Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Nona Sotoodehnia; Aaron Isaacs; Paul I. W. de Bakker; Marcus Doerr; Christopher Newton-Cheh; Ilja M. Nolte; Pim van der Harst; Martina Müller; Mark Eijgelsheim; Alvaro Alonso; Andrew A. Hicks; Sandosh Padmanabhan; Caroline Hayward; Albert Vernon Smith; Ozren Polasek; Steven Giovannone; Jingyuan Fu; Jared W. Magnani; Kristin D. Marciante; Arne Pfeufer; Sina A. Gharib; Alexander Teumer; Man Li; Joshua C. Bis; Fernando Rivadeneira; Thor Aspelund; Anna Köttgen; Toby Johnson; Kenneth Rice; Mark P. S. Sie; Ying A. Wang; Norman Klopp; Christian Fuchsberger; Sarah H. Wild; Irene Mateo Leach; Karol Estrada; Uwe Voelker; Alan F. Wright; Folkert W. Asselbergs; Jiaxiang Qu; Aravinda Chakravarti; Moritz F. Sinner; Jan A. Kors; Astrid Petersmann; Tamara B. Harris; Elsayed Z. Soliman; Patricia B. Munroe; Bruce M. Psaty; Ben A. Oostra; L. Adrienne Cupples; Siegfried Perz; Rudolf A. de Boer; Andre G. Uitterlinden; Henry Voelzke; Timothy D. Spector; Fang-Yu Liu; Eric Boerwinkle; Anna F. Dominiczak; Jerome I. Rotter; Ge van Herpen; Daniel Levy; H-Erich Wichmann; Wiek H. van Gilst; Jacqueline C. M. Witteman; Heyo K. Kroemer; W. H. Linda Kao; Susan R. Heckbert; Thomas Meitinger; Albert Hofman; Harry Campbell; Aaron R. Folsom; Dirk J. van Veldhuisen; Christine Schwienbacher; Christopher J. O'Donnell; Claudia Beu Volpato; Mark J. Caulfield; John M. Connell; Lenore Launer; Xiaowen Lu; Lude Franke; Rudolf S. N. Fehrmann; Gerard te Meerman; Harry J. M. Groen; Rinse K. Weersma; Leonard H. van den Berg; Cisca Wijmenga; Roel A. Ophoff; Gerjan Navis; Igor Rudan; Harold Snieder; James F. Wilson; Peter P. Pramstaller; David S. Siscovick; Thomas J. Wang; Vilmundur Gudnason; Cornelia M. van Duijn; Stephan B. Felix; Glenn I. Fishman; Yalda Jamshidi; Bruno H. Ch Stricker; Nilesh J. Samani; Stefan Kaeaeb; Dan E. Arking

doi:10.1038/ng.716

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Nona Sotoodehnia, Aaron Isaacs, Paul I. W. de Bakker, Marcus Doerr, Christopher Newton-Cheh, Ilja M. Nolte, Pim van der Harst, Martina Müller, Mark Eijgelsheim, Alvaro Alonso, Andrew A. Hicks, Sandosh Padmanabhan, Caroline Hayward, Albert Vernon Smith, Ozren Polasek, Steven Giovannone, Jingyuan Fu, Jared W. Magnani, Kristin D. Marciante, Arne PfeuferSina A. Gharib, Alexander Teumer, Man Li, Joshua C. Bis, Fernando Rivadeneira, Thor Aspelund, Anna Köttgen, Toby Johnson, Kenneth Rice, Mark P. S. Sie, Ying A. Wang, Norman Klopp, Christian Fuchsberger, Sarah H. Wild, Irene Mateo Leach, Karol Estrada, Uwe Voelker, Alan F. Wright, Folkert W. Asselbergs, Jiaxiang Qu, Aravinda Chakravarti, Moritz F. Sinner, Jan A. Kors, Astrid Petersmann, Tamara B. Harris, Elsayed Z. Soliman, Patricia B. Munroe, Bruce M. Psaty, Ben A. Oostra, L. Adrienne Cupples, Siegfried Perz, Rudolf A. de Boer, Andre G. Uitterlinden, Henry Voelzke, Timothy D. Spector, Fang-Yu Liu, Eric Boerwinkle, Anna F. Dominiczak, Jerome I. Rotter, Ge van Herpen, Daniel Levy, H-Erich Wichmann, Wiek H. van Gilst, Jacqueline C. M. Witteman, Heyo K. Kroemer, W. H. Linda Kao, Susan R. Heckbert, Thomas Meitinger, Albert Hofman, Harry Campbell, Aaron R. Folsom, Dirk J. van Veldhuisen, Christine Schwienbacher, Christopher J. O'Donnell, Claudia Beu Volpato, Mark J. Caulfield, John M. Connell, Lenore Launer, Xiaowen Lu, Lude Franke, Rudolf S. N. Fehrmann, Gerard te Meerman, Harry J. M. Groen, Rinse K. Weersma, Leonard H. van den Berg, Cisca Wijmenga, Roel A. Ophoff, Gerjan Navis, Igor Rudan, Harold Snieder, James F. Wilson, Peter P. Pramstaller, David S. Siscovick, Thomas J. Wang, Vilmundur Gudnason, Cornelia M. van Duijn, Stephan B. Felix, Glenn I. Fishman, Yalda Jamshidi, Bruno H. Ch Stricker, Nilesh J. Samani, Stefan Kaeaeb, Dan E. Arking

