Abstract
BackgroundNeurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures.MethodsWe present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single “seed” gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules.ResultsThe newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, and KCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling.ConclusionsIn summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available at https://github.com/jchow32/magi-s.
Highlights
Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills
We hypothesized that the phenotypic heterogeneity observed in NDDs can be better understood by dissecting the phenotype based on the pathways and modules disrupted in these disorders
Focusing on the more common comorbid feature of seizures, we applied MAGI-S to a subset of 111 seed genes strongly associated with NDDs, producing 1 module per seed gene
Summary
Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. We previously described MAGI, a tool to identify modules of genes significantly enriched for de novo variants in individuals with autism and ID/DD by integrating both protein-protein interaction networks and RNA sequencing data with variant calls [16] Using this method, we identified distinct gene modules for signaling pathways and synaptic transmission from a set of de novo variants, and patients with mutations in these modules were observed to have more severe ID phenotypes than other patients. Network and expression-based integration approaches that can accomplish this task are necessary to further understand the phenotypic heterogeneity of NDD-associated genes [1, 24]
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