker, use of class I or class III blocking medication, or pregnant. QT Interval ExomeChip Analysis Clinical characteristics summary statistics for each cohort are Identifies 6 Novel Loci provided in Table I in the Data Supplement. SNV effect size estimates are calculated via standard Meta-analysis identified SNVs in 25 loci associated with −7 inverse variance–weighted meta-analysis of results provided QT interval at ExomeChip-wide significance (P<2×10 ; by each cohort from a linear association model with QT/JT Figure I in the Data Supplement). Of these, 19 loci as the dependent variable, including covariates age, sex, RR were previously associated with QT interval, and 6 loci interval (inverse heart rate), height, body mass index, and were novel (Table 1). At 4 of these novel loci (PM20D1, cohort-specific adjustments (principal components, clinic, SLC4A3, CASR, and NRAP), the top hit is a nonsynony- family structure). Significance is similarly calculated by inverse
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