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

Resultado de la investigación: Contribución a RevistaArtículo

36 Citas (Scopus)

Resumen

© 2016 American College of Cardiology FoundationBackground 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.
Idioma originalEnglish (US)
Páginas (desde-hasta)1435-1448
Número de páginas14
PublicaciónJournal of the American College of Cardiology
DOI
EstadoPublished - sep 27 2016

Huella dactilar

Genetic Loci
Cardiomegaly
Meta-Analysis
Myocardium
Histone Code
Genome-Wide Association Study
Muscle Contraction
Drosophila melanogaster
Genes
Chromatin
Electrocardiography
Transcription Factors
Heart Failure
Genome
Phenotype
Therapeutics
In Vitro Techniques

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van der Harst, P., van Setten, J., Verweij, N., Vogler, G., Franke, L., Maurano, M. T., ... Lage, K. (2016). 52 Genetic Loci Influencing Myocardial Mass. Journal of the American College of Cardiology, 1435-1448. https://doi.org/10.1016/j.jacc.2016.07.729
van der Harst, Pim ; van Setten, Jessica ; Verweij, Niek ; Vogler, Georg ; Franke, Lude ; Maurano, Matthew T. ; Wang, Xinchen ; Mateo Leach, Irene ; Eijgelsheim, Mark ; Sotoodehnia, Nona ; Hayward, Caroline ; Sorice, Rossella ; Meirelles, Osorio ; Lyytikäinen, Leo Pekka ; Polašek, Ozren ; Tanaka, Toshiko ; Arking, Dan E. ; Ulivi, Sheila ; Trompet, Stella ; Müller-Nurasyid, Martina ; Smith, Albert V. ; Dörr, Marcus ; Kerr, Kathleen F. ; Magnani, Jared W. ; Del Greco M., Fabiola ; Zhang, Weihua ; Nolte, Ilja M. ; Silva, Claudia T. ; Padmanabhan, Sandosh ; Tragante, Vinicius ; Esko, Tõnu ; Abecasis, Gonçalo R. ; Adriaens, Michiel E. ; Andersen, Karl ; Barnett, Phil ; Bis, Joshua C. ; Bodmer, Rolf ; Buckley, Brendan M. ; Campbell, Harry ; Cannon, Megan V. ; Chakravarti, Aravinda ; Chen, Lin Y. ; Delitala, Alessandro ; Devereux, Richard B. ; Doevendans, Pieter A. ; Dominiczak, Anna F. ; Ferrucci, Luigi ; Ford, Ian ; Gieger, Christian ; Harris, Tamara B. ; Haugen, Eric ; Heinig, Matthias ; Hernandez, Dena G. ; Hillege, Hans L. ; Hirschhorn, Joel N. ; Hofman, Albert ; Hubner, Norbert ; Hwang, Shih Jen ; Iorio, Annamaria ; Kähönen, Mika ; Kellis, Manolis ; Kolcic, Ivana ; Kooner, Ishminder K. ; Kooner, Jaspal S. ; Kors, Jan A. ; Lakatta, Edward G. ; Lage, Kasper. / 52 Genetic Loci Influencing Myocardial Mass. En: Journal of the American College of Cardiology. 2016 ; pp. 1435-1448.
@article{51b205f1ec744a8d9d47a5dd716fd45a,
title = "52 Genetic Loci Influencing Myocardial Mass",
abstract = "{\circledC} 2016 American College of Cardiology FoundationBackground 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.",
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 Polašek 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{\cc}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",
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doi = "10.1016/j.jacc.2016.07.729",
language = "English (US)",
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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 2016, '52 Genetic Loci Influencing Myocardial Mass', Journal of the American College of Cardiology, pp. 1435-1448. https://doi.org/10.1016/j.jacc.2016.07.729

52 Genetic Loci Influencing Myocardial Mass. / van der Harst, Pim; van Setten, Jessica; Verweij, Niek; Vogler, Georg; Franke, Lude; Maurano, Matthew T.; Wang, Xinchen; Mateo Leach, Irene; Eijgelsheim, Mark; Sotoodehnia, Nona; Hayward, Caroline; Sorice, Rossella; Meirelles, Osorio; Lyytikäinen, Leo Pekka; Polašek, Ozren; Tanaka, Toshiko; Arking, Dan E.; Ulivi, Sheila; Trompet, Stella; Müller-Nurasyid, Martina; Smith, Albert V.; Dörr, Marcus; Kerr, Kathleen F.; Magnani, Jared W.; Del Greco M., Fabiola; Zhang, Weihua; Nolte, Ilja M.; Silva, Claudia T.; Padmanabhan, Sandosh; Tragante, Vinicius; Esko, Tõnu; Abecasis, Gonçalo R.; Adriaens, Michiel E.; Andersen, Karl; Barnett, Phil; Bis, Joshua C.; Bodmer, Rolf; Buckley, Brendan M.; Campbell, Harry; Cannon, Megan V.; Chakravarti, Aravinda; Chen, Lin Y.; Delitala, Alessandro; Devereux, Richard B.; Doevendans, Pieter A.; Dominiczak, Anna F.; Ferrucci, Luigi; Ford, Ian; Gieger, Christian; Harris, Tamara B.; Haugen, Eric; Heinig, Matthias; Hernandez, Dena G.; Hillege, Hans L.; Hirschhorn, Joel N.; Hofman, Albert; Hubner, Norbert; Hwang, Shih Jen; Iorio, Annamaria; Kähönen, Mika; Kellis, Manolis; Kolcic, Ivana; Kooner, Ishminder K.; Kooner, Jaspal S.; Kors, Jan A.; Lakatta, Edward G.; Lage, Kasper.

En: Journal of the American College of Cardiology, 27.09.2016, p. 1435-1448.

Resultado de la investigación: Contribución a RevistaArtículo

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

PY - 2016/9/27

Y1 - 2016/9/27

N2 - © 2016 American College of Cardiology FoundationBackground 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 - © 2016 American College of Cardiology FoundationBackground 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.

U2 - 10.1016/j.jacc.2016.07.729

DO - 10.1016/j.jacc.2016.07.729

M3 - Article

C2 - 27659466

SP - 1435

EP - 1448

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

ER -

van der Harst P, van Setten J, Verweij N, Vogler G, Franke L, Maurano MT y otros. 52 Genetic Loci Influencing Myocardial Mass. Journal of the American College of Cardiology. 2016 sep 27;1435-1448. https://doi.org/10.1016/j.jacc.2016.07.729