Integrative functional genomic analysis of human brain development and neuropsychiatric risks
Authors: Li Mingfeng , Santpere Gabriel , Imamura Kawasawa Yuka , Evgrafov Oleg V. , Gulden Forrest O. , Pochareddy Sirisha , Sunkin Susan M. , Li Zhen , Shin Yurae , Zhu Ying , Sousa André M. M. , Werling Donna M. , Kitchen Robert R. , Kang Hyo Jung , Pletikos Mihovil , Choi Jinmyung , Muchnik Sydney , Xu Xuming , Wang Daifeng , Lorente-Galdos Belen , Liu Shuang , Giusti-Rodríguez Paola , Won Hyejung , de Leeuw Christiaan A. , Pardiñas Antonio F. ,   BrainSpan Consortium,   PsychENCODE Consortium,   PsychENCODE Developmental Subgroup, Hu Ming , Jin Fulai , Li Yun , Owen Michael J. , O’Donovan Michael C. , Walters James T. R. , Posthuma Danielle , Reimers Mark A. , Levitt Pat , Weinberger Daniel R. , Hyde Thomas M. , Kleinman Joel E. , Geschwind Daniel H. , Hawrylycz Michael J. , State Matthew W. , Sanders Stephan J. , Sullivan Patrick F. , Gerstein Mark B. , Lein Ed S. , Knowles James A. , Sestan Nenad , Willsey A. Jeremy , Oldre Aaron , Szafer Aaron , Camarena Adrian , Cherskov Adriana , Charney Alexander W. , Abyzov Alexej , Kozlenkov Alexey , Safi Alexias , Jones Allan R. , Ashley-Koch Allison E. , Ebbert Amanda , Price Amanda J. , Sekijima Amanda , Kefi Amira , Bernard Amy , Amiri Anahita , Sboner Andrea , Clark Andrew , Jaffe Andrew E. , Tebbenkamp Andrew T. N. , Sodt Andy J. , Guillozet-Bongaarts Angie L. , Nairn Angus C. , Carey Anita , Huttner Anita , Chervenak Ann , Szekely Anna , Shieh Annie W. , Harmanci Arif , Lipska Barbara K. , Carlyle Becky C. , Gregor Ben W. , Kassim Bibi S. , Sheppard Brooke , Bichsel Candace , Hahn Chang-Gyu , Lee Chang-Kyu , Chen Chao , Kuan Chihchau L. , Dang Chinh , Lau Chris , Cuhaciyan Christine , Armoskus Christoper , Mason Christopher E. , Liu Chunyu , Slaughterbeck Cliff R. , Bennet Crissa , Pinto Dalila , Polioudakis Damon , Franjic Daniel , Miller Daniel J. , Bertagnolli Darren , Lewis David A. , Feng David , Sandman David , Clarke Declan , Williams Derric , DelValle Diane , Fitzgerald Dominic , Shen Elaine H. , Flatow Elie , Zharovsky Elizabeth , Burke Emily E. , Olson Eric , Fulfs Erich , Mattei Eugenio , Hadjimichael Evi , Deelman Ewa , Navarro Fabio C. P. , Wu Feinan , Lee Felix , Cheng Feng , Goes Fernando S. , Vaccarino Flora M. , Liu Fuchen , Hoffman Gabriel E. , Gürsoy Gamze , Gee Garrett , Mehta Gaurang , Coppola Gianfilippo , Giase Gina , Sedmak Goran , Johnson Graham D. , Wray Gregory A. , Crawford Gregory E. , Gu Guangyu , van Bakel Harm , Witt Heather , Yoon Hee Jae , Pratt Henry , Zhao Hongyu , Glass Ian A. , Huey Jack , Arnold James , Noonan James P. , Bendl Jaroslav , Jochim Jayson M. , Goldy Jeff , Herstein Jennifer , Wiseman Jennifer R. , Miller Jeremy A. , Mariani Jessica , Stoll Jessica , Moore Jill , Szatkiewicz Jin , Leng Jing , Zhang Jing , Parente Jody , Rozowsky Joel , Fullard John F. , Hohmann John G. , Morris John , Phillips John W. , Warrell Jonathan , Shin Joo Heon , An Joon-Yong , Belmont Judson , Nyhus Julie , Pendergraft Julie , Bryois Julien , Roll Katie , Grennan Kay S. , Aiona Kaylynn , White Kevin P. , Aldinger Kimberly A. , Smith Kimberly A. , Girdhar Kiran , Brouner Kristina , Mangravite Lara M. , Brown Leanne , Collado-Torres Leonardo , Cheng Lijun , Gourley Lindsey , Song Lingyun , Ubieta Luis De La Torre , Habegger Lukas , Ng Lydia , Hauberg Mads E. , Onorati Marco , Webster Maree J. , Kundakovic Marija , Skarica Mario , Reimers Mark , Johnson Matthew B. , Chen Maxine M. , Garrett Melanie E. , Sarreal Melanie , Reding Melissa , Gu Mengting , Peters Mette A. , Fisher Michael , Gandal Michael J. , Purcaro Michael , Smith Michael , Brown Miguel , Shibata Mikihito , Brown Mimi , Xu Min , Yang Mo , Ray Mohana , Shapovalova Nadiya V. , Francoeur Nancy , Sjoquist Nathan , Mastan Naveed , Kaur Navjot , Parikshak Neelroop , Mosqueda Nerick F. , Ngo Nhan-Kiet , Dee Nick , Ivanov Nikolay A. , Devillers Olivia , Roussos Panos , Parker Patrick D. , Manser Paul , Wohnoutka Paul , Farnham Peggy J. , Zandi Peter , Emani Prashant S. , Dalley Rachel A. , Mayani Rajiv , Tao Ran , Gittin Reaghan , Straub Richard E. , Lifton Richard P. , Jacobov Rivka , Howard Robert E. , Park Royce B. , Dai Rujia , Abramowicz Sandra , Akbarian Schahram , Schreiner Shannon , Ma Shaojie , Parry Sheana E. , Shapouri Sheila , Weissman Sherman , Caldejon Shiella , Mane Shrikant , Ding Song-Lin , Scuderi Soraya , Dracheva Stella , Butler Stephanie , Lisgo Steven N. , Rhie Suhn Kyong , Lindsay Susan , Datta Suvro , Souaiaia Tade , Roychowdhury Tanmoy , Gomez Teresa , Naluai-Cecchini Theresa , Beach Thomas G. , Goodman Thomas , Gao Tianliuyun , Dolbeare Tim A. , Fliss Tim , Reddy Timothy E. , Chen Ting , Hyde Tom M. , Brunetti Tonya , Lemon Tracy A. , Desta Tsega , Borrman Tyler , Haroutunian Vahram , Spitsyna Valeria N. , Swarup Vivek , Shi Xu , Jiang Yan , Xia Yan , Chen Yang-Ho , Jiang Yi , Wang Yongjun , Chae Yooree , Yang Yucheng T. , Kim Yunjung , Riley Zack L. , Krsnik Zeljka , Deng Zemin , Weng Zhiping , Lin Zhixiang , Li Zhuo 
Published: December 2018

INTRODUCTIONThe brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders.RATIONALEThe regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain.RESULTSHere we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes includingMEF2C,SATB2, andTCF4,with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity.CONCLUSIONWe generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.Spatiotemporal dynamics of human brain development and neuropsychiatric risks.Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.