Polygenic enrichment analysis in multi-omics levels identifies cell/tissue specific associations with schizophrenia...

Understanding the specific cellular origin and tissue heterogeneity in schizophrenia is critically important for exploring the disease etiology. This study aims to investigate these aspects by performing multiple analyses based on omics data.

We performed single-cell disease relevance score (scDRS) algorithm to link brain single-cell RNA sequencing (scRNA-seq) with schizophrenia risk across multi-omics scales at single-cell resolution. This approach identified cell types with overexpression of schizophrenia-related genes implicated by multi-omics panels (ATAC-seq, RNA-seq, TWAS, and GWAS). Schizophrenia-related genes from these multi-omics panels were extracted and combined with scRNA-seq data to calculate scDRS. Subsequently, the cell-type vs. disease association and tissue heterogeneity were assessed using scDRS for each omics panel.

We identified two novel cell subpopulations in the brain that differentially express SCUBE3 (59 cells, 7.0 %) and FN1 (21 cells, 2.5 %). At the individual cell level, schizophrenia-associated cell subpopulations included microglial cell associated with ATAC-seq panel (P_association = 0.002, P_{heterogeneity} = 0.009) and deep layer neuron suggestively associated with GWAS panel (P_association = 0.033, P_{heterogeneity} = 0.017). At the brain tissue level, microglial cell was significantly associated with cortical plate in ATAC-seq panel (P_association = 0.002, P_{heterogeneity} = 0.011). Gene level analysis identified several genes associated with schizophrenia across multi-omics panels.

Our study outlines the signature of cell subpopulations, brain regions, and disease risk genes in schizophrenia at single-cell resolution across multi-omics scales. These findings provide a reference for future precision medicine approaches targeting specific cell types and brain regions in schizophrenia.