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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of the American College of Cardiology |
| Vol/bind | 68 |
| Udgave nummer | 13 |
| Sider (fra-til) | 1435-48 |
| Antal sider | 14 |
| ISSN | 0735-1097 |
| DOI | |
| Status | Udgivet - 27 sep. 2016 |
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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; Launer, Lenore J; Levy, Daniel; Lundby, Alicia; Macfarlane, Peter W; May, Dalit; Meitinger, Thomas; Metspalu, Andres; Nappo, Stefania; Naitza, Silvia; Neph, Shane; Nord, Alex S; Nutile, Teresa; Okin, Peter M; Olsen, Jesper V; Oostra, Ben A; Penninger, Josef M; Pennacchio, Len A; Pers, Tune H; Perz, Siegfried; Peters, Annette; Pinto, Yigal M; Pfeufer, Arne; Pilia, Maria Grazia; Pramstaller, Peter P; Prins, Bram P; Raitakari, Olli T; Raychaudhuri, Soumya; Rice, Ken M; Rossin, Elizabeth J; Rotter, Jerome I; Schafer, Sebastian; Schlessinger, David; Schmidt, Carsten O; Sehmi, Jobanpreet; Silljé, Herman H W; Sinagra, Gianfranco; Sinner, Moritz F; Slowikowski, Kamil; Soliman, Elsayed Z; Spector, Timothy D; Spiering, Wilko; Stamatoyannopoulos, John A; Stolk, Ronald P; Strauch, Konstantin; Tan, Sian-Tsung; Tarasov, Kirill V; Trinh, Bosco; Uitterlinden, Andre G; van den Boogaard, Malou; van Duijn, Cornelia M; van Gilst, Wiek H; Viikari, Jorma S; Visscher, Peter M; Vitart, Veronique; Völker, Uwe; Waldenberger, Melanie; Weichenberger, Christian X; Westra, Harm-Jan; Wijmenga, Cisca; Wolffenbuttel, Bruce H; Yang, Jian; Bezzina, Connie R; Munroe, Patricia B; Snieder, Harold; Wright, Alan F; Rudan, Igor; Boyer, Laurie A; Asselbergs, Folkert W; van Veldhuisen, Dirk J; Stricker, Bruno H; Psaty, Bruce M; Ciullo, Marina; Sanna, Serena; Lehtimäki, Terho; Wilson, James F; Bandinelli, Stefania; Alonso, Alvaro; Gasparini, Paolo; Jukema, J Wouter; Kääb, Stefan; Gudnason, Vilmundur; Felix, Stephan B; Heckbert, Susan R; de Boer, Rudolf A; Newton-Cheh, Christopher; Hicks, Andrew A; Chambers, John C; Jamshidi, Yalda; Visel, Axel; Christoffels, Vincent M; Isaacs, Aaron; Samani, Nilesh J; de Bakker, Paul I W.
I: Journal of the American College of Cardiology, Bind 68, Nr. 13, 27.09.2016, s. 1435-48.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
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 - Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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.
U2 - 10.1016/j.jacc.2016.07.729
DO - 10.1016/j.jacc.2016.07.729
M3 - Journal article
C2 - 27659466
VL - 68
SP - 1435
EP - 1448
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 13
ER -