Single-cell multi-cohort dissection of the schizophrenia transcriptome

• Published in: Science (American Association for the Advancement of Science) Vol. 384; no. 6698; p. eadg5136
• Main Authors: Ruzicka, W. Brad, Mohammadi, Shahin, Fullard, John F., Davila-Velderrain, Jose, Subburaju, Sivan, Tso, Daniel Reed, Hourihan, Makayla, Jiang, Shan, Lee, Hao-Chih, Bendl, Jaroslav, Voloudakis, Georgios, Haroutunian, Vahram, Hoffman, Gabriel E., Roussos, Panos, Kellis, Manolis, Akbarian, Schahram, Abyzov, Alexej, Ahituv, Nadav, Arasappan, Dhivya, Almagro Armenteros, Jose Juan, Beliveau, Brian J., Berretta, Sabina, Bharadwaj, Rahul A., Bhattacharya, Arjun, Bicks, Lucy, Brennand, Kristen, Capauto, Davide, Champagne, Frances A., Chatterjee, Tanima, Chatzinakos, Chris, Chen, Yuhang, Chen, H. Isaac, Cheng, Yuyan, Cheng, Lijun, Chess, Andrew, Chien, Jo-fan, Chu, Zhiyuan, Clarke, Declan, Clement, Ashley, Collado-Torres, Leonardo, Cooper, Gregory M., Crawford, Gregory E., Dai, Rujia, Daskalakis, Nikolaos P., Deep-Soboslay, Amy, Deng, Chengyu, DiPietro, Christopher P., Dracheva, Stella, Drusinsky, Shiron, Duan, Ziheng, Duong, Duc, Dursun, Cagatay, Eagles, Nicholas J., Edelstein, Jonathan, Emani, Prashant S., Galani, Kiki, Galeev, Timur, Gandal, Michael J., Gaynor, Sophia, Gerstein, Mark, Geschwind, Daniel H., Girdhar, Kiran, Goes, Fernando S., Greenleaf, William, Grundman, Jennifer, Guo, Hanmin, Guo, Qiuyu, Gupta, Chirag, Hadas, Yoav, Hallmayer, Joachim, Han, Xikun, Hawken, Natalie, He, Chuan, Henry, Ella, Hicks, Stephanie C., Ho, Marcus, Ho, Li-Lun, Huang, Yiling, Huuki-Myers, Louise A., Hwang, Ahyeon, Hyde, Thomas M., Iatrou, Artemis, Inoue, Fumitaka, Jajoo, Aarti, Jensen, Matthew, Jiang, Lihua, Jin, Peng, Jin, Ting, Jops, Connor, Jourdon, Alexandre, Kawaguchi, Riki, Kleinman, Joel E., Kleopoulos, Steven P., Kozlenkov, Alex, Kriegstein, Arnold, Kundaje, Anshul, Kundu, Soumya, Lee, Cheyu, Lee, Donghoon, Li, Junhao
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 24.05.2024
• Subjects: Adult; Aged; Aged, 80 and over; Biological effects; Brain; Brain architecture; Bulk sampling; Cohort Studies; Developmental Delays; Etiology; Excitation spectra; Female; Frequency spectrum; Gene expression; Gene sequencing; Genes; Genetic Predisposition to Disease; Genetics; Genomics; Health risk assessment; Heterogeneity; Humans; Male; Mental disorders; Meta Analysis; Middle Aged; Neuroglia - metabolism; Neurons; Neurons - metabolism; Nuclei (cytology); Pathophysiology; Phenotypes; Populations; Prefrontal cortex; Prefrontal Cortex - metabolism; Ribonucleic acid; Risk Factors; RNA; Schizophrenia; Schizophrenia - genetics; Single-Cell Analysis; Subpopulations; Synapses; Synapses - metabolism; Transcription factors; Transcriptome; Transcriptomes; Transcriptomics; Young Adult
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adg5136

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.