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Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Original language	English
Pages (from-to)	1068-1076
Number of pages	11
Journal	Nature Genetics
Volume	42
Issue number	12
DOIs	https://doi.org/10.1038/ng.716
Publication status	Published - Dec 2010

Keywords

GENOME-WIDE ASSOCIATION
QT INTERVAL DURATION
RICH REPEAT PROTEIN
HEART-RATE
TRANSCRIPTION FACTOR
GENE-EXPRESSION
PR INTERVAL
SYSTEM
DISEASE
ELECTROCARDIOGRAM

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Sotoodehnia, N., Isaacs, A., de Bakker, P. I. W., Doerr, M., Newton-Cheh, C., Nolte, I. M., van der Harst, P., Müller, M., Eijgelsheim, M., Alonso, A., Hicks, A. A., Padmanabhan, S., Hayward, C., Smith, A. V., Polasek, O., Giovannone, S., Fu, J., Magnani, J. W., Marciante, K. D., ... Arking, D. E. (2010). Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nature Genetics, 42(12), 1068-1076. https://doi.org/10.1038/ng.716

@article{e810055c034a4ce496653b4f60fc5351,

title = "Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction",

abstract = "The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.",

keywords = "GENOME-WIDE ASSOCIATION, QT INTERVAL DURATION, RICH REPEAT PROTEIN, HEART-RATE, TRANSCRIPTION FACTOR, GENE-EXPRESSION, PR INTERVAL, SYSTEM, DISEASE, ELECTROCARDIOGRAM",

