Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

William J Young; Najim Lahrouchi; Aaron Isaacs; ThuyVy Duong; Luisa Foco; Farah Ahmed; Jennifer A Brody; Reem Salman; Raymond Noordam; Jan-Walter Benjamins; Jeffrey Haessler; Leo-Pekka Lyytikäinen; Linda Repetto; Maria Pina Concas; Marten E van den Berg; Stefan Weiss; Antoine R Baldassari; Traci M Bartz; James P Cook; Daniel S Evans; Rebecca Freudling; Oliver Hines; Jonas L Isaksen; Honghuang Lin; Hao Mei; Arden Moscati; Martina Müller-Nurasyid; Casia Nursyifa; Yong Qian; Anne Richmond; Carolina Roselli; Kathleen A Ryan; Eduardo Tarazona-Santos; Sébastien Thériault; Stefan van Duijvenboden; Helen R Warren; Jie Yao; Dania Raza; Stefanie Aeschbacher; Gustav Ahlberg; Alvaro Alonso; Laura Andreasen; Joshua C Bis; Eric Boerwinkle; Archie Campbell; Eulalia Catamo; Massimiliano Cocca; Michael J Cutler; Dawood Darbar; Alessandro De Grandi; Antonio De Luca; Jun Ding; Christina Ellervik; Patrick T Ellinor; Stephan B Felix; Philippe Froguel; Christian Fuchsberger; Martin Gögele; Claus Graff; Mariaelisa Graff; Xiuqing Guo; Torben Hansen; Susan R Heckbert; Paul L Huang; Heikki V Huikuri; Nina Hutri-Kähönen; M Arfan Ikram; Rebecca D Jackson; Juhani Junttila; Maryam Kavousi; Jan A Kors; Thiago P Leal; Rozenn N Lemaitre; Henry J Lin; Lars Lind; Allan Linneberg; Simin Liu; Peter W MacFarlane; Massimo Mangino; Thomas Meitinger; Massimo Mezzavilla; Pashupati P Mishra; Rebecca N Mitchell; Nina Mononen; May E Montasser; Alanna C Morrison; Matthias Nauck; Victor Nauffal; Pau Navarro; Kjell Nikus; Guillaume Pare; Kristen K Patton; Giulia Pelliccione; Alan Pittman; David J Porteous; Peter P Pramstaller; Michael H Preuss; Olli T Raitakari; Alexander P Reiner; Antonio Luiz P Ribeiro; Kenneth M Rice; Lorenz Risch; David Schlessinger; Ulrich Schotten; Claudia Schurmann; Xia Shen; M Benjamin Shoemaker; Gianfranco Sinagra; Moritz F Sinner; Elsayed Z Soliman; Monika Stoll; Konstantin Strauch; Kirill Tarasov; Kent D Taylor; Andrew Tinker; Stella Trompet; André Uitterlinden; Uwe Völker; Henry Völzke; Melanie Waldenberger; Lu-Chen Weng; Eric A Whitsel; James G Wilson; Christy L Avery; David Conen; Adolfo Correa; Francesco Cucca; Marcus Dörr; Sina A Gharib; Giorgia Girotto; Niels Grarup; Caroline Hayward; Yalda Jamshidi; Marjo-Riitta Järvelin; J Wouter Jukema; Stefan Kääb; Mika Kähönen; Jørgen K Kanters; Charles Kooperberg; Terho Lehtimäki; Maria Fernanda Lima-Costa; Yongmei Liu; Ruth J.F Loos; Steven A Lubitz; Dennis O Mook-Kanamori; Andrew P Morris; Jeffrey R O'Connell; Morten Salling Olesen; Michele Orini; Sandosh Padmanabhan; Cristian Pattaro; Annette Peters; Bruce M Psaty; Jerome I Rotter; Bruno Stricker; Pim van der Harst; Cornelia M van Duijn; Niek Verweij; James F Wilson; Dan E Arking; Julia Ramírez; Pier D Lambiase; Nona Sotoodehnia; Borbala Mifsud; Christopher Newton-Cheh; Patricia B Munroe

