Autism and Congenital Heart Disease Share Underlying Molecular Network
• Research Highlight
Autism spectrum disorder (ASD) and congenital heart disease are physiologically distinct disorders that often co-occur, suggesting that the two disorders have underlying mechanisms in common. A recent study of gene networks may hold some promising clues about those shared mechanisms. The study, supported by the National Institute of Mental Health (NIMH), comes out of NIMH’s Convergent Neuroscience initiative , which encourages researchers to examine links across multiple levels of analysis—including genes, cells, brain circuits, and behavior—to better understand mental disorders.
Researchers often look at genetic variation in a group of people to identify changes in genes that may be associated with certain disorders. To date, these studies have not revealed much overlap in the genes associated with ASD and congenital heart disease. Given that genes typically interact in complex systems, a team of researchers at the University of California, San Diego; the University of California, San Francisco; and Yale University hypothesized that a systems-level approach focused on whole gene networks might be an effective way to discover shared mechanisms.
The researchers examined existing data from 21 molecular interaction databases containing information on 2.7 million physical and functional associations among human genes. Employing an analytic approach called network propagation, they used genes with well-established links to either ASD or congenital heart disease as a starting point to identify additional genes that might be connected in a functional network.
The resulting network map for ASD contained 1,583 genes, including genes known to play a role in prenatal brain development and 27 genes that had not been linked with ASD in previous research. The parallel network map for congenital heart disease contained 1,081 genes, including genes previously associated with congenital heart disease in research with mice and 46 genes that had not been linked with congenital heart disease in previous research.
The overlap in the ASD and CHD networks was noticeable. Comparing data from the molecular interaction databases with data from a separate group of 2,628 people, the researchers found strong evidence for the role of 101 genes associated with both ASD and congenital heart disease. Of these 101 genes, 98 had not been previously linked with one or both disorders. This overlap suggests that the two disorders, although physiologically distinct, share an underlying molecular network.
In an experimental test, the researchers used Xenopus tropicalis, a species of frog frequently used by biologists as a model organism, to determine whether disrupting selected shared genes would have noticeable effects on anatomical development. As expected, disrupting the genes led to significant abnormalities in both the brain and heart.
In terms of function, the researchers found that systems related to the movement of ions—particles that carry an electric charge—in and out of cells were especially prominent in the shared gene network. This finding was unexpected because although ion channels are known to play a role in brain cell function and heart rhythm, their role in early development is not clear.
One ion transport gene, SCN2A, showed particularly strong network connections to both ASD and congenital heart disease. When the researchers disrupted SCN2A in the Xenopus model organism, they again observed noticeable brain and heart development abnormalities. These findings suggest that, in addition to its known role in the function of adult cells, SCN2A also influences the early development of organs, including the heart and brain.
The researchers note that their systems-level approach offered a methodological advantage over studies focused on individual genes, as it allowed them to examine many genes at one time and organize the genes by their functions and connections. Further research using these methods may reveal additional convergent molecular networks that explain why certain disorders and conditions co-occur in ways that affect multiple organs, which may be a critical step to improving early screening and intervention methods.
Reference
Rosenthal, S. B., Wilsey, H. R., Xu, Y., Mei, Y., Dea, J., Wang, S., Curtis, C., Sempou, E., Khokha, Mu. K., Chi, N. C., Willsey, A., J., Fisch, K. M., & Ideker, T. (2021). A convergent molecular network underlying autism and congenital heart disease. Cell Systems, 12. 1094-1107. https://doi.org/10.1016/j.cels.2021.07.009
Grants
MH115747-01A1 , GM103504 , HG009979 , TR001442 , HL149746