author = "Nona Sotoodehnia and Aaron Isaacs and {de Bakker}, {Paul I. W.} and Marcus Doerr and Christopher Newton-Cheh and Nolte, {Ilja M.} and {van der Harst}, Pim and Martina M{\"u}ller and Mark Eijgelsheim and Alvaro Alonso and Hicks, {Andrew A.} and Sandosh Padmanabhan and Caroline Hayward and Smith, {Albert Vernon} and Ozren Polasek and Steven Giovannone and Jingyuan Fu and Magnani, {Jared W.} and Marciante, {Kristin D.} and Arne Pfeufer and Gharib, {Sina A.} and Alexander Teumer and Man Li and Bis, {Joshua C.} and Fernando Rivadeneira and Thor Aspelund and Anna K{\"o}ttgen and Toby Johnson and Kenneth Rice and Sie, {Mark P. S.} and Wang, {Ying A.} and Norman Klopp and Christian Fuchsberger and Wild, {Sarah H.} and Leach, {Irene Mateo} and Karol Estrada and Uwe Voelker and Wright, {Alan F.} and Asselbergs, {Folkert W.} and Jiaxiang Qu and Aravinda Chakravarti and Sinner, {Moritz F.} and Kors, {Jan A.} and Astrid Petersmann and Harris, {Tamara B.} and Soliman, {Elsayed Z.} and Munroe, {Patricia B.} and Psaty, {Bruce M.} and Oostra, {Ben A.} and Cupples, {L. Adrienne} and Siegfried Perz and {de Boer}, {Rudolf A.} and Uitterlinden, {Andre G.} and Henry Voelzke and Spector, {Timothy D.} and Fang-Yu Liu and Eric Boerwinkle and Dominiczak, {Anna F.} and Rotter, {Jerome I.} and {van Herpen}, Ge and Daniel Levy and H-Erich Wichmann and {van Gilst}, {Wiek H.} and Witteman, {Jacqueline C. M.} and Kroemer, {Heyo K.} and Kao, {W. H. Linda} and Heckbert, {Susan R.} and Thomas Meitinger and Albert Hofman and Harry Campbell and Folsom, {Aaron R.} and {van Veldhuisen}, {Dirk J.} and Christine Schwienbacher and O'Donnell, {Christopher J.} and Volpato, {Claudia Beu} and Caulfield, {Mark J.} and Connell, {John M.} and Lenore Launer and Xiaowen Lu and Lude Franke and Fehrmann, {Rudolf S. N.} and Meerman, {Gerard te} and Groen, {Harry J. M.} and Weersma, {Rinse K.} and {van den Berg}, {Leonard H.} and Cisca Wijmenga and Ophoff, {Roel A.} and Gerjan Navis and Igor Rudan and Harold Snieder and Wilson, {James F.} and Pramstaller, {Peter P.} and Siscovick, {David S.} and Wang, {Thomas J.} and Vilmundur Gudnason and {van Duijn}, {Cornelia M.} and Felix, {Stephan B.} and Fishman, {Glenn I.} and Yalda Jamshidi and Stricker, {Bruno H. Ch} and Samani, {Nilesh J.} and Stefan Kaeaeb and Arking, {Dan E.}",

year = "2010",

month = dec,

doi = "10.1038/ng.716",

language = "English",

volume = "42",

pages = "1068--1076",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Sotoodehnia, N, Isaacs, A, de Bakker, PIW, Doerr, M, Newton-Cheh, C, Nolte, IM, van der Harst, P, Müller, M, Eijgelsheim, M, Alonso, A, Hicks, AA, Padmanabhan, S, Hayward, C, Smith, AV, Polasek, O, Giovannone, S, Fu, J, Magnani, JW, Marciante, KD, Pfeufer, A, Gharib, SA, Teumer, A, Li, M, Bis, JC, Rivadeneira, F, Aspelund, T, Köttgen, A, Johnson, T, Rice, K, Sie, MPS, Wang, YA, Klopp, N, Fuchsberger, C, Wild, SH, Leach, IM, Estrada, K, Voelker, U, Wright, AF, Asselbergs, FW, Qu, J, Chakravarti, A, Sinner, MF, Kors, JA, Petersmann, A, Harris, TB, Soliman, EZ, Munroe, PB, Psaty, BM, Oostra, BA, Cupples, LA, Perz, S, de Boer, RA, Uitterlinden, AG, Voelzke, H, Spector, TD, Liu, F-Y, Boerwinkle, E, Dominiczak, AF, Rotter, JI, van Herpen, G, Levy, D, Wichmann, H-E, van Gilst, WH, Witteman, JCM, Kroemer, HK, Kao, WHL, Heckbert, SR, Meitinger, T, Hofman, A, Campbell, H, Folsom, AR, van Veldhuisen, DJ, Schwienbacher, C, O'Donnell, CJ, Volpato, CB, Caulfield, MJ, Connell, JM, Launer, L, Lu, X, Franke, L, Fehrmann, RSN, Meerman, GT, Groen, HJM, Weersma, RK, van den Berg, LH, Wijmenga, C, Ophoff, RA, Navis, G, Rudan, I, Snieder, H, Wilson, JF, Pramstaller, PP, Siscovick, DS, Wang, TJ, Gudnason, V, van Duijn, CM, Felix, SB, Fishman, GI, Jamshidi, Y, Stricker, BHC, Samani, NJ, Kaeaeb, S & Arking, DE 2010, 'Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction', Nature Genetics, vol. 42, no. 12, pp. 1068-1076. https://doi.org/10.1038/ng.716

TY - JOUR

T1 - Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

AU - Sotoodehnia, Nona

AU - Isaacs, Aaron

AU - de Bakker, Paul I. W.

