Integrating cell-type-specific gene expression and genome-wide associations identifies risk genes for schizophrenia

Integrative studies such as transcriptome-wide association studies (TWAS) and Mendelian randomization (MR) have identified multiple risk genes whose expression level is associated with schizophrenia (SCZ). However, the vast majority of integrative studies are based on quantitative trait loci (QTL) data from bulk brain tissues. Given that gene expression and genetic regulatory effects are highly dependent on cell types, it is important to conduct integrative studies using expression data from specific brain cell types. Here, we investigate the causality between cell-type-specific gene expression and SCZ. We first conducted MR by integrating four cell-type-specific expression quantitative trait loci (eQTL) datasets and genome-wide associations of SCZ separately. We then performed a meta-analysis to explore the causal relationships between gene expression in different human brain cell types and SCZ. We identified multiple genes whose cell-type-specific expression levels are causally associated with SCZ, including 148 significant genes in excitatory neurons, 71 in inhibitory neurons, 63 in astrocytes, 48 in microglia, 70 in oligodendrocytes, 39 in oligodendrocyte precursor cells, 20 in endothelial cells, and 7 in pericytes. We also performed MR using eQTL data from brain tissues and identified 206 genes whose expression levels are causally associated with SCZ. By integrating multiple lines of evidence, we prioritized the most plausible causal genes, including the MAU2 and PPP1R13B. Finally, we performed a drug target analysis to evaluate the therapeutic potential of these genes. Our study reveals the causal relationships between cell-type-specific gene expression and SCZ, providing promising targets for mechanistic investigation and therapeutic interventions.