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

N Sotoodehnia; Aaron Isaacs; PIW de Bakker; M Dorr; C Newton-Cheh; IM (Ilja) Nolte; P van der Harst; M (Majon) Muller; Mark Eijgelsheim; A Alonso; AA Hicks; S Padmanabhan; C Hayward; AV Smith; O Polasek; S Giovannone; JY Fu; JW Magnani; KD Marciante; A Pfeufer; SA Gharib; A Teumer; M Li; JC Bis; Fernando Rivadeneira; T Aspelund; A Kottgen; T Johnson; K Rice; MPS Sie; YA Wang; N Klopp; C Fuchsberger; SH Wild; IM Leach; Karol Estrada Gil; U Volker; AF Wright; FW Asselbergs; JX Qu; A Chakravarti; MF Sinner; Jan Kors; A Petersmann; TB Harris; EZ Soliman; PB Munroe; BM Psaty; Ben Oostra; LA Cupples; S Perz; RA de Boer; André Uitterlinden; H Volzke; TD Spector; FY Liu; E Boerwinkle; AF Dominiczak; JI Rotter; null Herpen; D Levy; HE Wichmann; WH van Gilst; JCM Witteman; HK Kroemer; WHL Kao; SR Heckbert; T Meitinger; Bert Hofman; H Campbell; AR Folsom; DJ Veldhuisen; C Schwienbacher; CJ O'Donnell; CB Volpato; MJ Caulfield; JM Connell; L Launer; XW Lu; L Franke; RSN Fehrmann; GT Meerman; HJM Groen; RK Weersma; LH van den Berg; C Wijmenga; RA Ophoff; G Navis; I Rudan; H Snieder; JF Wilson; PP Pramstaller; DS Siscovick; TJ Wang; V Gudnason; Cornelia Duijn; SB Felix; GI Fishman; Y Jamshidi

doi:10.1038/ng.716

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

N Sotoodehnia, Aaron Isaacs, PIW de Bakker, M Dorr, C Newton-Cheh, IM (Ilja) Nolte, P van der Harst, M (Majon) Muller, Mark Eijgelsheim, A Alonso, AA Hicks, S Padmanabhan, C Hayward, AV Smith, O Polasek, S Giovannone, JY Fu, JW Magnani, KD Marciante, A PfeuferSA Gharib, A Teumer, M Li, JC Bis, Fernando Rivadeneira, T Aspelund, A Kottgen, T Johnson, K Rice, MPS Sie, YA Wang, N Klopp, C Fuchsberger, SH Wild, IM Leach, Karol Estrada Gil, U Volker, AF Wright, FW Asselbergs, JX Qu, A Chakravarti, MF Sinner, Jan Kors, A Petersmann, TB Harris, EZ Soliman, PB Munroe, BM Psaty, Ben Oostra, LA Cupples, S Perz, RA de Boer, André Uitterlinden, H Volzke, TD Spector, FY Liu, E Boerwinkle, AF Dominiczak, JI Rotter, Herpen, D Levy, HE Wichmann, WH van Gilst, JCM Witteman, HK Kroemer, WHL Kao, SR Heckbert, T Meitinger, Bert Hofman, H Campbell, AR Folsom, DJ Veldhuisen, C Schwienbacher, CJ O'Donnell, CB Volpato, MJ Caulfield, JM Connell, L Launer, XW Lu, L Franke, RSN Fehrmann, GT Meerman, HJM Groen, RK Weersma, LH van den Berg, C Wijmenga, RA Ophoff, G Navis, I Rudan, H Snieder, JF Wilson, PP Pramstaller, DS Siscovick, TJ Wang, V Gudnason, Cornelia Duijn, SB Felix, GI Fishman, Y Jamshidi

Research output: Contribution to journal › Article › Academic › peer-review

292 Citations (Scopus)

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	Undefined/Unknown
Pages (from-to)	1068-1076
Number of pages	9
Journal	Nature Genetics
Volume	42
Issue number	12
DOIs	https://doi.org/10.1038/ng.716
Publication status	Published - 2010

Research programs

EMC MM-01-39-02
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-03-77-01

Access to Document

10.1038/ng.716

http://hdl.handle.net/1765/28354

Cite this

Sotoodehnia, N., Isaacs, A., de Bakker, PIW., Dorr, M., Newton-Cheh, C., Nolte, IM., van der Harst, P., Muller, M., Eijgelsheim, M., Alonso, A., Hicks, AA., Padmanabhan, S., Hayward, C., Smith, AV., Polasek, O., Giovannone, S., Fu, JY., Magnani, JW., Marciante, KD., ... Jamshidi, Y. (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{ace01b5b7af647c9951fb1a666c72234,

