52 Genetic Loci Influencing Myocardial Mass

Pim van der Harst; Jessica van Setten; Niek Verweij; Georg Vogler; Lude Franke; Matthew T. Maurano; Xinchen Wang; Irene Mateo Leach; Mark Eijgelsheim; Nona Sotoodehnia; Caroline Hayward; Rossella Sorice; Osorio Meirelles; Leo Pekka Lyytikäinen; Ozren Polašek; Toshiko Tanaka; Dan E. Arking; Sheila Ulivi; Stella Trompet; Martina Müller-Nurasyid; Albert V. Smith; Marcus Dörr; Kathleen F. Kerr; Jared W. Magnani; Fabiola Del Greco M.; Weihua Zhang; Ilja M. Nolte; Claudia T. Silva; Sandosh Padmanabhan; Vinicius Tragante; Tõnu Esko; Gonçalo R. Abecasis; Michiel E. Adriaens; Karl Andersen; Phil Barnett; Joshua C. Bis; Rolf Bodmer; Brendan M. Buckley; Harry Campbell; Megan V. Cannon; Aravinda Chakravarti; Lin Y. Chen; Alessandro Delitala; Richard B. Devereux; Pieter A. Doevendans; Anna F. Dominiczak; Luigi Ferrucci; Ian Ford; Christian Gieger; Tamara B. Harris; Eric Haugen; Matthias Heinig; Dena G. Hernandez; Hans L. Hillege; Joel N. Hirschhorn; Albert Hofman; Norbert Hubner; Shih Jen Hwang; Annamaria Iorio; Mika Kähönen; Manolis Kellis; Ivana Kolcic; Ishminder K. Kooner; Jaspal S. Kooner; Jan A. Kors; Edward G. Lakatta; Kasper Lage; Lenore J. Launer; Daniel Levy; Alicia Lundby; Peter W. Macfarlane; Dalit May; Thomas Meitinger; Andres Metspalu; Stefania Nappo; Silvia Naitza; Shane Neph; Alex S. Nord; Teresa Nutile; Peter M. Okin; Jesper V. Olsen; Ben A. Oostra; Josef M. Penninger; Len A. Pennacchio; Tune H. Pers; Siegfried Perz; Annette Peters; Yigal M. Pinto; Arne Pfeufer; Maria Grazia Pilia; Peter P. Pramstaller; Bram P. Prins; Olli T. Raitakari; Soumya Raychaudhuri; Ken M. Rice; Elizabeth J. Rossin; Jerome I. Rotter; Sebastian Schafer; David Schlessinger; Carsten O. Schmidt; Jobanpreet Sehmi; Herman H W Silljé; Gianfranco Sinagra; Moritz F. Sinner; Kamil Slowikowski; Elsayed Z. Soliman; Timothy D. Spector; Wilko Spiering; John A. Stamatoyannopoulos; Ronald P. Stolk; Konstantin Strauch; Sian Tsung Tan; Kirill V. Tarasov; Bosco Trinh; Andre G. Uitterlinden; Malou van den Boogaard; Cornelia M. van Duijn; Wiek H. van Gilst; Jorma S. Viikari; Peter M. Visscher; Veronique Vitart; Uwe Völker; Melanie Waldenberger; Christian X. Weichenberger; Harm Jan Westra; Cisca Wijmenga; Bruce H. Wolffenbuttel; Jian Yang; Connie R. Bezzina; Patricia B. Munroe; Harold Snieder; Alan F. Wright; Igor Rudan; Laurie A. Boyer; Folkert W. Asselbergs; Dirk J. van Veldhuisen; Bruno H. Stricker; Bruce M. Psaty; Marina Ciullo; Serena Sanna; Terho Lehtimäki; James F. Wilson; Stefania Bandinelli; Alvaro Alonso; Paolo Gasparini; J. Wouter Jukema; Stefan Kääb; Vilmundur Gudnason; Stephan B. Felix; Susan R. Heckbert; Rudolf A. de Boer; Christopher Newton-Cheh; Andrew A. Hicks; John C. Chambers; Yalda Jamshidi; Axel Visel; Vincent M. Christoffels; Aaron Isaacs; Nilesh J. Samani; Paul I W de Bakker

