Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Nat Commun. 2017 May 25:8:15481. doi: 10.1038/ncomms15481.


Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Aortic Valve / abnormalities*
  • Aortic Valve / embryology
  • Aortic Valve / metabolism
  • Bicuspid Aortic Valve Disease
  • CRISPR-Cas Systems
  • Case-Control Studies
  • Cell Transdifferentiation / genetics
  • Female
  • GATA4 Transcription Factor / deficiency
  • GATA4 Transcription Factor / genetics*
  • GATA4 Transcription Factor / metabolism
  • Gene Regulatory Networks
  • Genetic Variation*
  • Genome-Wide Association Study
  • Heart Defects, Congenital / genetics
  • Heart Valve Diseases / embryology
  • Heart Valve Diseases / genetics*
  • Heart Valve Diseases / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Mutation, Missense
  • Phenotype
  • RNA, Untranslated / genetics


  • GATA4 Transcription Factor
  • GATA4 protein, human
  • RNA, Untranslated