52 Genetic Loci Influencing Myocardial Mass

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  • 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
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  • Weihua Zhang
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  • Tõnu Esko
  • Gonçalo R Abecasis
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  • Karl Andersen
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  • 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
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  • Dena G Hernandez
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  • Len A Pennacchio
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  • Annette Peters
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  • Arne Pfeufer
  • Maria Grazia Pilia
  • Peter P Pramstaller
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  • Olli T Raitakari
  • Soumya Raychaudhuri
  • Ken M Rice
  • Elizabeth J Rossin
  • Jerome I Rotter
  • Sebastian Schafer
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  • Carsten O Schmidt
  • Jobanpreet Sehmi
  • Herman H W Silljé
  • Gianfranco Sinagra
  • Moritz F Sinner
  • Kamil Slowikowski
  • Elsayed Z Soliman
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  • 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
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  • Peter M Visscher
  • Veronique Vitart
  • Uwe Völker
  • Melanie Waldenberger
  • Christian X Weichenberger
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  • 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

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
JournalJournal of the American College of Cardiology
Volume68
Issue number13
Pages (from-to)1435-48
Number of pages14
ISSN0735-1097
DOIs
Publication statusPublished - 27 Sep 2016

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