Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development

Research output: Contribution to journalJournal articleResearchpeer-review

Kasper Lage Hansen, Steven C Greenway, Jill A Rosenfeld, Hiroko Wakimoto, Joshua M Gorham, Ayellet V Segrè, Amy E Roberts, Leslie B Smoot, William T Pu, Alexandre C Pereira, Sonia M Mesquita, Niels Tommerup, Søren Brunak, Blake C Ballif, Lisa G Shaffer, Patricia K Donahoe, Mark J Daly, Jonathan G Seidman, Christine E Seidman, Lars A Larsen

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
JournalProceedings of the National Academy of Sciences USA (PNAS)
Volume109
Issue number35
Pages (from-to)14035-40
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 2012

ID: 40803966