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

Author

Listed:
  • Bo Yang

    (University of Michigan
    Frankel Cardiovascular Center, University of Michigan)

  • Wei Zhou

    (University of Michigan)

  • Jiao Jiao

    (University of Michigan)

  • Jonas B. Nielsen

    (University of Michigan)

  • Michael R. Mathis

    (University of Michigan)

  • Mahyar Heydarpour

    (Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School)

  • Guillaume Lettre

    (Montreal Heart Institute
    Université de Montréal)

  • Lasse Folkersen

    (Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska University Hospital Solna, Karolinska Institutet
    Center for Biological Sequence Analysis, Technical University of Denmark)

  • Siddharth Prakash

    (University of Texas Health Science Center at Houston McGovern Medical School)

  • Claudia Schurmann

    (The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai)

  • Lars Fritsche

    (University of Michigan
    Norwegian University of Science and Technology)

  • Gregory A. Farnum

    (University of Michigan)

  • Maoxuan Lin

    (University of Michigan)

  • Mohammad Othman

    (University of Michigan)

  • Whitney Hornsby

    (Frankel Cardiovascular Center, University of Michigan)

  • Anisa Driscoll

    (Frankel Cardiovascular Center, University of Michigan)

  • Alexandra Levasseur

    (Frankel Cardiovascular Center, University of Michigan)

  • Marc Thomas

    (Frankel Cardiovascular Center, University of Michigan)

  • Linda Farhat

    (Frankel Cardiovascular Center, University of Michigan)

  • Marie-Pierre Dubé

    (Montreal Heart Institute
    Université de Montréal)

  • Eric M. Isselbacher

    (Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School)

  • Anders Franco-Cereceda

    (Cardiothoracic Surgery Unit, Karolinska University Hospital Solna, Karolinska Institutet)

  • Dong-chuan Guo

    (University of Texas Health Science Center at Houston McGovern Medical School)

  • Erwin P. Bottinger

    (The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai)

  • G. Michael Deeb

    (University of Michigan
    Frankel Cardiovascular Center, University of Michigan)

  • Anna Booher

    (Frankel Cardiovascular Center, University of Michigan
    University of Michigan)

  • Sachin Kheterpal

    (University of Michigan)

  • Y. Eugene Chen

    (University of Michigan
    Frankel Cardiovascular Center, University of Michigan
    University of Michigan)

  • Hyun Min Kang

    (University of Michigan)

  • Jacob Kitzman

    (University of Michigan
    University of Michigan)

  • Heather J. Cordell

    (Institute of Genetic Medicine, Newcastle University)

  • Bernard D. Keavney

    (Faculty of Biology, Medicine and Health, The University of Manchester
    Manchester Heart Centre, Central Manchester University Hospitals NHS Foundation Trust)

  • Judith A. Goodship

    (Institute of Genetic Medicine, Newcastle University)

  • Santhi K. Ganesh

    (Frankel Cardiovascular Center, University of Michigan
    University of Michigan
    University of Michigan)

  • Gonçalo Abecasis

    (University of Michigan)

  • Kim A. Eagle

    (Frankel Cardiovascular Center, University of Michigan
    University of Michigan)

  • Alan P. Boyle

    (University of Michigan
    University of Michigan)

  • Ruth J. F. Loos

    (The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
    The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai)

  • Per Eriksson

    (Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska University Hospital Solna, Karolinska Institutet)

  • Jean-Claude Tardif

    (Montreal Heart Institute
    Université de Montréal)

  • Chad M. Brummett

    (University of Michigan)

  • Dianna M. Milewicz

    (University of Texas Health Science Center at Houston McGovern Medical School)

  • Simon C. Body

    (Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School)

  • Cristen J. Willer

    (Frankel Cardiovascular Center, University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

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.

Suggested Citation

  • Bo Yang & Wei Zhou & Jiao Jiao & Jonas B. Nielsen & Michael R. Mathis & Mahyar Heydarpour & Guillaume Lettre & Lasse Folkersen & Siddharth Prakash & Claudia Schurmann & Lars Fritsche & Gregory A. Farn, 2017. "Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15481
    DOI: 10.1038/ncomms15481
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    Cited by:

    1. Pengfei Lu & Ping Wang & Bingruo Wu & Yidong Wang & Yang Liu & Wei Cheng & Xuhui Feng & Xinchun Yuan & Miriam M. Atteya & Haleigh Ferro & Yukiko Sugi & Grant Rydquist & Mahdi Esmaily & Jonathan T. But, 2022. "A SOX17-PDGFB signaling axis regulates aortic root development," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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