doi:10.1101/2021.11.04.21265866

Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

William J Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E van den Berg, Stefan Weiss, Antoine R Baldassari, Traci M Bartz, James P Cook, Daniel S EvansRebecca Freudling, Oliver Hines, Jonas L Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T Ellinor, Stephan B Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R Heckbert, Paul L Huang, Heikki V Huikuri, Nina Hutri-Kähönen, M Arfan Ikram, Rebecca D Jackson, Juhani Junttila, Maryam Kavousi, Jan A Kors, Thiago P Leal, Rozenn N Lemaitre, Henry J Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P Mishra, Rebecca N Mitchell, Nina Mononen, May E Montasser, Alanna C Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K Patton, Giulia Pelliccione, Alan Pittman, David J Porteous, Peter P Pramstaller, Michael H Preuss, Olli T Raitakari, Alexander P Reiner, Antonio Luiz P Ribeiro, Kenneth M Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M Benjamin Shoemaker, Gianfranco Sinagra, Moritz F Sinner, Elsayed Z Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A Whitsel, James G Wilson, Christy L Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J.F Loos, Steven A Lubitz, Dennis O Mook-Kanamori, Andrew P Morris, Jeffrey R O'Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M Psaty, Jerome I Rotter, Bruno Stricker, Pim van der Harst, Cornelia M van Duijn, Niek Verweij, James F Wilson, Dan E Arking, Julia Ramírez, Pier D Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B Munroe

Publikation: Working paper/Preprint › Preprint

Abstrakt

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Originalsprog	Engelsk
Udgiver	Cold Spring Harbor Laboratory Press
Antal sider	90
DOI	https://doi.org/10.1101/2021.11.04.21265866
Status	Udgivet - 2021

Emneord

genetic and genomic medicine

Adgang til dokumentet

10.1101/2021.11.04.21265866

Citationsformater

Young, W. J., Lahrouchi, N., Isaacs, A., Duong, T., Foco, L., Ahmed, F., Brody, J. A., Salman, R., Noordam, R., Benjamins, J-W., Haessler, J., Lyytikäinen, L-P., Repetto, L., Concas, M. P., van den Berg, M. E., Weiss, S., Baldassari, A. R., Bartz, T. M., Cook, J. P., ... Munroe, P. B. (2021). Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization. Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/2021.11.04.21265866

