Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2,160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) to transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. Additionally, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene co-expression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene co-expression variability. We identified several gene co-expression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules including those encoding SCN2A, FGF14, and C3. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction, and implicate immune and synaptic-related pathways in these sex differences.

中文翻译：

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精神疾病患者死后脑样本的转录组性别差异


许多精神疾病表现出性别差异，但其潜在机制仍知之甚少。我们在性别分层研究设计中分析了来自 PsychENCODE 联盟的 2,160 个死后成人前额皮质大脑样本的转录组学数据。我们将精神分裂症（SCZ）、双相情感障碍（BD）和自闭症谱系障碍（ASD）患者死后大脑样本的转录组学数据与无已知精神疾病史的个体死后对照大脑的转录组学数据进行了比较。我们发现，患有 SCZ、BD 和 ASD 的女性大脑样本比患有这些疾病的男性大脑样本显示出更高的转录组功能障碍负担。这一观察结果得到了女性与男性大脑标本中观察到的大量差异表达基因（DEG）和更大程度的基因表达变化的支持。此外，女性患者大脑样本显示出更大的整体连接功能障碍，其定义为具有连接变化的基因共表达模块的比例更高，连接负担更高，表明基因共表达变异程度更大。我们鉴定了几个富含性别偏差 DEG 的基因共表达模块，并从全基因组关联研究中鉴定了涉及不同脑细胞类型的免疫和突触功能的基因。我们发现许多基因作为这些模块中的中心，包括编码 SCN2A、FGF14 和 C3 的基因。我们的结果表明，在精神疾病的背景下，男性和女性表现出不同程度的转录组功能障碍，并暗示这些性别差异中存在免疫和突触相关途径。