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

Congenital heart disease (CHD) occurs in similar to 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.

Danish Heart Foundation

Danish Heart Foundation

Forskningsradet for Sundhed og Sygdom

Forskningsradet for Sundhed og Sygdom

Eleanor and Miles Shore Fellowship

Eleanor and Miles Shore Fellowship

Pediatric Scientist Developmental Program

Pediatric Scientist Developmental Program

National Institutes of Health [NICHD HD055150-03, 1P01HD068250-01, NHLBI UO1 HL098166, U01 HL098147]

National Institutes of Health

Howard Hughes Medical Institute

Howard Hughes Medical Institute