Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

精神分裂症是一种复杂的神经精神疾病，具有性别二态性特征，包括差异症状、药物反应和男性发病率。先前对精神分裂症性别差异的大规模转录组分析主要集中在前额叶皮层。通过分析 BrainSeq Consortium 数据（尾状核：n = 399，背外侧前额叶皮层：n = 377，海马体：n = 394），我们确定了 831 个独特的基因，这些基因在不同大脑区域表现出性别差异，丰富了免疫相关通路。我们观察到男性精神分裂症患者海马体中 X 染色体剂量减少。我们的性别互动模型揭示了精神分裂症中 148 个连接点以性别特异性方式失调。性别特异性精神分裂症分析发现了数十个差异表达基因，尤其富含免疫相关途径。最后，我们的性别相互作用表达数量性状位点分析揭示了 704 个独特基因，其中 9 个与精神分裂症风险相关。这些发现强调了对性二态性特征进行性别知情分析的重要性，为精神分裂症的个性化治疗策略提供信息，并强调需要增加女性样本进行精神分裂症分析。