doi:10.1016/j.jacc.2016.07.729

52 Genetic Loci Influencing Myocardial Mass

Pim van der Harst, Jessica van Setten, Niek Verweij, Georg Vogler, Lude Franke, Matthew T. Maurano, Xinchen Wang, Irene Mateo Leach, Mark Eijgelsheim, Nona Sotoodehnia, Caroline Hayward, Rossella Sorice, Osorio Meirelles, Leo Pekka Lyytikäinen, Ozren Polašek, Toshiko Tanaka, Dan E. Arking, Sheila Ulivi, Stella Trompet, Martina Müller-NurasyidAlbert V. Smith, Marcus Dörr, Kathleen F. Kerr, Jared W. Magnani, Fabiola Del Greco M., Weihua Zhang, Ilja M. Nolte, Claudia T. Silva, Sandosh Padmanabhan, Vinicius Tragante, Tõnu Esko, Gonçalo R. Abecasis, Michiel E. Adriaens, Karl Andersen, Phil Barnett, Joshua C. Bis, Rolf Bodmer, Brendan M. Buckley, Harry Campbell, Megan V. Cannon, Aravinda Chakravarti, Lin Y. Chen, Alessandro Delitala, Richard B. Devereux, Pieter A. Doevendans, Anna F. Dominiczak, Luigi Ferrucci, Ian Ford, Christian Gieger, Tamara B. Harris, Eric Haugen, Matthias Heinig, Dena G. Hernandez, Hans L. Hillege, Joel N. Hirschhorn, Albert Hofman, Norbert Hubner, Shih Jen Hwang, Annamaria Iorio, Mika Kähönen, Manolis Kellis, Ivana Kolcic, Ishminder K. Kooner, Jaspal S. Kooner, Jan A. Kors, Edward G. Lakatta, Kasper Lage, Lenore J. Launer, Daniel Levy, Alicia Lundby, Peter W. Macfarlane, Dalit May, Thomas Meitinger, Andres Metspalu, Stefania Nappo, Silvia Naitza, Shane Neph, Alex S. Nord, Teresa Nutile, Peter M. Okin, Jesper V. Olsen, Ben A. Oostra, Josef M. Penninger, Len A. Pennacchio, Tune H. Pers, Siegfried Perz, Annette Peters, Yigal M. Pinto, Arne Pfeufer, Maria Grazia Pilia, Peter P. Pramstaller, Bram P. Prins, Olli T. Raitakari, Soumya Raychaudhuri, Ken M. Rice, Elizabeth J. Rossin, Jerome I. Rotter, Sebastian Schafer, David Schlessinger, Carsten O. Schmidt, Jobanpreet Sehmi, Herman H W Silljé, Gianfranco Sinagra, Moritz F. Sinner, Kamil Slowikowski, Elsayed Z. Soliman, Timothy D. Spector, Wilko Spiering, John A. Stamatoyannopoulos, Ronald P. Stolk, Konstantin Strauch, Sian Tsung Tan, Kirill V. Tarasov, Bosco Trinh, Andre G. Uitterlinden, Malou van den Boogaard, Cornelia M. van Duijn, Wiek H. van Gilst, Jorma S. Viikari, Peter M. Visscher, Veronique Vitart, Uwe Völker, Melanie Waldenberger, Christian X. Weichenberger, Harm Jan Westra, Cisca Wijmenga, Bruce H. Wolffenbuttel, Jian Yang, Connie R. Bezzina, Patricia B. Munroe, Harold Snieder, Alan F. Wright, Igor Rudan, Laurie A. Boyer, Folkert W. Asselbergs, Dirk J. van Veldhuisen, Bruno H. Stricker, Bruce M. Psaty, Marina Ciullo, Serena Sanna, Terho Lehtimäki, James F. Wilson, Stefania Bandinelli, Alvaro Alonso, Paolo Gasparini, J. Wouter Jukema, Stefan Kääb, Vilmundur Gudnason, Stephan B. Felix, Susan R. Heckbert, Rudolf A. de Boer, Christopher Newton-Cheh, Andrew A. Hicks, John C. Chambers, Yalda Jamshidi, Axel Visel, Vincent M. Christoffels, Aaron Isaacs, Nilesh J. Samani, Paul I W de Bakker

