TY - JOUR

T1 - Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development

AU - Hansen, Kasper Lage

AU - Greenway, Steven C

AU - Rosenfeld, Jill A

AU - Wakimoto, Hiroko

AU - Gorham, Joshua M

AU - Segrè, Ayellet V

AU - Roberts, Amy E

AU - Smoot, Leslie B

AU - Pu, William T

AU - C Pereira, Alexandre

AU - Mesquita, Sonia M

AU - Tommerup, Niels

AU - Brunak, Søren

AU - Ballif, Blake C

AU - Shaffer, Lisa G

AU - Donahoe, Patricia K

AU - Daly, Mark J

AU - Seidman, Jonathan G

AU - Seidman, Christine E

AU - Larsen, Lars A

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1210730109

DO - 10.1073/pnas.1210730109

M3 - Journal article

C2 - 22904188

VL - 109

SP - 14035

EP - 14040

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 35

ER -