Gene Screening for Autism Based on Cell-type-specific Predictive Models

Abstract

Autism spectrum disorder (ASD), with substantial genetic and phenotypic heterogeneity, is characterized by difficulties in social interaction and communication, and restricted and repetitive behaviors. Recent studies based on bulk RNA-seq data of brains from ASD patients have revealed the affected pathways in ASD, while the cell type heterogeneity of ASD is still needed to be explored. Gene prioritization studies can be conducted for screening gene candidates with high confidence, providing new insights for experimental studies. Based on the single-nucleus RNA-seq data of brains from ASD and healthy individuals, we identify cell-type-specific differential expressed genes by applying three kinds of methods for differential expression analysis and then construct cell-type-specific classification models for ASD adopting the algorithm of stochastic gradient boosting. We find layer 2/3 and 4 excitatory neurons, layer 5/6 cortico-cortical projection neurons, and protoplasmic astrocytes are vulnerable in ASD. Then we calculate gene importance to prioritize cell-type-specific differential expressed genes, and compare the top important genes across different cell types. Our results suggest that causal genes are distinct and dysregulated gene functions are different across brain cells in ASD. The constructed classification models can predict the diagnosis for a nucleus with given cell type, promoting the detection of ASD. The prioritized cell-type-specific genes may be used as potential ASD biomarkers, promoting the development of effective interventions.