Medicine - Cardiology Division

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

78 Scopus citations

Abstract

Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10⁻⁸. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

Original language	English (US)
Pages (from-to)	1435-1448
Number of pages	14
Journal	Journal of the American College of Cardiology
Volume	68
Issue number	13
DOIs	https://doi.org/10.1016/j.jacc.2016.07.729
State	Published - Sep 27 2016

Bibliographical note

Funding Information:
Dr. Abecasis has served on the scientific advisory board for Regeneron Genetics Center. Dr. Haugen’s current employer (Altius Institute) receives research funding from GlaxoSmithKline. Dr. Pennacchio is a salaried employee and owns stock in Metabiota. Dr. Stamatoyannopoulos is the director of a nonprofit research institute. Dr. Psaty has served on the data and safety monitoring board for a clinical trial funded by Zoll LifeCor; and has served on the steering committee of the Yale Open Data Access project funded by Johnson & Johnson. Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Harst, van Setten, Verweij, Vogler, Franke, Maurano, Wang, Mateo Leach, Chambers, Jamshidi, Visel, Christoffels, Isaacs, Samani, and de Bakker contributed equally to this work.

Publisher Copyright:
© 2016 American College of Cardiology Foundation

Keywords

QRS
electrocardiogram
genetic association study
heart failure
left ventricular hypertrophy

Publisher link

10.1016/j.jacc.2016.07.729

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van der Harst, P., van Setten, J., Verweij, N., Vogler, G., Franke, L., Maurano, M. T., Wang, X., Mateo Leach, I., Eijgelsheim, M., Sotoodehnia, N., Hayward, C., Sorice, R., Meirelles, O., Lyytikäinen, L. P., Polašek, O., Tanaka, T., Arking, D. E., Ulivi, S., Trompet, S., ... de Bakker, P. I. W. (2016). 52 Genetic Loci Influencing Myocardial Mass. Journal of the American College of Cardiology, 68(13), 1435-1448. https://doi.org/10.1016/j.jacc.2016.07.729

