52 Genetic Loci Influencing Myocardial Mass.
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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
Аннотация
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.