Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve
Yang, Bo; Zhou, Wei; Jiao, Jiao; Nielsen, Jonas Bille; Mathis, Michael R; Heydarpour, Mahyar; Lettre, Guillaume; Folkersen, Lasse; Prakash, Siddharth; Schurmann, Claudia; Fritsche, Lars; Farnum, Gregory A; Lin, Maoxuan; Othman, Mohamed; Hornsby, Whitney; Driscoll, Anisa; Levasseur, Alexandra; Thomas, Marc; Farhat, Linda; Dube, Marie-Pierre; Isselbacher, Eric M.; Franco-Cereceda, Anders; Guo, Dong-Chuan; Bottinger, Erwin P; Deeb, G Michael; Booher, Anna; Kheterpal, Sachin; Chen, Y. Eugene; Kang, Hyun Min; Kitzman, Jacob; Cordell, Heather J.; Keavney, Bernard D; Goodship, Judith A; Ganesh, Santhi K; Abecasis, Goncalo; Eagle, Kim A.; Boyle, Alan P; Loos, Ruth J. F.; Eriksson, Per; Tardif, Jean-Claude; Brummett, Chad M; Milewicz, Dianna M; Body, Simon C; Willer, Cristen J
Journal article, Peer reviewed
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Original versionNature Communications. 2017, 8 . 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.