van der Harst, P, van Setten, J, Verweij, N, Vogler, G, Franke, L, Maurano, MT, Wang, X, Mateo Leach, I, Eijgelsheim, M, Sotoodehnia, N, Hayward, C, Sorice, R, Meirelles, O, Lyytikäinen, LP, Polašek, O, Tanaka, T, Arking, DE, Ulivi, S, Trompet, S, Müller-Nurasyid, M, Smith, AV, Dörr, M, Kerr, KF, Magnani, JW, Del Greco M., F, Zhang, W, Nolte, IM, Silva, CT, Padmanabhan, S, Tragante, V, Esko, T, Abecasis, GR, Adriaens, ME, Andersen, K, Barnett, P, Bis, JC, Bodmer, R, Buckley, BM, Campbell, H, Cannon, MV, Chakravarti, A, Chen, LY, Delitala, A, Devereux, RB, Doevendans, PA, Dominiczak, AF, Ferrucci, L, Ford, I, Gieger, C, Harris, TB, Haugen, E, Heinig, M, Hernandez, DG, Hillege, HL, Hirschhorn, JN, Hofman, A, Hubner, N, Hwang, SJ, Iorio, A, Kähönen, M, Kellis, M, Kolcic, I, Kooner, IK, Kooner, JS, Kors, JA, Lakatta, EG, Lage, K, Launer, LJ, Levy, D, Lundby, A, Macfarlane, PW, May, D, Meitinger, T, Metspalu, A, Nappo, S, Naitza, S, Neph, S, Nord, AS, Nutile, T, Okin, PM, Olsen, JV, Oostra, BA, Penninger, JM, Pennacchio, LA, Pers, TH, Perz, S, Peters, A, Pinto, YM, Pfeufer, A, Pilia, MG, Pramstaller, PP, Prins, BP, Raitakari, OT, Raychaudhuri, S, Rice, KM, Rossin, EJ, Rotter, JI, Schafer, S, Schlessinger, D, Schmidt, CO, Sehmi, J, Silljé, HHW, Sinagra, G, Sinner, MF, Slowikowski, K, Soliman, EZ, Spector, TD, Spiering, W, Stamatoyannopoulos, JA, Stolk, RP, Strauch, K, Tan, ST, Tarasov, KV, Trinh, B, Uitterlinden, AG, van den Boogaard, M, van Duijn, CM, van Gilst, WH, Viikari, JS, Visscher, PM, Vitart, V, Völker, U, Waldenberger, M, Weichenberger, CX, Westra, HJ, Wijmenga, C, Wolffenbuttel, BH, Yang, J, Bezzina, CR, Munroe, PB, Snieder, H, Wright, AF, Rudan, I, Boyer, LA, Asselbergs, FW, van Veldhuisen, DJ, Stricker, BH, Psaty, BM, Ciullo, M, Sanna, S, Lehtimäki, T, Wilson, JF, Bandinelli, S, Alonso, A, Gasparini, P, Jukema, JW, Kääb, S, Gudnason, V, Felix, SB, Heckbert, SR, de Boer, RA, Newton-Cheh, C, Hicks, AA, Chambers, JC, Jamshidi, Y, Visel, A, Christoffels, VM, Isaacs, A, Samani, NJ & de Bakker, PIW 2016, '52 Genetic Loci Influencing Myocardial Mass', Journal of the American College of Cardiology, vol. 68, no. 13, pp. 1435-1448. https://doi.org/10.1016/j.jacc.2016.07.729

@article{c3b6c9fa71564fdcb05f270e4330fbe0,

title = "52 Genetic Loci Influencing Myocardial Mass",

abstract = "Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.",

keywords = "QRS, electrocardiogram, genetic association study, heart failure, left ventricular hypertrophy",

