Hospital Gregorio Marañón, IiSGM, School of Medicine, Calle Dr Esquerdo, 46, Madrid 28007, Spain.
Instituto de Investigación Sanitaria de Santiago, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde, Santiago de Compostela, Spain; Grupo de Xenética Psiquiátrica, Santiago de Compostela, A Coruña, Spain.
Neurobiol Dis. 2019 Jan;121:305-314. doi: 10.1016/j.nbd.2018.10.013. Epub 2018 Oct 19.
The transcriptome profiles of the cingulate gyrus region from the postmortem brain tissues of a set of well-characterized patients with schizophrenia (SCZ) and matched controls were investigated using an integrated approach that analyzed both the alterations in transcription expression pattern and rare genetic variants in expressed genes. We demonstrated increased expression of astrocyte-related genes using spatiotemporal co-expression modules that have previously been established for developing human brain, and showed these results are independent of medication dosage. The relationship between genetic variants and expression pattern in the context of neurodevelopment was further investigated, and we identified an enrichment of rare genetic variants in a set of signature genes that were specific to astrocytes and up-regulated in the patients with SCZ. Our result suggested the involvement of astrocyte malfunction in SCZ pathophysiology. In addition, our approach indicated a novel strategy of narrowing down genetic variants that might contribute to the pathophysiology in the patients with SCZ to a subset of genes that are highly expressed in an affected brain region.
我们采用综合分析的方法，研究了一组具有明确特征的精神分裂症（SCZ）患者和匹配对照者的扣带回皮质区的转录组图谱，该方法同时分析了转录表达模式的改变和表达基因中的罕见遗传变异。我们使用先前为发育中的人类大脑建立的时空共表达模块，证明了星形胶质细胞相关基因的表达增加，并且这些结果独立于药物剂量。我们进一步研究了神经发育背景下遗传变异与表达模式之间的关系，发现一组特异性上调的星形胶质细胞特征基因中的罕见遗传变异富集。我们的结果表明星形胶质细胞功能障碍可能参与了 SCZ 的病理生理学。此外，我们的方法还表明，一种新的策略可以将可能导致 SCZ 患者病理生理学的遗传变异缩小到在受影响脑区中高表达的一组基因子集。
