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 Bendl, Georgios Voloudakis, Vahram Haroutunian, Gabriel E. Hoffman, Panos Roussos, Manolis Kellis, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Sabina Berretta, Rahul Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Lijun Cheng, H. Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew 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 Dracheva, Shiron Drusinsky, Ziheng Duan, Duc M. 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 Girdhar, Fernando S. Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Natalie Hawken, Marcus Ho, Ella Henry, Stephanie C. Hicks, Marcus 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 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 Liu, Shaoke Lou, Chunyu Liu, Dan Lü, Shaoke Lou, Jacob M. Loupe, Dan Lü, Shaojie Ma, Liang Ma, Michael 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 Moran, Eran A. Mukamel, Angus C. Nairn, Charles B. Nemeroff, Pengyu Ni, Scott Norton, Tomasz J. Nowakowski, Larsson Omberg, Stephanie C. Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Mette A. Peters, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Katherine S. Pollard, Alex A. Pollen, Henry Pratt, Pawel F. Przytycki, Carolin Purmann, Zhaohui Qin, Pingping Qu, Diana Quintero, Towfique Raj, Ananya S. Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J. Ressler, Deanna Ross, Joel 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 Steyert, Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban, Flora M. Vaccarino, Harm van Bakel, Daniel Vo, Brie Wamsley, Yifan Wang, Sidney H. Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Cindy Wen, Annika K. Weimer, Daniel R. Weinberger, Cindy Wen, Zhiping Weng, Sean Whalen, Kevin P. White, A. 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 Zhou, Ryan Ziffra, Zane Zeier, Trisha M. Zintel · 发表于：Science · 年份：2024 · DOI：10.1126/science.adg5136 · 被引用次数：141 · 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.