author = "{van der Harst}, Pim and {van Setten}, Jessica and Niek Verweij and Georg Vogler and Lude Franke and Maurano, {Matthew T.} and Xinchen Wang and {Mateo Leach}, Irene and Mark Eijgelsheim and Nona Sotoodehnia and Caroline Hayward and Rossella Sorice and Osorio Meirelles and Lyytik{\"a}inen, {Leo Pekka} and Ozren Pola{\v s}ek and Toshiko Tanaka and Arking, {Dan E.} and Sheila Ulivi and Stella Trompet and Martina M{\"u}ller-Nurasyid and Smith, {Albert V.} and Marcus D{\"o}rr and Kerr, {Kathleen F.} and Magnani, {Jared W.} and {Del Greco M.}, Fabiola and Weihua Zhang and Nolte, {Ilja M.} and Silva, {Claudia T.} and Sandosh Padmanabhan and Vinicius Tragante and T{\~o}nu Esko and Abecasis, {Gon{\c c}alo R.} and Adriaens, {Michiel E.} and Karl Andersen and Phil Barnett and Bis, {Joshua C.} and Rolf Bodmer and Buckley, {Brendan M.} and Harry Campbell and Cannon, {Megan V.} and Aravinda Chakravarti and Chen, {Lin Y.} and Alessandro Delitala and Devereux, {Richard B.} and Doevendans, {Pieter A.} and Dominiczak, {Anna F.} and Luigi Ferrucci and Ian Ford and Christian Gieger and Harris, {Tamara B.} and Eric Haugen and Matthias Heinig and Hernandez, {Dena G.} and Hillege, {Hans L.} and Hirschhorn, {Joel N.} and Albert Hofman and Norbert Hubner and Hwang, {Shih Jen} and Annamaria Iorio and Mika K{\"a}h{\"o}nen and Manolis Kellis and Ivana Kolcic and Kooner, {Ishminder K.} and Kooner, {Jaspal S.} and Kors, {Jan A.} and Lakatta, {Edward G.} and Kasper Lage and Launer, {Lenore J.} and Daniel Levy and Alicia Lundby and Macfarlane, {Peter W.} and Dalit May and Thomas Meitinger and Andres Metspalu and Stefania Nappo and Silvia Naitza and Shane Neph and Nord, {Alex S.} and Teresa Nutile and Okin, {Peter M.} and Olsen, {Jesper V.} and Oostra, {Ben A.} and Penninger, {Josef M.} and Pennacchio, {Len A.} and Pers, {Tune H.} and Siegfried Perz and Annette Peters and Pinto, {Yigal M.} and Arne Pfeufer and Pilia, {Maria Grazia} and Pramstaller, {Peter P.} and Prins, {Bram P.} and Raitakari, {Olli T.} and Soumya Raychaudhuri and Rice, {Ken M.} and Rossin, {Elizabeth J.} and Rotter, {Jerome I.} and Sebastian Schafer and David Schlessinger and Schmidt, {Carsten O.} and Jobanpreet Sehmi and Sillj{\'e}, {Herman H W} and Gianfranco Sinagra and Sinner, {Moritz F.} and Kamil Slowikowski and Soliman, {Elsayed Z.} and Spector, {Timothy D.} and Wilko Spiering and Stamatoyannopoulos, {John A.} and Stolk, {Ronald P.} and Konstantin Strauch and Tan, {Sian Tsung} and Tarasov, {Kirill V.} and Bosco Trinh and Uitterlinden, {Andre G.} and {van den Boogaard}, Malou and {van Duijn}, {Cornelia M.} and {van Gilst}, {Wiek H.} and Viikari, {Jorma S.} and Visscher, {Peter M.} and Veronique Vitart and Uwe V{\"o}lker and Melanie Waldenberger and Weichenberger, {Christian X.} and Westra, {Harm Jan} and Cisca Wijmenga and Wolffenbuttel, {Bruce H.} and Jian Yang and Bezzina, {Connie R.} and Munroe, {Patricia B.} and Harold Snieder and Wright, {Alan F.} and Igor Rudan and Boyer, {Laurie A.} and Asselbergs, {Folkert W.} and {van Veldhuisen}, {Dirk J.} and Stricker, {Bruno H.} and Psaty, {Bruce M.} and Marina Ciullo and Serena Sanna and Terho Lehtim{\"a}ki and Wilson, {James F.} and Stefania Bandinelli and Alvaro Alonso and Paolo Gasparini and Jukema, {J. Wouter} and Stefan K{\"a}{\"a}b and Vilmundur Gudnason and Felix, {Stephan B.} and Heckbert, {Susan R.} and {de Boer}, {Rudolf A.} and Christopher Newton-Cheh and Hicks, {Andrew A.} and Chambers, {John C.} and Yalda Jamshidi and Axel Visel and Christoffels, {Vincent M.} and Aaron Isaacs and Samani, {Nilesh J.} and {de Bakker}, {Paul I W}",

note = "Funding Information: Dr. Abecasis has served on the scientific advisory board for Regeneron Genetics Center. Dr. Haugen{\textquoteright}s current employer (Altius Institute) receives research funding from GlaxoSmithKline. Dr. Pennacchio is a salaried employee and owns stock in Metabiota. Dr. Stamatoyannopoulos is the director of a nonprofit research institute. Dr. Psaty has served on the data and safety monitoring board for a clinical trial funded by Zoll LifeCor; and has served on the steering committee of the Yale Open Data Access project funded by Johnson & Johnson. Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Harst, van Setten, Verweij, Vogler, Franke, Maurano, Wang, Mateo Leach, Chambers, Jamshidi, Visel, Christoffels, Isaacs, Samani, and de Bakker contributed equally to this work. Publisher Copyright: {\textcopyright} 2016 American College of Cardiology Foundation",