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.",

author = "N Sotoodehnia and Aaron Isaacs and {de Bakker}, PIW and M Dorr and C Newton-Cheh and Nolte, {IM (Ilja)} and {van der Harst}, P and Muller, {M (Majon)} and Mark Eijgelsheim and A Alonso and AA Hicks and S Padmanabhan and C Hayward and AV Smith and O Polasek and S Giovannone and JY Fu and JW Magnani and KD Marciante and A Pfeufer and SA Gharib and A Teumer and M Li and JC Bis and Fernando Rivadeneira and T Aspelund and A Kottgen and T Johnson and K Rice and MPS Sie and YA Wang and N Klopp and C Fuchsberger and SH Wild and IM Leach and {Estrada Gil}, Karol and U Volker and AF Wright and FW Asselbergs and JX Qu and A Chakravarti and MF Sinner and Jan Kors and A Petersmann and TB Harris and EZ Soliman and PB Munroe and BM Psaty and Ben Oostra and LA Cupples and S Perz and {de Boer}, RA and Andr{\'e} Uitterlinden and H Volzke and TD Spector and FY Liu and E Boerwinkle and AF Dominiczak and JI Rotter and Herpen and D Levy and HE Wichmann and {van Gilst}, WH and JCM Witteman and HK Kroemer and WHL Kao and SR Heckbert and T Meitinger and Bert Hofman and H Campbell and AR Folsom and DJ Veldhuisen and C Schwienbacher and CJ O'Donnell and CB Volpato and MJ Caulfield and JM Connell and L Launer and XW Lu and L Franke and RSN Fehrmann and GT Meerman and HJM Groen and RK Weersma and {van den Berg}, LH and C Wijmenga and RA Ophoff and G Navis and I Rudan and H Snieder and JF Wilson and PP Pramstaller and DS Siscovick and TJ Wang and V Gudnason and Cornelia Duijn and SB Felix and GI Fishman and Y Jamshidi",

year = "2010",

doi = "10.1038/ng.716",

language = "Undefined/Unknown",

volume = "42",

pages = "1068--1076",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Sotoodehnia, N, Isaacs, A, de Bakker, PIW, Dorr, M, Newton-Cheh, C, Nolte, IM, van der Harst, P, Muller, M, Eijgelsheim, M, Alonso, A, Hicks, AA, Padmanabhan, S, Hayward, C, Smith, AV, Polasek, O, Giovannone, S, Fu, JY, Magnani, JW, Marciante, KD, Pfeufer, A, Gharib, SA, Teumer, A, Li, M, Bis, JC, Rivadeneira, F, Aspelund, T, Kottgen, A, Johnson, T, Rice, K, Sie, MPS, Wang, YA, Klopp, N, Fuchsberger, C, Wild, SH, Leach, IM, Estrada Gil, K, Volker, U, Wright, AF, Asselbergs, FW, Qu, JX, Chakravarti, A, Sinner, MF, Kors, J, Petersmann, A, Harris, TB, Soliman, EZ, Munroe, PB, Psaty, BM, Oostra, B, Cupples, LA, Perz, S, de Boer, RA, Uitterlinden, A, Volzke, H, Spector, TD, Liu, FY, Boerwinkle, E, Dominiczak, AF, Rotter, JI, Herpen, Levy, D, Wichmann, HE, van Gilst, WH, Witteman, JCM, Kroemer, HK, Kao, WHL, Heckbert, SR, Meitinger, T, Hofman, B, Campbell, H, Folsom, AR, Veldhuisen, DJ, Schwienbacher, C, O'Donnell, CJ, Volpato, CB, Caulfield, MJ, Connell, JM, Launer, L, Lu, XW, 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, Duijn, C, Felix, SB, Fishman, GI & Jamshidi, Y 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, N

AU - Isaacs, Aaron

AU - de Bakker, PIW

AU - Dorr, M

AU - Newton-Cheh, C

AU - Nolte, IM (Ilja)

AU - van der Harst, P

AU - Muller, M (Majon)

AU - Eijgelsheim, Mark

AU - Alonso, A

AU - Hicks, AA

AU - Padmanabhan, S

AU - Hayward, C

AU - Smith, AV

AU - Polasek, O

AU - Giovannone, S

AU - Fu, JY

AU - Magnani, JW

AU - Marciante, KD

AU - Pfeufer, A

AU - Gharib, SA

AU - Teumer, A

AU - Li, M

AU - Bis, JC

AU - Rivadeneira, Fernando

AU - Aspelund, T

AU - Kottgen, A

AU - Johnson, T

AU - Rice, K

AU - Sie, MPS

AU - Wang, YA

AU - Klopp, N

AU - Fuchsberger, C

AU - Wild, SH

AU - Leach, IM

AU - Estrada Gil, Karol

AU - Volker, U

AU - Wright, AF

AU - Asselbergs, FW

AU - Qu, JX

AU - Chakravarti, A

AU - Sinner, MF

AU - Kors, Jan

AU - Petersmann, A

AU - Harris, TB

AU - Soliman, EZ

AU - Munroe, PB

AU - Psaty, BM

AU - Oostra, Ben

AU - Cupples, LA

AU - Perz, S

AU - de Boer, RA

AU - Uitterlinden, André

AU - Volzke, H

AU - Spector, TD

AU - Liu, FY

AU - Boerwinkle, E

AU - Dominiczak, AF

AU - Rotter, JI

AU - Herpen, null

AU - Levy, D

AU - Wichmann, HE

AU - van Gilst, WH

AU - Witteman, JCM

AU - Kroemer, HK

AU - Kao, WHL

AU - Heckbert, SR

AU - Meitinger, T

AU - Hofman, Bert

AU - Campbell, H

AU - Folsom, AR

AU - Veldhuisen, DJ

AU - Schwienbacher, C

AU - O'Donnell, CJ

AU - Volpato, CB

AU - Caulfield, MJ

AU - Connell, JM

AU - Launer, L

AU - Lu, XW

AU - Franke, L

AU - Fehrmann, RSN

AU - Meerman, GT

AU - Groen, HJM

AU - Weersma, RK

AU - van den Berg, LH

AU - Wijmenga, C

AU - Ophoff, RA

AU - Navis, G

AU - Rudan, I

AU - Snieder, H

AU - Wilson, JF

AU - Pramstaller, PP

AU - Siscovick, DS

AU - Wang, TJ

AU - Gudnason, V

AU - Duijn, Cornelia

AU - Felix, SB

AU - Fishman, GI

AU - Jamshidi, Y

PY - 2010

Y1 - 2010

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.

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 -