• Author: Hansen, Kasper Lage

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark

  • Author: Greenway, Steven C.

    Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Rosenfeld, Jill A.

    Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, United States

  • Author: Wakimoto, Hiroko

    Department of Cardiology, Boston Children’s Hospital, United States

  • Author: Gorham, Joshua M.

    Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Segrè, Ayellet V.

    Broad Institute of Harvard University and Massachusetts Institute of Technology, United States

  • Author: Roberts, Amy E.

    Department of Molecular Biology, and Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Smoot, Leslie B.

    Department of Molecular Biology, and Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Pu, William T.

    Department of Molecular Biology, and Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: C. Pereira, Alexandre

    University of São Paulo, Brazil

  • Author: Mesquita, Sonia M.

    University of São Paulo, Brazil

  • Author: Tommerup, Niels

    University of Copenhagen, Denmark

  • Author: Brunak, Søren

    CFB - Metagenomic Systems Biology, Novo Nordisk Foundation Center for Biosustainability, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Denmark

  • Author: Ballif, Blake C.

    Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, United States

  • Author: Shaffer, Lisa G.

    Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, United States

  • Author: Donahoe, Patricia K.

    Pediatric Surgical Research Laboratories, Analytical and Translational Genetics Unit, United States

  • Author: Daly, Mark J.

    Broad Institute of Harvard University and Massachusetts Institute of Technology, United States

  • Author: Seidman, Jonathan G.

    Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Seidman, Christine E.

    Analytical and Translational Genetics Unit, Massachusetts General Hospital, United States

  • Author: Larsen, Lars

    University of Copenhagen, Denmark

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Congenital heart disease (CHD) occurs in ∼1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development.
Original languageEnglish
JournalNational Academy of Sciences. Proceedings
Publication date2012
Volume109
Issue35
Pages14035-14040
ISSN0027-8424
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 10

Keywords

  • genetics, transcriptional profiles, systems biology, developmental biology
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