Decoding schizophrenia through postmortem human brain transcriptomics

Schizophrenia is a highly heritable neuropsychiatric disorder affecting approximately 1% of the population, yet its pathophysiology has remained elusive due to the absence of gross neuropathological changes. In recent years, advances in transcriptomic profiling of postmortem human brain tissue have begun to illuminate the disease's molecular architecture. This mini-review synthesizes findings from case-control bulk tissue and single-nucleus transcriptomics studies, revealing that schizophrenia is characterized by widespread but subtle gene expression changes concentrated in excitatory neurons within the prefrontal cortex. Downregulation of synaptic and metabolic genes emerges as a consistent theme, accompanied by secondary activation of glial populations. Single-cell resolution studies demonstrate that these transcriptional alterations are cell type-specific and heterogeneous across individuals, with upper-layer excitatory neurons showing particular vulnerability. Despite methodological challenges inherent to postmortem tissue analysis, convergent evidence across multiple large-scale consortia establishes transcriptional dysregulation as a core feature of schizophrenia pathophysiology. Future directions include expanded cohorts and additional brain regions, as well as spatial transcriptomics and isoform-level analyses to fully map the molecular landscape of this complex disorder.