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 Müller-Nurasyid; Jennifer E Huffman; Niek Verweij; Xiuqing Guo; Jie Yao; Ruifang Li-Gao; Marten van den Berg; Stefan Weiss; Bram P Prins; Jessica van Setten; Jeffrey Haessler; Leo-Pekka Lyytikäinen; 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; Renée de Mutsert; Stella Trompet; J Wouter Jukema; Arie C Maan; Bruno H C Stricker; Fernando Rivadeneira; André Uitterlinden; Uwe Völker; Georg Homuth; Henry Völzke; Stephan B Felix; Massimo Mangino; Timothy D Spector; Michiel L Bots; Marco Perez; Olli T Raitakari; Mika Kähönen; 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; Jørgen K Kanters; James G Wilson; Stefan Kääb; Ozren Polasek; Pim van der Harst; Susan R Heckbert; Jerome I Rotter; Dennis O Mook-Kanamori; Mark Eijgelsheim; Marcus Dörr; Yalda Jamshidi; Folkert W Asselbergs; Charles Kooperberg; Terho Lehtimäki; Dan E Arking; Nona Sotoodehnia

doi:10.1161/CIRCGEN.117.001758

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 Müller-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 Lyytikäinen, 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, Renée de Mutsert, Stella Trompet, J Wouter Jukema, Arie C Maan, Bruno H C Stricker, Fernando Rivadeneira, André Uitterlinden, Uwe Völker, Georg Homuth, Henry Völzke, Stephan B Felix, Massimo Mangino, Timothy D Spector, Michiel L Bots, Marco Perez, Olli T Raitakari, Mika Kähönen, 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, Jørgen K Kanters, James G Wilson, Stefan Kääb, Ozren Polasek, Pim van der Harst, Susan R Heckbert, Jerome I Rotter, Dennis O Mook-Kanamori, Mark Eijgelsheim, Marcus Dörr, Yalda Jamshidi, Folkert W Asselbergs, Charles Kooperberg, Terho Lehtimäki, Dan E Arking, Nona Sotoodehnia

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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 language	English
Article number	e001758
Journal	Circulation. Genomic and precision medicine
Volume	11
Issue number	1
Early online date	11 Jan 2018
DOIs	https://doi.org/10.1161/CIRCGEN.117.001758
Publication status	Published - Jan 2018

Bibliographical note

Funded in part by training grant (National Institute of General Medical Sciences) 5T32GM07814 (Dr Bihlmeyer ), and R01HL116747 (Drs Arking, Bihlmeyer, and Sotoodehnia), and R01 HL111089 (Drs Sotoodehnia and Arking). Dr Sotoodehnia is also supported by the Laughlin Family. This material is based on work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1232825 (Dr Bihlmeyer). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.

Keywords

Journal Article
arrhythmias, cardiac
death, sudden, cardiac
genetics
genome
humans

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10.1161/CIRCGEN.117.001758Licence: CC BY-NC-ND

ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals
© 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-CommercialNoDerivs 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. https://creativecommons.org/licenses/by-nc-nd/4.0/
Final published version, 3.08 MBLicence: CC BY-NC-ND

Cite this

Bihlmeyer, N. A., Brody, J. A., Smith, A. V., Warren, H. R., Lin, H., Isaacs, A., Liu, C-T., Marten, J., Radmanesh, F., Hall, L. M., Grarup, N., Mei, H., Müller-Nurasyid, M., Huffman, J. E., Verweij, N., Guo, X., Yao, J., Li-Gao, R., van den Berg, M., ... 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]. https://doi.org/10.1161/CIRCGEN.117.001758

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, 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-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, 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 & 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, vol. 11, no. 1, e001758. https://doi.org/10.1161/CIRCGEN.117.001758

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

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.",

keywords = "Journal Article, arrhythmias, cardiac, death, sudden, cardiac, genetics, genome , humans",

author = "Bihlmeyer, {Nathan A} and Brody, {Jennifer A} and Smith, {Albert Vernon} and Warren, {Helen R} and Honghuang Lin and Aaron Isaacs and Ching-Ti Liu and Jonathan Marten and Farid Radmanesh and Hall, {Leanne M} and Niels Grarup and Hao Mei and Martina M{\"u}ller-Nurasyid and Huffman, {Jennifer E} and Niek Verweij and Xiuqing Guo and Jie Yao and Ruifang Li-Gao and {van den Berg}, Marten and Stefan Weiss and Prins, {Bram P} and {van Setten}, Jessica and Jeffrey Haessler and Leo-Pekka Lyytik{\"a}inen and Man Li and Alvaro Alonso and Soliman, {Elsayed Z} and Bis, {Joshua C} and Tom Austin and Chen, {Yii-Der Ida} and Psaty, {Bruce M} and Harrris, {Tamara B} and Launer, {Lenore J} and Sandosh Padmanabhan and Anna Dominiczak and Huang, {Paul L} and Zhijun Xie and Ellinor, {Patrick T} and Kors, {Jan A} and Archie Campbell and Murray, {Alison D} and Nelson, {Christopher P} and Tobin, {Martin D} and Jette Bork-Jensen and Torben Hansen and Oluf Pedersen and Allan Linneberg and Sinner, {Moritz F} and Annette Peters and Melanie Waldenberger and Thomas Meitinger and Siegfried Perz and Ivana Kolcic and Igor Rudan and {de Boer}, {Rudolf A} and {van der Meer}, Peter and Lin, {Henry J} and Taylor, {Kent D} and {de Mutsert}, Ren{\'e}e and Stella Trompet and Jukema, {J Wouter} and Maan, {Arie C} and Stricker, {Bruno H C} and Fernando Rivadeneira and Andr{\'e} Uitterlinden and Uwe V{\"o}lker and Georg Homuth and Henry V{\"o}lzke and Felix, {Stephan B} and Massimo Mangino and Spector, {Timothy D} and Bots, {Michiel L} and Marco Perez and Raitakari, {Olli T} and Mika K{\"a}h{\"o}nen and Nina Mononen and Vilmundur Gudnason and Munroe, {Patricia B} and Lubitz, {Steven A} and {van Duijn}, {Cornelia M} and Newton-Cheh, {Christopher H} and Caroline Hayward and Jonathan Rosand and Samani, {Nilesh J} and Kanters, {J{\o}rgen K} and Wilson, {James G} and Stefan K{\"a}{\"a}b and Ozren Polasek and {van der Harst}, Pim and Heckbert, {Susan R} and Rotter, {Jerome I} and Mook-Kanamori, {Dennis O} and Mark Eijgelsheim and Marcus D{\"o}rr and Yalda Jamshidi and Asselbergs, {Folkert W} and Charles Kooperberg and Terho Lehtim{\"a}ki and Arking, {Dan E} and Nona Sotoodehnia",

