Single-cell multi-cohort dissection of the schizophrenia transcriptome
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 ,   PsychENCODE Consortium§, 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 , Li Mingfeng , Lin Xiao , Liu Shuang , Liu Jason , Liu Jianyin , Liu Chunyu , Liu Shuang , Lou Shaoke , Loupe Jacob M. , Lu Dan , Ma Shaojie , Ma Liang , Margolis Michael , Mariani Jessica , Martinowich Keri , Maynard Kristen R. , Mazariegos Samantha , Meng Ran , Myers Richard M. , Micallef Courtney , Mikhailova Tatiana , Ming Guo-li , Monte Emma , Montgomery Kelsey S. , Moore Jill E. , Moran Jennifer R. , Mukamel Eran A. , Nairn Angus C. , Nemeroff Charles B. , Ni Pengyu , Norton Scott , Nowakowski Tomasz , Omberg Larsson , Page Stephanie C. , Park Saejeong , Patowary Ashok , Pattni Reenal , Pertea Geo , Peters Mette A. , Phalke Nishigandha , Pinto Dalila , Pjanic Milos , Pochareddy Sirisha , Pollard Katherine S. , Pollen Alex , Pratt Henry , Przytycki Pawel F. , Purmann Carolin , Qin Zhaohui S. , Qu Ping-Ping , Quintero Diana , Raj Towfique , Rajagopalan Ananya S. , Reach Sarah , Reimonn Thomas , Ressler Kerry J. , Ross Deanna , Rozowsky Joel , Ruth Misir , Sanders Stephan J. , Schneider Juliane M. , Scuderi Soraya , Sebra Robert , Sestan Nenad , Seyfried Nicholas , Shao Zhiping , Shedd Nicole , Shieh Annie W. , Shin Joo Heon , Skarica Mario , Snijders Clara , Song Hongjun , State Matthew W. , Stein Jason , Steyert Marilyn , Sudhof Thomas , Snyder Michael , Tao Ran , Therrien Karen , Tsai Li-Huei , Urban Alexander E. , Vaccarino Flora M. , van Bakel Harm , Vo Daniel , Wamsley Brie , Wang Tao , Wang Sidney H. , Wang Daifeng , Wang Yifan , Warrell Jonathan , Wei Yu , Weimer Annika K. , Weinberger Daniel R. , Wen Cindy , Weng Zhiping , Whalen Sean , White Kevin P. , Willsey A. Jeremy , Won Hyejung , Wong Wing , Wu Hao , Wu Feinan , Wuchty Stefan , Wylie Dennis , Xu Siwei , Yap Chloe X. , Zeng Biao , Zhang Pan , Zhang Chunling , Zhang Bin , Zhang Jing , Zhang Yanqiong , Zhou Xiao , Ziffra Ryan , Zeier Zane R. , Zintel Trisha M. 
Published: May 2024

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.