Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

Background In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of 'brain to behaviour' pathogenic mechanisms, remains largely unknown. Methods We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). Results We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 x 10(-11)) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 x 10(-11), oligodendrocyte, p < 1.31 x 10(-09)). Conclusion Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.

Automated summary

Recent research has uncovered hundreds of genes implicated in autism spectrum disorder (ASD), affecting various molecular pathways. However, the specific molecular mechanisms underlying ASD, particularly in relation to brain function and behavior, remain largely unknown. Integrating large-scale single-cell brain transcriptomes and de novo loss-of-function ASD variants, a study identified patterns of spatial-temporal and cell type expression of ASD-implicated genes across different developmental brain regions. The findings suggest a strong association between subtypes of non-neuronal glial cells and the pathogenesis of ASD, urging further exploration of alternative biological pathways for this disorder.