note = "Funded in part by training grant (National Institute of General Medical Sciences) 5T32GM07814 (Dr Bihlmeyer ), and R01HL116747 (Drs Arking, Bihlmeyer, and Sotoodehnia), and R01 HL111089 (Drs Sotoodehnia and Arking). Dr Sotoodehnia is also supported by the Laughlin Family. This material is based on work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1232825 (Dr Bihlmeyer). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.",

year = "2018",

month = jan,

doi = "10.1161/CIRCGEN.117.001758",

language = "English",

volume = "11",

journal = "Circulation. Genomic and precision medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "1",

}

TY - JOUR

T1 - ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

AU - Bihlmeyer, Nathan A

AU - Brody, Jennifer A

AU - Smith, Albert Vernon

AU - Warren, Helen R

AU - Lin, Honghuang

AU - Isaacs, Aaron

AU - Liu, Ching-Ti

AU - Marten, Jonathan

AU - Radmanesh, Farid

AU - Hall, Leanne M

AU - Grarup, Niels

AU - Mei, Hao

AU - Müller-Nurasyid, Martina

AU - Huffman, Jennifer E

AU - Verweij, Niek

AU - Guo, Xiuqing

AU - Yao, Jie

AU - Li-Gao, Ruifang

AU - van den Berg, Marten

AU - Weiss, Stefan

AU - Prins, Bram P

AU - van Setten, Jessica

AU - Haessler, Jeffrey

AU - Lyytikäinen, Leo-Pekka

AU - Li, Man

AU - Alonso, Alvaro

AU - Soliman, Elsayed Z

AU - Bis, Joshua C

AU - Austin, Tom

AU - Chen, Yii-Der Ida

AU - Psaty, Bruce M

AU - Harrris, Tamara B

AU - Launer, Lenore J

AU - Padmanabhan, Sandosh

AU - Dominiczak, Anna

AU - Huang, Paul L

AU - Xie, Zhijun

AU - Ellinor, Patrick T

AU - Kors, Jan A

AU - Campbell, Archie

AU - Murray, Alison D

AU - Nelson, Christopher P

AU - Tobin, Martin D

AU - Bork-Jensen, Jette

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Linneberg, Allan

AU - Sinner, Moritz F

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Meitinger, Thomas

AU - Perz, Siegfried

AU - Kolcic, Ivana

AU - Rudan, Igor

AU - de Boer, Rudolf A

AU - van der Meer, Peter

AU - Lin, Henry J

AU - Taylor, Kent D

AU - de Mutsert, Renée

AU - Trompet, Stella

AU - Jukema, J Wouter

AU - Maan, Arie C

AU - Stricker, Bruno H C

AU - Rivadeneira, Fernando

AU - Uitterlinden, André

AU - Völker, Uwe

AU - Homuth, Georg

AU - Völzke, Henry

AU - Felix, Stephan B

AU - Mangino, Massimo

AU - Spector, Timothy D

AU - Bots, Michiel L

AU - Perez, Marco

AU - Raitakari, Olli T

AU - Kähönen, Mika

AU - Mononen, Nina

AU - Gudnason, Vilmundur

AU - Munroe, Patricia B

AU - Lubitz, Steven A

AU - van Duijn, Cornelia M

AU - Newton-Cheh, Christopher H

AU - Hayward, Caroline

AU - Rosand, Jonathan

AU - Samani, Nilesh J

AU - Kanters, Jørgen K

AU - Wilson, James G

AU - Kääb, Stefan

AU - Polasek, Ozren

AU - van der Harst, Pim

AU - Heckbert, Susan R

AU - Rotter, Jerome I

AU - Mook-Kanamori, Dennis O

AU - Eijgelsheim, Mark

AU - Dörr, Marcus

AU - Jamshidi, Yalda

AU - Asselbergs, Folkert W

AU - Kooperberg, Charles

AU - Lehtimäki, Terho

AU - Arking, Dan E

AU - Sotoodehnia, Nona

N1 - Funded in part by training grant (National Institute of General Medical Sciences) 5T32GM07814 (Dr Bihlmeyer ), and R01HL116747 (Drs Arking, Bihlmeyer, and Sotoodehnia), and R01 HL111089 (Drs Sotoodehnia and Arking). Dr Sotoodehnia is also supported by the Laughlin Family. This material is based on work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1232825 (Dr Bihlmeyer). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Journal Article

KW - arrhythmias, cardiac

KW - death, sudden, cardiac

KW - genetics

KW - genome

KW - humans

U2 - 10.1161/CIRCGEN.117.001758

DO - 10.1161/CIRCGEN.117.001758

M3 - Article

C2 - 29874175

SN - 2574-8300

VL - 11

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

IS - 1

M1 - e001758

ER -

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

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