Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Cell. 2013 Aug 1;154(3):518-29. doi: 10.1016/j.cell.2013.06.049.
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
精神分裂症患者中可能会出现新出现的突变，这些突变源自原本健康的家庭中的受影响个体。此外，在正常的大脑发育过程中，基因的表达模式具有特定的发育阶段和神经解剖结构特征。我们在精神分裂症患者中发现了新出现的突变，然后将负责的基因映射到正常人类脑组织的转录组图谱上，这些组织来自妊娠 13 周至成年的各个阶段。在胎儿发育过程中的背外侧和腹外侧前额叶皮层中，携带精神分裂症中新出现的破坏性突变的基因形成了一个网络，该网络在转录共表达和蛋白质相互作用方面显著富集。该网络中的 50 个基因在神经元迁移、突触传递、信号转导、转录调控和运输等方面发挥作用。这些结果表明，胎儿前额叶皮质神经发生的破坏对精神分裂症的病理生理学至关重要。这些结果还支持将基因组和转录组分析整合起来，以在时间和空间上对大脑中的关键神经发育过程进行映射的可行性。
