52 Genetic Loci Influencing Myocardial Mass.

Authors:
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 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

J Am Coll Cardiol 2016 09;68(13):1435-1448

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.

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.

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Source
http://dx.doi.org/10.1016/j.jacc.2016.07.729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478167PMC
September 2016
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