52 Genetic Loci Influencing Myocardial Mass

作者：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 Maria Nolte, Claudia Silva, Sandosh Padmanabhan, Vinicius Tragante, Tõnu Esko, Gonçalo R. Abecasis, Michiel E. Adriaens, Karl K Andersen, Phil Barnett, Joshua C. Bis, Rolf Bodmer, Brendan Martin 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 N. Haugen, Matthias Heinig, Dena G. Hernandez, Hans L. Hillege, Joel N. Hirschhorn, Albert Hofman, Norbert Hübner, Shih-Jen Hwang, Annamaria Iorio, Mika A. P. Kähönen, M Kellis, Ivana Kolčić, Ishminder K. Kooner, Jaspal Singh 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 J. Neph, Alex S. Nord, Teresa Nutile, Peter M. Okin, Jesper Velgaard Olsen, Ben A. Oostra, Josef Martin Penninger, Len A. Pennacchio, Tune H. Pers, Siegfried Perz, Annette Peters, Yigal M. Pinto, Arne Pfeufer, Maria Grazia Pilia, Peter Paul Pramstaller, Bram Peter Prins, Olli Tuomas Raitakari, Soumya Raychaudhuri, Kenneth M. Rice, Elizabeth J. Rossin, Jerome I. Rotter, Sebastian Schäfer, David Schlessinger, Carsten Oliver 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, André Gerardus Uitterlinden, Malou van den Boogaard, Cornelia M. van Duijn, Wiek H. van Gilst, Jorma S.A. Viikari, Peter M. Visscher, Véronique Vitart, Uwe Völker, Mélanie Waldenberger, Christian X. Weichenberger, Harm-Jan Westra, Cisca Wijmenga, Bruce H. R. Wolffenbuttel, Jian Yang, Connie R. Bezzina, Patricia B. Munroe, Harold Snieder, Alan F. Wright, Igor Rudan, Laurie A. Boyer, Folkert Wouter Asselbergs, Dirk J. van Veldhuisen, Bruno H. Ch. Stricker, Bruce M. Psaty, Marina Ciullo, Serena Sanna, Terho J. Lehtimäki, James Fox Wilson, Stefania Bandinelli, Álvaro Alonso, Paolo Gasparini, J. Wouter Jukema, Stefan Kääb, Vilmundur G. Gudnason, Stephan Burkhard Felix, Susan R. Heckbert, Rudolf A. de Boer, Christopher Newton‐Cheh, Andrew A. Hicks, John Campbell Chambers, Yalda Jamshidi, Axel Visel, Vincent M. Christoffels, Aaron J. Isaacs, Nilesh J. Samani, Paul I. W. de Bakker · 发表于：Journal of the American College of Cardiology · 年份：2016 · DOI：10.1016/j.jacc.2016.07.729 · 被引用次数：136 · 研究领域：Cardiac electrophysiology and arrhythmias、Genetic Associations and Epidemiology、Genetics and Physical Performance

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 n...