|
Abstract
|
Understanding the functional implications of genes’ variants related to autism heterogeneity represents a crucial challenge. We aimed to identify gene sets (i.e., groups of genes with convergent biological functions) potentially relevant to autism subtyping in terms of different loads of possibly damaging variants (PDVs) among two subgroups of autistic children.
After subdividing our sample of 71 autistic children (3-12 years) in two subgroups with higher ( > 80; n=43) and lower ( ⩽ 80; n=28) intelligence quotient (IQ), a gene set variants enrichment analysis identified gene sets with significantly different incidence of PDVs between the subgroups. Significant gene sets were then clustered into modules of genes. Their brain expression was investigated according to the BrainSpan Atlas of the Developing Human Brain. Next, we extended each module by selecting the genes that are both spatio-temporally co-expressed in the developing brain and physically interacting with those in the modules. Last, we explored the incidence of autism susceptibility genes.
Our analysis identified 38 significant gene sets (FDR, q < 0.05), which clustered in four gene modules involved in ion cell communication, neurocognition, gastrointestinal function, and immune system. Those modules were highly expressed in specific brain structures across development. Spatio-temporal brain co-expression across development and physical protein interactions identified extended clusters of genes in which we found an over-representation of autism susceptibility genes.
Our unbiased approach identified modules of genes functionally meaningful to autism in a relatively small set of participants, providing evidence of their implication in the phenotypic differences of autism subgroups. Moreover, our results suggest that diversity in autism likely originates from multiple interacting pathways. Future research could leverage the present approach to identify genetic pathways relevant to autism subtyping.
|