AU - Doerr, Marcus

AU - Newton-Cheh, Christopher

AU - Nolte, Ilja M.

AU - van der Harst, Pim

AU - Müller, Martina

AU - Eijgelsheim, Mark

AU - Alonso, Alvaro

AU - Hicks, Andrew A.

AU - Padmanabhan, Sandosh

AU - Hayward, Caroline

AU - Smith, Albert Vernon

AU - Polasek, Ozren

AU - Giovannone, Steven

AU - Fu, Jingyuan

AU - Magnani, Jared W.

AU - Marciante, Kristin D.

AU - Pfeufer, Arne

AU - Gharib, Sina A.

AU - Teumer, Alexander

AU - Li, Man

AU - Bis, Joshua C.

AU - Rivadeneira, Fernando

AU - Aspelund, Thor

AU - Köttgen, Anna

AU - Johnson, Toby

AU - Rice, Kenneth

AU - Sie, Mark P. S.

AU - Wang, Ying A.

AU - Klopp, Norman

AU - Fuchsberger, Christian

AU - Wild, Sarah H.

AU - Leach, Irene Mateo

AU - Estrada, Karol

AU - Voelker, Uwe

AU - Wright, Alan F.

AU - Asselbergs, Folkert W.

AU - Qu, Jiaxiang

AU - Chakravarti, Aravinda

AU - Sinner, Moritz F.

AU - Kors, Jan A.

AU - Petersmann, Astrid

AU - Harris, Tamara B.

AU - Soliman, Elsayed Z.

AU - Munroe, Patricia B.

AU - Psaty, Bruce M.

AU - Oostra, Ben A.

AU - Cupples, L. Adrienne

AU - Perz, Siegfried

AU - de Boer, Rudolf A.

AU - Uitterlinden, Andre G.

AU - Voelzke, Henry

AU - Spector, Timothy D.

AU - Liu, Fang-Yu

AU - Boerwinkle, Eric

AU - Dominiczak, Anna F.

AU - Rotter, Jerome I.

AU - van Herpen, Ge

AU - Levy, Daniel

AU - Wichmann, H-Erich

AU - van Gilst, Wiek H.

AU - Witteman, Jacqueline C. M.

AU - Kroemer, Heyo K.

AU - Kao, W. H. Linda

AU - Heckbert, Susan R.

AU - Meitinger, Thomas

AU - Hofman, Albert

AU - Campbell, Harry

AU - Folsom, Aaron R.

AU - van Veldhuisen, Dirk J.

AU - Schwienbacher, Christine

AU - O'Donnell, Christopher J.

AU - Volpato, Claudia Beu

AU - Caulfield, Mark J.

AU - Connell, John M.

AU - Launer, Lenore

AU - Lu, Xiaowen

AU - Franke, Lude

AU - Fehrmann, Rudolf S. N.

AU - Meerman, Gerard te

AU - Groen, Harry J. M.

AU - Weersma, Rinse K.

AU - van den Berg, Leonard H.

AU - Wijmenga, Cisca

AU - Ophoff, Roel A.

AU - Navis, Gerjan

AU - Rudan, Igor

AU - Snieder, Harold

AU - Wilson, James F.

AU - Pramstaller, Peter P.

AU - Siscovick, David S.

AU - Wang, Thomas J.

AU - Gudnason, Vilmundur

AU - van Duijn, Cornelia M.

AU - Felix, Stephan B.

AU - Fishman, Glenn I.

AU - Jamshidi, Yalda

AU - Stricker, Bruno H. Ch

AU - Samani, Nilesh J.

AU - Kaeaeb, Stefan

AU - Arking, Dan E.

PY - 2010/12

Y1 - 2010/12

N2 - The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

AB - The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

KW - GENOME-WIDE ASSOCIATION

KW - QT INTERVAL DURATION

KW - RICH REPEAT PROTEIN

KW - HEART-RATE

KW - TRANSCRIPTION FACTOR

KW - GENE-EXPRESSION

KW - PR INTERVAL

KW - SYSTEM

KW - DISEASE

KW - ELECTROCARDIOGRAM

U2 - 10.1038/ng.716

DO - 10.1038/ng.716

M3 - Article

C2 - 21076409

SN - 1061-4036

VL - 42

SP - 1068

EP - 1076

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

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Keywords

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