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
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands.
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
J Am Coll Cardiol. 2016 Sep 27;68(13):1435-1448. doi: 10.1016/j.jacc.2016.07.729.
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.
This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
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.
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.
Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
心肌质量是心肌功能和肥大的关键决定因素。导致心肌收缩的心肌去极化由心电图（ECG）上QRS波群的振幅和持续时间反映。异常的QRS振幅或持续时间反映心肌质量和传导的变化，并与心力衰竭和死亡风险增加相关。
本荟萃分析旨在深入了解心肌质量的遗传决定因素。
我们对多达73518名欧洲血统个体的4种QRS特征进行了全基因组关联荟萃分析，随后进行了广泛的生物学和功能评估。
我们鉴定出52个基因组位点，其中32个是新发现的，这些位点在p < 1×10⁻⁸时与1种或多种QRS表型可靠相关。这些位点在开放染色质、组蛋白修饰和转录因子结合区域富集，表明它们代表了在人类心脏中活跃转录的基因组区域。通路分析提供了证据表明这些位点在心肌肥大中起作用。我们进一步突出了在已鉴定位点的67个候选基因，这些基因在心脏组织中优先表达，并与黑腹果蝇和小家鼠的心脏异常相关。我们在体外和体内验证了SCN5A/SCN10A位点一个新变异的调控功能。
综上所述，我们的发现为控制心肌质量的基因和生物学通路提供了新的见解，并可能有助于识别新的治疗靶点。
