Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders
Authors: Xia Yan , Xia Cuihua , Jiang Yi , Chen Yu , Zhou Jiaqi , Dai Rujia , Han Cong , Mao Zhongzheng ,   PsychENCODE Consortium, Liu Chunyu , Chen Chao , Akbarian Schahram , Abyzov Alexej , Ahituv Nadav , Arasappan Dhivya , Almagro Armenteros Jose Juan , Beliveau Brian J. , Bendl Jaroslav , 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. , Daskalakis Nikolaos P. , Davila-Velderrain Jose , 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. , Fullard John F. , 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 , Haroutunian Vahram , Hawken Natalie , He Chuan , Henry Ella , Hicks Stephanie C. , Ho Marcus , Ho Li-Lun , Hoffman Gabriel E. , 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 , Kellis Manolis , Khullar Saniya , 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 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 , Mohammadi Shahin , 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 , Roussos Panos , Rozowsky Joel , Ruth Misir , Ruzicka W. Brad , 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 , Subburaju Sivan , Sudhof Thomas , Snyder Michael , Tao Ran , Therrien Karen , Tsai Li-Huei , Urban Alexander E. , Vaccarino Flora M. , van Bake Harm , Vo Daniel , Voloudakis Georgios , 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

Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) with transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD, and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. In addition, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene coexpression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene coexpression variability. We identified several gene coexpression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules, including those encoding
SCN2A
,
FGF14
, and
C3
. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction and implicate immune and synaptic-related pathways in these sex differences.