Single-cell multi-cohort dissection of the schizophrenia transcriptome

作者：W. Brad Ruzicka, Shahin Mohammadi, Shahin Mohammadi, John F. Fullard, John F. Fullard, Jose Davila-Velderrain, Jose Davila-Velderrain, Sivan Subburaju, Daniel Reed Tso, Makayla Hourihan, Shan Jiang, Hao-Chih Lee, Jaroslav M. Bendl, Georgios Voloudakis, Vahram H. Haroutunian, Gabriel E. Hoffman, Panos Roussos, Manolis Kellis, Schahram Akbarian, Alexej S. Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Sabina Berretta, Rahul A. Bharadwaj, Arjun Bhattacharya, Lucy K. Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Lijun Cheng, H. Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew J. Chess, Jo-fan Chien, Zhiyuan Chu, Declan Clarke, Ashley Clement, Leonardo Collado‐Torres, Gregory M. Cooper, Gregory E. Crawford, Rujia Dai, Nikolaos P. Daskalakis, Amy Deep‐Soboslay, Chengyu Deng, Christopher P. DiPietro, Stella M. Dracheva, Shiron Drusinsky, Ziheng Duan, Duc Minh Duong, Cagatay Dursun, Nicholas J. Eagles, Jonathan I. Edelstein, Prashant S. Emani, Kiki Galani, Timur R. Galeev, Michael J. Gandal, Sophia C. Gaynor, Mark Gerstein, Daniel H. Geschwind, Kiran Kumar Girdhar, Fernando S. Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Franz Hallmayer, Xikun Han, Natalie M. Hawken, Marcus C. Ho, Ella Henry, Stephanie C. Hicks, Marcus C. Ho, Li‐Lun Ho, Yi‐Ling Huang, Louise A. Huuki-Myers, Ahyeon Hwang, Thomas M. Hyde, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew L. Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor T. Jops, Alexandre Jourdon, Riki Kawaguchi, Joel E. Kleinman, Steven P. Kleopoulos, Alex Kozlenkov, Arnold R. Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Shuang Liu, Mingfeng Li, Xiao Lin, Chunyu Liu, Jason J. Liu, Shaoke Lou, Chunyu Liu, Dan Lü, Shaoke Lou, Jacob M. Loupe, Dan Lü, Shaojie Ma, Liang Ma, Michael P. Margolis, Jessica Mariani, Keri Martinowich, Kristen R. Maynard, Samantha Mazariegos, Ran Meng, R Myers, Courtney Micallef, Tatiana Mikhailova, Guo‐li Ming, Emma Monte, Kelsey S. Montgomery, Jill E. Moore, Jennifer R. Moran, Eran A. Mukamel, Angus C. Nairn, Charles B. Nemeroff, Pengyu Ni, Scott S. Norton, Tomasz Jan Nowakowski, Larsson Omberg, Stephanie C. Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo M. Pertea, Mette A. Peters, Nishigandha N. Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Katherine S. Pollard, Alex A. Pollen, Henry Pratt, Pawel F. Przytycki, Carolin Purmann, Zhaohui Steve Qin, Pingping Qu, Diana R. Quintero, Towfique Raj, Ananya S. Rajagopalan, Sarah M. Reach, Thomas M. Reimonn, Kerry James Ressler, Deanna Ross, Joel S. Rozowsky, Misir Ruth, Stephan Sanders, Juliane M. Schneider, Soraya Scuderi, Robert Sebra, Nenad Šestan, Nicholas T. Seyfried, Zhiping Shao, Nicole Shedd, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Clara Snijders, Hongjun Song, Matthew W. State, Jason L. Stein, Marilyn R. Steyert, Thomas C. Südhof, Michael Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander Eckehart Urban, Flora M. Vaccarino, Harm van Bakel, Daniel Vo, Brie Wamsley, Yifan Wang, Sidney H. Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Cindy H. Wen, Annika K. Weimer, Daniel R. Weinberger, Cindy H. Wen, Zhiping Weng, Sean Whalen, Kevin P. White, Arthur Jeremy Willsey, Hyejung Won, Wing Hung Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X. Yap, Bin Zhang, Pan Zhang, Yanqiong Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Ming Zhou, Ryan S. Ziffra, Zane R. Zeier, Trisha M. Zintel · 发表于：Science · 年份：2024 · DOI：10.1126/science.adg5136 · 被引用次数：145 · 研究领域：Single-cell and spatial transcriptomics、Tryptophan and brain disorders、Gut microbiota and health

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.