研究人员对两个独立队列中140人的人类前额叶皮层中与精神分裂症相关的转录组变化进行了单细胞分析。兴奋性神经元是受影响最严重的细胞群，其转录变化集中在神经发育和突触相关的分子通路上。转录改变包括已知的遗传风险因素，这表明罕见和常见基因组变异在精神分裂症的神经元群体特异性改变上趋于一致。
根据精神分裂症相关转录变化的程度，研究人员确定了以特定兴奋性和抑制性神经元细胞状态表达为标志的两个精神分裂症患者群体。该单细胞图谱将转录组变化与病因遗传风险因素联系起来，将已有知识与人类皮层细胞结构相结合，促进了对精神分裂症病理生理学和异质性的机理理解。
据介绍，精神分裂症的复杂性和异质性阻碍了机理的阐明和更有效疗法的开发。
附：英文原文
Title: Single-cell multi-cohort dissection of the schizophrenia transcriptome
Author: W. Brad Ruzicka, Shahin Mohammadi, John F. Fullard, Jose Davila-Velderrain, Sivan Subburaju, Daniel Reed Tso, Makayla Hourihan, Shan Jiang, Hao-Chih Lee, Jaroslav Bendl, PsychENCODE Consortium§, Georgios Voloudakis, Vahram Haroutunian, Gabriel E. Hoffman, Panos Roussos, Manolis Kellis
Issue&Volume: 2024-05-24
Abstract: The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.
DOI: adg5136
Source: https://www.science.org/doi/10.1126/science.adg5136