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Nat Commun. 2017 May 25;8:15481. doi: 10.1038/ncomms15481.

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

Author information

1
Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
2
Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
3
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
4
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
5
Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
6
Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
7
Montreal Heart Institute, Montreal, Quebec, Canada HIT 1C8.
8
Department of Medicine, Université de Montréal, Montreal, Quebec, Canada QC H3T 1J4.
9
Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
10
Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen DK-2800, Denmark.
11
Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
12
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
13
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
14
Norwegian University of Science and Technology, Trondheim 7491, Norway.
15
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA.
16
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
17
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
18
Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
19
Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
20
Manchester Heart Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.
21
The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Abstract

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.

PMID:
28541271
PMCID:
PMC5458508
DOI:
10.1038/ncomms15481
[Indexed for MEDLINE]
Free PMC Article

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