@techreport{5a5487d276a1400b962e72e76412ad5c,

title = "Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization",

abstract = "The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.",

keywords = "genetic and genomic medicine",

author = "Young, {William J} and Najim Lahrouchi and Aaron Isaacs and ThuyVy Duong and Luisa Foco and Farah Ahmed and Brody, {Jennifer A} and Reem Salman and Raymond Noordam and Jan-Walter Benjamins and Jeffrey Haessler and Leo-Pekka Lyytik{\"a}inen and Linda Repetto and Concas, {Maria Pina} and {van den Berg}, {Marten E} and Stefan Weiss and Baldassari, {Antoine R} and Bartz, {Traci M} and Cook, {James P} and Evans, {Daniel S} and Rebecca Freudling and Oliver Hines and Isaksen, {Jonas L} and Honghuang Lin and Hao Mei and Arden Moscati and Martina M{\"u}ller-Nurasyid and Casia Nursyifa and Yong Qian and Anne Richmond and Carolina Roselli and Ryan, {Kathleen A} and Eduardo Tarazona-Santos and S{\'e}bastien Th{\'e}riault and {van Duijvenboden}, Stefan and Warren, {Helen R} and Jie Yao and Dania Raza and Stefanie Aeschbacher and Gustav Ahlberg and Alvaro Alonso and Laura Andreasen and Bis, {Joshua C} and Eric Boerwinkle and Archie Campbell and Eulalia Catamo and Massimiliano Cocca and Cutler, {Michael J} and Dawood Darbar and {De Grandi}, Alessandro and {De Luca}, Antonio and Jun Ding and Christina Ellervik and Ellinor, {Patrick T} and Felix, {Stephan B} and Philippe Froguel and Christian Fuchsberger and Martin G{\"o}gele and Claus Graff and Mariaelisa Graff and Xiuqing Guo and Torben Hansen and Heckbert, {Susan R} and Huang, {Paul L} and Huikuri, {Heikki V} and Nina Hutri-K{\"a}h{\"o}nen and Ikram, {M Arfan} and Jackson, {Rebecca D} and Juhani Junttila and Maryam Kavousi and Kors, {Jan A} and Leal, {Thiago P} and Lemaitre, {Rozenn N} and Lin, {Henry J} and Lars Lind and Allan Linneberg and Simin Liu and MacFarlane, {Peter W} and Massimo Mangino and Thomas Meitinger and Massimo Mezzavilla and Mishra, {Pashupati P} and Mitchell, {Rebecca N} and Nina Mononen and Montasser, {May E} and Morrison, {Alanna C} and Matthias Nauck and Victor Nauffal and Pau Navarro and Kjell Nikus and Guillaume Pare and Patton, {Kristen K} and Giulia Pelliccione and Alan Pittman and Porteous, {David J} and Pramstaller, {Peter P} and Preuss, {Michael H} and Raitakari, {Olli T} and Reiner, {Alexander P} and Ribeiro, {Antonio Luiz P} and Rice, {Kenneth M} and Lorenz Risch and David Schlessinger and Ulrich Schotten and Claudia Schurmann and Xia Shen and Shoemaker, {M Benjamin} and Gianfranco Sinagra and Sinner, {Moritz F} and Soliman, {Elsayed Z} and Monika Stoll and Konstantin Strauch and Kirill Tarasov and Taylor, {Kent D} and Andrew Tinker and Stella Trompet and Andr{\'e} Uitterlinden and Uwe V{\"o}lker and Henry V{\"o}lzke and Melanie Waldenberger and Lu-Chen Weng and Whitsel, {Eric A} and Wilson, {James G} and Avery, {Christy L} and David Conen and Adolfo Correa and Francesco Cucca and Marcus D{\"o}rr and Gharib, {Sina A} and Giorgia Girotto and Niels Grarup and Caroline Hayward and Yalda Jamshidi and Marjo-Riitta J{\"a}rvelin and Jukema, {J Wouter} and Stefan K{\"a}{\"a}b and Mika K{\"a}h{\"o}nen and Kanters, {J{\o}rgen K} and Charles Kooperberg and Terho Lehtim{\"a}ki and Lima-Costa, {Maria Fernanda} and Yongmei Liu and Loos, {Ruth J.F} and Lubitz, {Steven A} and Mook-Kanamori, {Dennis O} and Morris, {Andrew P} and O'Connell, {Jeffrey R} and Olesen, {Morten Salling} and Michele Orini and Sandosh Padmanabhan and Cristian Pattaro and Annette Peters and Psaty, {Bruce M} and Rotter, {Jerome I} and Bruno Stricker and {van der Harst}, Pim and {van Duijn}, {Cornelia M} and Niek Verweij and Wilson, {James F} and Arking, {Dan E} and Julia Ram{\'i}rez and Lambiase, {Pier D} and Nona Sotoodehnia and Borbala Mifsud and Christopher Newton-Cheh and Munroe, {Patricia B}",

