Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
Authors: Hu Benxia , Won Hyejung , Mah Won , Park Royce B. , Kassim Bibi , Spiess Keeley , Kozlenkov Alexey , Crowley Cheynna A. , Pochareddy Sirisha ,   The PsychENCODE Consortium, Ashley-Koch Allison E. , Crawford Gregory E. , Garrett Melanie E. , Song Lingyun , Safi Alexias , Johnson Graham D. , Wray Gregory A. , Reddy Timothy E. , Goes Fernando S. , Zandi Peter , Bryois Julien , Jaffe Andrew E. , Price Amanda J. , Ivanov Nikolay A. , Collado-Torres Leonardo , Hyde Thomas M. , Burke Emily E. , Kleiman Joel E. , Tao Ran , Shin Joo Heon , Girdhar Kiran , Jiang Yan , Kundakovic Marija , Brown Leanne , Wiseman Jennifer R. , Zharovsky Elizabeth , Jacobov Rivka , Devillers Olivia , Flatow Elie , Hoffman Gabriel E. , Belmont Judson , Del Valle Diane , Francoeur Nancy , Hadjimichael Evi , Pinto Dalila , van Bakel Harm , Roussos Panos , Fullard John F. , Bendl Jaroslav , Hauberg Mads E. , Charney Alexander W. , Haroutunian Vahram , Lipska Barbara K. , Lewis David A. , Hahn Chang-Gyu , Mangravite Lara M. , Peters Mette A. , Chae Yooree , Peng Junmin , Niu Mingming , Wang Xusheng , Webster Maree J. , Beach Thomas G. , Chen Chao , Jiang Yi , Dai Rujia , Wang Yongjun , Xia Yan , Shieh Annie W. , Liu Chunyu , Grennan Kay S. , Vadukapuram Ramu , Giase Gina , Fitzgerald Dominic , Cheng Lijun , Brown Miguel , Brown Mimi , Brunetti Tonya , Goodman Thomas , Alsayed Majd , White Kevin P. , Ray Mohana , Polioudakis Damon , Wamsley Brie , Yin Jiani , De La Torre Ubieta Luis , Gandal Michael J. , Swarup Vivek , Sanders Stephan J. , State Matthew W. , Werling Donna M. , An Joon-Yong , Sheppard Brooke , Willsey A. Jeremy , Kefi Amira , Mattei Eugenio , Purcaro Michael , Weng Zhiping , Moore Jill , Pratt Henry , Huey Jack , Borrman Tyler , Sullivan Patrick F. , Giusti-Rodriguez Paola , Kim Yunjung , Szatkiewicz Jin , Rhie Suhn Kyong , Armoskus Christoper , Camarena Adrian , Farnham Peggy J. , Spitsyna Valeria N. , Witt Heather , Schreiner Shannon , Evgrafov Oleg V. , Knowles James A. , Gerstein Mark , Liu Shuang , Navarro Fabio C. P. , Warrell Jonathan , Clarke Declan , Emani Prashant S. , Gu Mengting , Shi Xu , Xu Min , Yang Yucheng T. , Kitchen Robert R. , Gürsoy Gamze , Zhang Jing , Carlyle Becky C. , Nairn Angus C. , Li Mingfeng , Skarica Mario , Li Zhen , Sousa Andre M. M. , Santpere Gabriel , Choi Jinmyung , Zhu Ying , Gao Tianliuyun , Miller Daniel J. , Cherskov Adriana , Yang Mo , Amiri Anahita , Coppola Gianfilippo , Mariani Jessica , Scuderi Soraya , Szekely Anna , Vaccarino Flora M. , Wu Feinan , Weissman Sherman , Wang Daifeng , Roychowdhury Tanmoy , Abyzov Alexej , Li Yun , Dracheva Stella , Sestan Nenad , Akbarian Schahram , Geschwind Daniel H. 
Published: June 2021

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer’s disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.