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

Date Issued
2017
Author(s)
Yang, B.
Zhou, W.
Jiao, J.
Nielsen, J.B.
Mathis, M.R.
Heydarpour, M.
Lettre, G.
Folkersen, L.
Prakash, S.
Schurmann, C.
Fritsche, L.
Farnum, G.A.
Lin, M.
Othman, M.
Hornsby, W.
Driscoll, A.
Levasseur, A.
Thomas, M.
Farhat, L.
Dub\'e, M.-P.
Isselbacher, E.M.
Franco-Cereceda, A.
Guo, D.-C.
Bottinger, E.P.
Deeb, G.M.
Booher, A.
Kheterpal, S.
Chen, Y.E.
Kang, H.M.
Kitzman, J.
Cordell, H.J.
Keavney, B.D.
Goodship, J.A.
Ganesh, S.K.
Abecasis, G.
Eagle, K.A.
Boyle, A.P.
Loos, R.J.F.
Eriksson, P.
Tardif, J.-C.
Brummett, C.M.
Milewicz, D.M.
Body, S.C.
Willer, C.J.
Abstract
\textcopyright 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.