note = "NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice",

year = "2021",

doi = "10.1101/2021.11.04.21265866",

language = "English",

publisher = "Cold Spring Harbor Laboratory Press",

type = "WorkingPaper",

institution = "Cold Spring Harbor Laboratory Press",

}

Young, WJ, Lahrouchi, N, Isaacs, A, Duong, T, Foco, L, Ahmed, F, Brody, JA, Salman, R, Noordam, R, Benjamins, J-W, Haessler, J, Lyytikäinen, L-P, Repetto, L, Concas, MP, van den Berg, ME, Weiss, S, Baldassari, AR, Bartz, TM, Cook, JP, Evans, DS, Freudling, R, Hines, O, Isaksen, JL, Lin, H, Mei, H, Moscati, A, Müller-Nurasyid, M, Nursyifa, C, Qian, Y, Richmond, A, Roselli, C, Ryan, KA, Tarazona-Santos, E, Thériault, S, van Duijvenboden, S, Warren, HR, Yao, J, Raza, D, Aeschbacher, S, Ahlberg, G, Alonso, A, Andreasen, L, Bis, JC, Boerwinkle, E, Campbell, A, Catamo, E, Cocca, M, Cutler, MJ, Darbar, D, De Grandi, A, De Luca, A, Ding, J, Ellervik, C, Ellinor, PT, Felix, SB, Froguel, P, Fuchsberger, C, Gögele, M, Graff, C, Graff, M, Guo, X, Hansen, T, Heckbert, SR, Huang, PL, Huikuri, HV, Hutri-Kähönen, N, Ikram, MA, Jackson, RD, Junttila, J, Kavousi, M, Kors, JA, Leal, TP, Lemaitre, RN, Lin, HJ, Lind, L, Linneberg, A, Liu, S, MacFarlane, PW, Mangino, M, Meitinger, T, Mezzavilla, M, Mishra, PP, Mitchell, RN, Mononen, N, Montasser, ME, Morrison, AC, Nauck, M, Nauffal, V, Navarro, P, Nikus, K, Pare, G, Patton, KK, Pelliccione, G, Pittman, A, Porteous, DJ, Pramstaller, PP, Preuss, MH, Raitakari, OT, Reiner, AP, Ribeiro, ALP, Rice, KM, Risch, L, Schlessinger, D, Schotten, U, Schurmann, C, Shen, X, Shoemaker, MB, Sinagra, G, Sinner, MF, Soliman, EZ, Stoll, M, Strauch, K, Tarasov, K, Taylor, KD, Tinker, A, Trompet, S, Uitterlinden, A, Völker, U, Völzke, H, Waldenberger, M, Weng, L-C, Whitsel, EA, Wilson, JG, Avery, CL, Conen, D, Correa, A, Cucca, F, Dörr, M, Gharib, SA, Girotto, G, Grarup, N, Hayward, C, Jamshidi, Y, Järvelin, M-R, Jukema, JW, Kääb, S, Kähönen, M, Kanters, JK, Kooperberg, C, Lehtimäki, T, Lima-Costa, MF, Liu, Y, Loos, RJF, Lubitz, SA, Mook-Kanamori, DO, Morris, AP, O'Connell, JR, Olesen, MS, Orini, M, Padmanabhan, S, Pattaro, C, Peters, A, Psaty, BM, Rotter, JI, Stricker, B, van der Harst, P, van Duijn, CM, Verweij, N, Wilson, JF, Arking, DE, Ramírez, J, Lambiase, PD, Sotoodehnia, N, Mifsud, B, Newton-Cheh, C & Munroe, PB 2021 'Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization' Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/2021.11.04.21265866

