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, Lyytikainen, Leo-Pekka, Polasek, Ozren, Tanaka, Toshiko, Arking, Dan E., Ulivi, Sheila, Trompet, Stella, Muller-Nurasyid, Martina, Smith, Albert V., Dorr, Marcus, Kerr, Kathleen F., Magnani, Jared W., Del Greco, 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, Kahonen, 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, Sillje, 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, Volker, 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, Lehtimaki, Terho, Wilson, James F., Bandinelli, Stefania, Alonso, Alvaro, Gasparini, Paolo, Jukema, J. Wouter, Kaab, 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. and de Bakker, Paul I. W. (2016) 52 genetic loci influencing myocardial mass. Journal of the American College of Cardiology, 68 13: 1435-1448. doi:10.1016/j.jacc.2016.07.729


Author 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
Lyytikainen, Leo-Pekka
Polasek, Ozren
Tanaka, Toshiko
Arking, Dan E.
Ulivi, Sheila
Trompet, Stella
Muller-Nurasyid, Martina
Smith, Albert V.
Dorr, Marcus
Kerr, Kathleen F.
Magnani, Jared W.
Del Greco, 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
Kahonen, 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
Sillje, 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
Volker, 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
Lehtimaki, Terho
Wilson, James F.
Bandinelli, Stefania
Alonso, Alvaro
Gasparini, Paolo
Jukema, J. Wouter
Kaab, 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.
Title 52 genetic loci influencing myocardial mass
Journal name Journal of the American College of Cardiology   Check publisher's open access policy
ISSN 1558-3597
0735-1097
Publication date 2016-09-27
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.jacc.2016.07.729
Open Access Status Not yet assessed
Volume 68
Issue 13
Start page 1435
End page 1448
Total pages 14
Place of publication San Diego, CA, United States
Publisher Elsevier
Language eng
Abstract 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.
Formatted 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.
Keyword Electrocardiogram
Genetic association study
Heart failure
Left ventricular hypertrophy
QRS
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 HG003988
HHSN268201100012C
R01 HL103612
N01 AG012100
HHSN268201100010C
UL1 RR025005
N01 HC095167
HHSN268201100008C
U01 HL080295
UL1 TR001079
R01 HL059367
U01 HL130114
HHSN268201100007C
HHSN268200800007C
N01 HC025195
HHSN268201100011C
R01 HL086694
N02 HL64278
N01 HC095164
U01 DE024427
R01 HL087652
N01 HC095166
U01 HG004402
T32 GM007753
UL1 TR000124
N01 HC095160
N01HC55222
N02HL64278
N01HC85086
R01 HL105756
P30 DK063491
HHSN268201100006C
HHSN268201200036C
UM1 HL098166
R01 LM010098
F32 GM105202
N01 HC095169
N01 AG012109
MC_PC_U127561128
N01 HC095165
HHSN268201500003I
N01HC85082
HHSN268201100009C
N01HC85083
HHSN268201100005C
N01 HC095168
UL1 TR000040
N01 HC095163
U54 HG006997
N01HC85079
R01 AG023629
R01 HL087641
N01 HC095162
R24 HL123879
N01HC85080
K23 HL080025
R01 HL111089
R01 HL116747
PG/12/38/29615
N01 HC095159
N01HC85081
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
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