Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain
Authors: Wen Cindy , Margolis Michael , Dai Rujia , Zhang Pan , Przytycki Pawel F. , Vo Daniel D. , Bhattacharya Arjun , Matoba Nana , Tang Miao , Jiao Chuan , Kim Minsoo , Tsai Ellen , Hoh Celine , Aygün Nil , Walker Rebecca L. , Chatzinakos Christos , Clarke Declan , Pratt Henry ,   PsychENCODE Consortium†, Peters Mette A. , Gerstein Mark , Daskalakis Nikolaos P. , Weng Zhiping , Jaffe Andrew E. , Kleinman Joel E. , Hyde Thomas M. , Weinberger Daniel R. , Bray Nicholas J. , Sestan Nenad , Geschwind Daniel H. , Roeder Kathryn , Gusev Alexander , Pasaniuc Bogdan , Stein Jason L. , Love Michael I. , Pollard Katherine S. , Liu Chunyu , Gandal Michael J. , Akbarian Schahram , Abyzov Alexej , Ahituv Nadav , Arasappan Dhivya , Almagro Armenteros Jose Juan , Beliveau Brian J. , Bendl Jaroslav , Berretta Sabina , Bharadwaj Rahul A. , 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 , Clement Ashley , Collado-Torres Leonardo , Cooper Gregory M. , Crawford Gregory E. , 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 , Gaynor Sophia , 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 , Iatrou Artemis , Inoue Fumitaka , Jajoo Aarti , Jensen Matthew , Jiang Lihua , Jin Peng , Jin Ting , Jops Connor , Jourdon Alexandre , Kawaguchi Riki , Kellis Manolis , 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 , 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 , Phalke Nishigandha , Pinto Dalila , Pjanic Milos , Pochareddy Sirisha , Pollen Alex , 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 , Seyfried Nicholas , Shao Zhiping , Shedd Nicole , Shieh Annie W. , Shin Joo Heon , Skarica Mario , Snijders Clara , Song Hongjun , State Matthew W. , Steyert Marilyn , Subburaju Sivan , Sudhof Thomas , Snyder Michael , Tao Ran , Therrien Karen , Tsai Li-Huei , Urban Alexander E. , Vaccarino Flora M. , van Bakel Harm , Voloudakis Georgios , Wamsley Brie , Wang Tao , Wang Sidney H. , Wang Daifeng , Wang Yifan , Warrell Jonathan , Wei Yu , Weimer Annika K. , 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 Chunling , Zhang Bin , Zhang Jing , Zhang Yanqiong , Zhou Xiao , Ziffra Ryan , Zeier Zane R. , Zintel Trisha M. 
Published: May 2024

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.