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

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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 languageEnglish (US)
Pages (from-to)1435-1448
Number of pages14
JournalJournal of the American College of Cardiology
Issue number13
StatePublished - 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


  • QRS
  • electrocardiogram
  • genetic association study
  • heart failure
  • left ventricular hypertrophy


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