Published in
Nature Research, Nature Communications, 1(8), 2017
DOI: 10.1038/ncomms15481
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Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve
,
Michael R. Mathis,
Mahyar Heydarpour,
Guillaume Lettre,
Lasse Folkersen,
Siddharth Prakash,
Claudia Schurmann,
Lars Fritsche ,
Gregory A. Farnum ,
Maoxuan Lin,
Mohammad Othman,
Whitney Hornsby
and other authors.
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Abstract
AbstractBicuspid 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.