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

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....

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Published in:	Nature communications Vol. 8; no. 1; pp. 15481 - 10
Main Authors:	Yang, Bo, Zhou, Wei, Jiao, Jiao, Nielsen, Jonas B., Mathis, Michael R., Heydarpour, Mahyar, Lettre, Guillaume, Folkersen, Lasse, Prakash, Siddharth, Schurmann, Claudia, Fritsche, Lars, Farnum, Gregory A., Lin, Maoxuan, Othman, Mohammad, Hornsby, Whitney, Driscoll, Anisa, Levasseur, Alexandra, Thomas, Marc, Farhat, Linda, Dubé, 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, Gonçalo, 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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25.05.2017 Nature Publishing Group Nature Portfolio
Subjects:	13 13/89 14 45 45/43 631/208/205/2138 631/208/4041/3196 692/4019/592/2727 692/699/75/1539 82/80 Amino Acid Substitution Anesthesiology Aortic Valve - abnormalities Aortic Valve - embryology Aortic Valve - metabolism Bicuspid Aortic Valve Disease Case-Control Studies Cell Transdifferentiation - genetics CRISPR CRISPR-Cas Systems Female GATA4 Transcription Factor - deficiency GATA4 Transcription Factor - genetics GATA4 Transcription Factor - metabolism Gene Regulatory Networks Genetic variance Genetic Variation Genome-Wide Association Study Genomes Heart Heart Defects, Congenital - genetics Heart Valve Diseases - embryology Heart Valve Diseases - genetics Heart Valve Diseases - metabolism Hospitals Humanities and Social Sciences Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Internal medicine Male Medicine multidisciplinary Mutation, Missense Phenotype Proteins Risk factors RNA, Untranslated - genetics Science Science (multidisciplinary) Stem cells Surgery Transcription factors New York Canada Sweden United Kingdom > UK United States > US Quebec Canada Montreal Quebec Canada Ann Arbor Michigan Michigan
ISSN:	2041-1723, 2041-1723
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Summary:	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. Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work These authors jointly supervised this work
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms15481