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

Bo Yang, Wei-Wu Zhou, Jiao Jiao, Jonas B. Nielsen, Michael R. Mathis, Mahyar Heydarpour, Guillaume Lettre, Lasse Westergaard Folkersen, Siddharth Prakash, Claudia Schurmann, Lars Fritsche, Gregory A. Farnum, Maoxuan Lin, Mohammad Othman, Whitney Hornsby, Anisa Driscoll, Alexandra Levasseur, Marc Thomas, Linda Farhat, Marie-Pierre DubeEric M. Isselbacher, Anders Franco-Cereceda, Dong-Chuan Guo, Erwin P. Bottinger, G. Michael Deeb, Anna Booher, Sachin Kheterpal, Y. Eugene Chen, Hyun Min Kang, Jacob Kitzman, Heather J. Cordell, Bernard D. Keavney, Judith A. Goodship, Santhi K. Ganesh, Goncalo Abecasis, Kim A. Eagle, Alan P. Boyle, Ruth J. F. Loos, Per Eriksson, Jean-Claude Tardif, Chad M. Brummett, Dianna M. Milewicz, Simon C. Body, Cristen J. Willer

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    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.
    Original languageEnglish
    Article number15481
    JournalNature Communications
    Number of pages10
    Publication statusPublished - 2017


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