Single-Cell Transcriptional Profiling Reveals Cell Type-Specific Sex-Dependent Molecular Patterns of Schizophrenia

Schizophrenia (SCZ) is a debilitating psychiatric disorder marked by alterations in cognition and social behavior, resulting in profound impacts on individuals and society. Although sex-dependent disparities in the epidemiology of SCZ are well established, the biological molecular basis of these disparities remains poorly understood. Investigating cell type-specific transcriptomic profiles is critical for identifying regulatory components underlying sex-dependent molecular dysregulation in SCZ, which could serve as targets for sex-specific therapeutic interventions. To address this, we systematically analyzed publicly available single-nucleus RNA sequencing datasets to characterize cell type-specific sex-dependent gene expression profiles in the prefrontal cortex of SCZ cases. Functional enrichment analyses revealed sex-dependent dysregulation patterns of SCZ at the pathway level. Furthermore, we constructed cell type-specific gene regulatory networks for males and females, identifying SCZ-associated transcription factors that interact with sex hormones and their receptors. By incorporating drug screening results from the Connectivity Map, we established disease-gene-drug connections, elucidating sex-dependent molecular mechanisms of SCZ from the single-gene to the regulatory network level. Our findings delineate the molecular patterns of sex-dependent disparities in SCZ, uncover regulatory mechanisms driving SCZ-associated sex-dependent dysregulation, and illustrate the signal flow through which the biological sex influences downstream cellular pathways in SCZ cases. Our study provides significant evidence supporting the neuroprotective role of estrogen in the pathophysiology of female SCZ cases, while also establishing a robust foundation for the development of sex-specific therapeutic approaches for both sexes.