year = "2016",

month = sep,

day = "27",

doi = "10.1016/j.jacc.2016.07.729",

language = "English (US)",

volume = "68",

pages = "1435--1448",

journal = "Journal of the American College of Cardiology.",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "13",

}

TY - JOUR

T1 - 52 Genetic Loci Influencing Myocardial Mass

AU - van der Harst, Pim

AU - van Setten, Jessica

AU - Verweij, Niek

AU - Vogler, Georg

AU - Franke, Lude

AU - Maurano, Matthew T.

AU - Wang, Xinchen

AU - Mateo Leach, Irene

AU - Eijgelsheim, Mark

AU - Sotoodehnia, Nona

AU - Hayward, Caroline

AU - Sorice, Rossella

AU - Meirelles, Osorio

AU - Lyytikäinen, Leo Pekka

AU - Polašek, Ozren

AU - Tanaka, Toshiko

AU - Arking, Dan E.

AU - Ulivi, Sheila

AU - Trompet, Stella

AU - Müller-Nurasyid, Martina

AU - Smith, Albert V.

AU - Dörr, Marcus

AU - Kerr, Kathleen F.

AU - Magnani, Jared W.

AU - Del Greco M., Fabiola

AU - Zhang, Weihua

AU - Nolte, Ilja M.

AU - Silva, Claudia T.

AU - Padmanabhan, Sandosh

AU - Tragante, Vinicius

AU - Esko, Tõnu

AU - Abecasis, Gonçalo R.

AU - Adriaens, Michiel E.

AU - Andersen, Karl

AU - Barnett, Phil

AU - Bis, Joshua C.

AU - Bodmer, Rolf

AU - Buckley, Brendan M.

AU - Campbell, Harry

AU - Cannon, Megan V.

AU - Chakravarti, Aravinda

AU - Chen, Lin Y.

AU - Delitala, Alessandro

AU - Devereux, Richard B.

AU - Doevendans, Pieter A.

AU - Dominiczak, Anna F.

AU - Ferrucci, Luigi

AU - Ford, Ian

AU - Gieger, Christian

AU - Harris, Tamara B.

AU - Haugen, Eric

AU - Heinig, Matthias

AU - Hernandez, Dena G.

AU - Hillege, Hans L.

AU - Hirschhorn, Joel N.

AU - Hofman, Albert

AU - Hubner, Norbert

AU - Hwang, Shih Jen

AU - Iorio, Annamaria

AU - Kähönen, Mika

AU - Kellis, Manolis

AU - Kolcic, Ivana

AU - Kooner, Ishminder K.

AU - Kooner, Jaspal S.

AU - Kors, Jan A.

AU - Lakatta, Edward G.

AU - Lage, Kasper

AU - Launer, Lenore J.

AU - Levy, Daniel

AU - Lundby, Alicia

AU - Macfarlane, Peter W.

AU - May, Dalit

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Nappo, Stefania

AU - Naitza, Silvia

AU - Neph, Shane

AU - Nord, Alex S.

AU - Nutile, Teresa

AU - Okin, Peter M.

AU - Olsen, Jesper V.

AU - Oostra, Ben A.

AU - Penninger, Josef M.

AU - Pennacchio, Len A.

AU - Pers, Tune H.

AU - Perz, Siegfried

AU - Peters, Annette

AU - Pinto, Yigal M.

AU - Pfeufer, Arne

AU - Pilia, Maria Grazia

AU - Pramstaller, Peter P.

AU - Prins, Bram P.

