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

Lookup NU author(s): Professor Heather Cordell, Professor Bernard Keavney, Professor Judith Goodship

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Abstract

© The Author(s) 2017. 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.

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Author(s): Yang B, Zhou W, Jiao J, Nielsen JB, Mathis MR, Heydarpour M, Lettre G, Folkersen L, Prakash S, Schurmann C, Fritsche L, Farnum GA, Lin M, Othman M, Hornsby W, Driscoll A, Levasseur A, Thomas M, Farhat L, Dube M-P, Isselbacher EM, Franco-Cereceda A, Guo D-C, Bottinger EP, Deeb GM, Booher A, Kheterpal S, Chen YE, Kang HM, Kitzman J, Cordell HJ, Keavney BD, Goodship JA, Ganesh SK, Abecasis G, Eagle KA, Boyle AP, Loos RJF, Eriksson P, Tardif J-C, Brummett CM, Milewicz DM, Body SC, Willer CJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2017

Volume: 8

Online publication date: 25/05/2017

Acceptance date: 31/03/2017

Date deposited: 20/06/2017

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms15481

DOI: 10.1038/ncomms15481

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