TY - UNPB

T1 - Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

AU - Young, William J

AU - Lahrouchi, Najim

AU - Isaacs, Aaron

AU - Duong, ThuyVy

AU - Foco, Luisa

AU - Ahmed, Farah

AU - Brody, Jennifer A

AU - Salman, Reem

AU - Noordam, Raymond

AU - Benjamins, Jan-Walter

AU - Haessler, Jeffrey

AU - Lyytikäinen, Leo-Pekka

AU - Repetto, Linda

AU - Concas, Maria Pina

AU - van den Berg, Marten E

AU - Weiss, Stefan

AU - Baldassari, Antoine R

AU - Bartz, Traci M

AU - Cook, James P

AU - Evans, Daniel S

AU - Freudling, Rebecca

AU - Hines, Oliver

AU - Isaksen, Jonas L

AU - Lin, Honghuang

AU - Mei, Hao

AU - Moscati, Arden

AU - Müller-Nurasyid, Martina

AU - Nursyifa, Casia

AU - Qian, Yong

AU - Richmond, Anne

AU - Roselli, Carolina

AU - Ryan, Kathleen A

AU - Tarazona-Santos, Eduardo

AU - Thériault, Sébastien

AU - van Duijvenboden, Stefan

AU - Warren, Helen R

AU - Yao, Jie

AU - Raza, Dania

AU - Aeschbacher, Stefanie

AU - Ahlberg, Gustav

AU - Alonso, Alvaro

AU - Andreasen, Laura

AU - Bis, Joshua C

AU - Boerwinkle, Eric

AU - Campbell, Archie

AU - Catamo, Eulalia

AU - Cocca, Massimiliano

AU - Cutler, Michael J

AU - Darbar, Dawood

AU - De Grandi, Alessandro

AU - De Luca, Antonio

AU - Ding, Jun

AU - Ellervik, Christina

AU - Ellinor, Patrick T

AU - Felix, Stephan B

AU - Froguel, Philippe

AU - Fuchsberger, Christian

AU - Gögele, Martin

AU - Graff, Claus

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Hansen, Torben

AU - Heckbert, Susan R

AU - Huang, Paul L

AU - Huikuri, Heikki V

AU - Hutri-Kähönen, Nina

AU - Ikram, M Arfan

AU - Jackson, Rebecca D

AU - Junttila, Juhani

AU - Kavousi, Maryam

AU - Kors, Jan A

AU - Leal, Thiago P

AU - Lemaitre, Rozenn N

AU - Lin, Henry J

AU - Lind, Lars

AU - Linneberg, Allan

AU - Liu, Simin

AU - MacFarlane, Peter W

AU - Mangino, Massimo

AU - Meitinger, Thomas

AU - Mezzavilla, Massimo

AU - Mishra, Pashupati P

AU - Mitchell, Rebecca N

AU - Mononen, Nina

AU - Montasser, May E

AU - Morrison, Alanna C

AU - Nauck, Matthias

AU - Nauffal, Victor

AU - Navarro, Pau

AU - Nikus, Kjell

AU - Pare, Guillaume

AU - Patton, Kristen K

AU - Pelliccione, Giulia

AU - Pittman, Alan

AU - Porteous, David J

AU - Pramstaller, Peter P

AU - Preuss, Michael H

AU - Raitakari, Olli T

AU - Reiner, Alexander P

AU - Ribeiro, Antonio Luiz P

AU - Rice, Kenneth M

AU - Risch, Lorenz

AU - Schlessinger, David

AU - Schotten, Ulrich

AU - Schurmann, Claudia

AU - Shen, Xia

AU - Shoemaker, M Benjamin

AU - Sinagra, Gianfranco

AU - Sinner, Moritz F

AU - Soliman, Elsayed Z

AU - Stoll, Monika

AU - Strauch, Konstantin

AU - Tarasov, Kirill

AU - Taylor, Kent D

AU - Tinker, Andrew

AU - Trompet, Stella

AU - Uitterlinden, André

AU - Völker, Uwe

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Weng, Lu-Chen

AU - Whitsel, Eric A

AU - Wilson, James G

AU - Avery, Christy L

AU - Conen, David

AU - Correa, Adolfo

AU - Cucca, Francesco

AU - Dörr, Marcus

AU - Gharib, Sina A

AU - Girotto, Giorgia

AU - Grarup, Niels

AU - Hayward, Caroline

AU - Jamshidi, Yalda

AU - Järvelin, Marjo-Riitta

AU - Jukema, J Wouter

AU - Kääb, Stefan

AU - Kähönen, Mika

AU - Kanters, Jørgen K

AU - Kooperberg, Charles

AU - Lehtimäki, Terho

AU - Lima-Costa, Maria Fernanda

AU - Liu, Yongmei

AU - Loos, Ruth J.F

AU - Lubitz, Steven A

AU - Mook-Kanamori, Dennis O

AU - Morris, Andrew P

AU - O'Connell, Jeffrey R

AU - Olesen, Morten Salling

AU - Orini, Michele

AU - Padmanabhan, Sandosh

AU - Pattaro, Cristian

AU - Peters, Annette

AU - Psaty, Bruce M

AU - Rotter, Jerome I

AU - Stricker, Bruno

AU - van der Harst, Pim

AU - van Duijn, Cornelia M

AU - Verweij, Niek

AU - Wilson, James F

AU - Arking, Dan E

AU - Ramírez, Julia

AU - Lambiase, Pier D

AU - Sotoodehnia, Nona

AU - Mifsud, Borbala

AU - Newton-Cheh, Christopher

AU - Munroe, Patricia B

N1 - NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice

PY - 2021

Y1 - 2021

N2 - The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

AB - The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

KW - genetic and genomic medicine

U2 - 10.1101/2021.11.04.21265866

DO - 10.1101/2021.11.04.21265866

M3 - Preprint

BT - Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

PB - Cold Spring Harbor Laboratory Press

ER -

Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Abstrakt

Emneord

Adgang til dokumentet

Fingeraftryk

Citationsformater