Human brain cell type-specific gene co-expression associated with autism spectrum disorder

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder with substantial phenotypic and genetic heterogeneity. Until now, about a thousand diverse genes have been associated with ASD, while it remains elusive that how disruptions in these different genes can lead to a common clinical phenotype. Therefore, it is essential to understand how ASD candidate genes relate to each other and identify potential shared molecular pathways. Human brain is a highly heterogeneous organ involving multiple cell types. Different functions in different types of cells may be dysregulated in ASD; investigating functional interactions between ASD candidate genes in normal human brain cells may shed new light on the genetic heterogeneity of ASD. To this end, we construct cell type-associated gene co-expression networks based on human brain cell gene expression data. Then we identify seven cell type-specific gene modules and analyze the specific gene functions in each cell type. We also identify six ASD-associated gene modules and study the dysregulated functions in ASD. Lastly, we obtain two ASD-associated cell type-specific gene modules for studying the cell type-specific aberrant functions in ASD. It is found that ASD-associated astrocytes-specific gene modules are relevant to endocytosis, neuron differentiation and cell projection organization, while ASD-associated neurons-specific gene modules are relevant to presynapse, glutamatergic synapse and neuron projection morphogenesis. Our method has been proven to be effective in discovering ASD-associated cell type-specific gene expression pattern. Our findings can promote the study of the heterogeneity of ASD in gene expression between different cell types, providing new insights into the molecular mechanisms underlying the pathogenesis of ASD.