AU - Raitakari, Olli T.

AU - Raychaudhuri, Soumya

AU - Rice, Ken M.

AU - Rossin, Elizabeth J.

AU - Rotter, Jerome I.

AU - Schafer, Sebastian

AU - Schlessinger, David

AU - Schmidt, Carsten O.

AU - Sehmi, Jobanpreet

AU - Silljé, Herman H W

AU - Sinagra, Gianfranco

AU - Sinner, Moritz F.

AU - Slowikowski, Kamil

AU - Soliman, Elsayed Z.

AU - Spector, Timothy D.

AU - Spiering, Wilko

AU - Stamatoyannopoulos, John A.

AU - Stolk, Ronald P.

AU - Strauch, Konstantin

AU - Tan, Sian Tsung

AU - Tarasov, Kirill V.

AU - Trinh, Bosco

AU - Uitterlinden, Andre G.

AU - van den Boogaard, Malou

AU - van Duijn, Cornelia M.

AU - van Gilst, Wiek H.

AU - Viikari, Jorma S.

AU - Visscher, Peter M.

AU - Vitart, Veronique

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Weichenberger, Christian X.

AU - Westra, Harm Jan

AU - Wijmenga, Cisca

AU - Wolffenbuttel, Bruce H.

AU - Yang, Jian

AU - Bezzina, Connie R.

AU - Munroe, Patricia B.

AU - Snieder, Harold

AU - Wright, Alan F.

AU - Rudan, Igor

AU - Boyer, Laurie A.

AU - Asselbergs, Folkert W.

AU - van Veldhuisen, Dirk J.

AU - Stricker, Bruno H.

AU - Psaty, Bruce M.

AU - Ciullo, Marina

AU - Sanna, Serena

AU - Lehtimäki, Terho

AU - Wilson, James F.

AU - Bandinelli, Stefania

AU - Alonso, Alvaro

AU - Gasparini, Paolo

AU - Jukema, J. Wouter

AU - Kääb, Stefan

AU - Gudnason, Vilmundur

AU - Felix, Stephan B.

AU - Heckbert, Susan R.

AU - de Boer, Rudolf A.

AU - Newton-Cheh, Christopher

AU - Hicks, Andrew A.

AU - Chambers, John C.

AU - Jamshidi, Yalda

AU - Visel, Axel

AU - Christoffels, Vincent M.

AU - Isaacs, Aaron

AU - Samani, Nilesh J.

AU - de Bakker, Paul I W

N1 - Funding Information: Dr. Abecasis has served on the scientific advisory board for Regeneron Genetics Center. Dr. Haugen’s current employer (Altius Institute) receives research funding from GlaxoSmithKline. Dr. Pennacchio is a salaried employee and owns stock in Metabiota. Dr. Stamatoyannopoulos is the director of a nonprofit research institute. Dr. Psaty has served on the data and safety monitoring board for a clinical trial funded by Zoll LifeCor; and has served on the steering committee of the Yale Open Data Access project funded by Johnson & Johnson. Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Harst, van Setten, Verweij, Vogler, Franke, Maurano, Wang, Mateo Leach, Chambers, Jamshidi, Visel, Christoffels, Isaacs, Samani, and de Bakker contributed equally to this work. Publisher Copyright: © 2016 American College of Cardiology Foundation

PY - 2016/9/27

Y1 - 2016/9/27

N2 - Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

AB - Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

KW - QRS

KW - electrocardiogram

KW - genetic association study

KW - heart failure

KW - left ventricular hypertrophy

UR - http://www.scopus.com/inward/record.url?scp=84990929556&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990929556&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2016.07.729

DO - 10.1016/j.jacc.2016.07.729

M3 - Article

C2 - 27659466

AN - SCOPUS:84990929556

SN - 0735-1097

VL - 68

SP - 1435

EP - 1448

JO - Journal of the American College of Cardiology.

JF - Journal of the American College of Cardiology.

IS - 13

ER -