Genetic insights of schizophrenia via single cell RNA-sequencing analyses

Schizophrenia is a complex and heterogeneous disorder involving multiple regions and types of cells in the brain. Despite rapid progress made by genome-wide association studies (GWAS) of schizophrenia, the mechanisms of the illness underlying the GWAS significant loci remain less clear.

Researchers at the Chinese Academy of Sciences investigated schizophrenia risk genes using summary-data-based Mendelian randomization based on single-cell sequencing data, and explored the types of brain cells involved in schizophrenia through the expression weighted cell-type enrichment analysis.

The researchers identified 54 schizophrenia risk genes (two-thirds of these genes were not identified using sequencing data of bulk tissues) using single-cell RNA-sequencing data. Further cell type enrichment analysis showed that schizophrenia risk genes were highly expressed in excitatory neurons and caudal ganglionic eminence interneurons, suggesting putative roles of these cells in the pathogenesis of schizophrenia. They also found that these risk genes identified using single-cell sequencing results could form a large protein-protein interaction network with genes affected by disease-causing rare variants.

(A) Venn plot of number of genes identified in bulk tissues level and single-cell level. (B) Upset plot of genes identified in different single cell types. Horizontal bar on left represents number of genes identified in each cell types. Dots and lines represent subsets of genes. Vertical histogram represents number of genes in each subset. Genes both identified in bulk tissue level and single-cell level were red marked. Micro, microglia; Endo, endothelial; Astro, astrocyte; Sert, serotonergic-like neuron; Da, dopaminergic neuron; Per, pericyte; In, inhibitory neuron; OPC, oligodendrocyte precursors; Oligo, oligodendrocyte; Ex, excitatory neuron.

Through integrative analyses using expression data at single-cell levels, we identified 54 risk genes associated with schizophrenia. Notably, many of these genes were only identified using single-cell RNA-sequencing data, and their altered expression levels in particular types of cells, rather than in the bulk tissues, were related to the increased risk of schizophrenia. These results provide novel insight into the biological mechanisms of schizophrenia, and future single-cell studies are necessary to further facilitate the understanding of the disorder.