Journal article
Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development
Department of Systems Biology, Technical University of Denmark1
CFB - Metagenomic Systems Biology, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark2
Pediatric Surgical Research Laboratories3
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
Massachusetts General Hospital5
PerkinElmer, Inc.6
Boston Children's Hospital7
Broad Institute of Harvard University and Massachusetts Institute of Technology8
Universidade de São Paulo9
University of Copenhagen10
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark11
...and 1 moreCongenital 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.
Language: | English |
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Publisher: | National Academy of Sciences |
Year: | 2012 |
Pages: | 14035-14040 |
ISSN: | 10916490 and 00278424 |
Types: | Journal article |
DOI: | 10.1073/pnas.1210730109 |
ORCIDs: | 0000-0003-0316-5866 |