| Summary: | Multiple genetic factors contribute to the pathogenesis of autism spectrum disorder (ASD), a kind of neurodevelopmental disorder. Genes were usually studied separately for their associations with ASD. However, genes associated with ASD do not act alone but interact with each other in a network module. The identification of these modules is the basis for the systematic understanding of the pathogenesis of ASD. Moreover, ASD is characterized by highly pathogenic heterogeneity, and gene modules associated with ASD are cell-type-specific. In this study, based on the single-nucleus RNA sequencing data of 41 post-mortem tissue samples from the prefrontal cortex and anterior cingulate cortex of 19 ASD patients and 16 control individuals, we applied sparse module activity factorization, a matrix decomposition method consistent with the multi-factor and heterogeneous characteristics of ASD pathogenesis, to identify cell-type-specific gene modules. Then, statistical procedures were performed to detect highly reproducible cell-type-specific ASD-associated gene modules. Through the enrichment analysis of cell markers, 31 cell-type-specific gene modules related to ASD were further screened out. These 31 gene modules are all enriched with curated ASD risk genes. Finally, we utilized the expression patterns of these cell-type-specific ASD-associated gene modules to build predictive models for ASD. The excellent predictive performance also proved the associations between these gene modules and ASD. Our study confirmed the multifactorial and cell-type-specific characteristics of ASD pathogeneses. The results showed that excitatory neurons such as L2/3, L4, and L5/6-CC play essential roles in ASD’s pathogenic processes. We identified the potential ASD target genes that act together in cell-type-specific modules, such as <i>NRG3</i>, <i>KCNIP4</i>, <i>BAI3</i>, <i>PTPRD</i>, <i>LRRTM4</i>, and <i>LINGO2</i> in the L2/3 gene modules. Our study offers new potential genomic targets for ASD and provides a novel method to study gene modules involved in the pathogenesis of ASD.
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