Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development.
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.
Pediatric Surgical Research Laboratories, Department of Molecular Biology, and Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. lage.kasper@mgh.harvard.edu
Kasper
K
Lage
Steven C
SC
Greenway
Jill A
JA
Rosenfeld
Hiroko
H
Wakimoto
Joshua M
JM
Gorham
Ayellet V
AV
Segrè
Amy E
AE
Roberts
Leslie B
LB
Smoot
William T
WT
Pu
Alexandre C
AC
Pereira
Sonia M
SM
Mesquita
Niels
N
Tommerup
Søren
S
Brunak
Blake C
BC
Ballif
Lisa G
LG
Shaffer
Patricia K
PK
Donahoe
Mark J
MJ
Daly
Jonathan G
JG
Seidman
Christine E
CE
Seidman
Lars A
LA
Larsen
D030541:Databases, Genetic; D004777:Environment; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006228:Hand Deformities, Congenital / Q000453:epidemiology* / Q000235:genetics*; D006321:Heart / Q000196:embryology; D006801:Humans; D007231:Infant, Newborn; D060066:Protein Interaction Maps / Q000235:genetics*; D012307:Risk Factors; D018709:Statistics, Nonparametric; D059467:Transcriptome