Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
Benxia Hu, Hyejung Won, Won Mah, Royce Park, Bibi Kassim, Keeley Spiess, Alexey Kozlenkov, Cheynna Crowley, Sirisha Pochareddy, Allison E. Ashley‐Koch, Gregory E. Crawford, Melanie E. Garrett, Lingyun Song, Alexias Safi, Graham D. Johnson, Gregory A. Wray, Timothy E. Reddy, Fernando S. Goes, Peter P. Zandi, Julien Bryois, Andrew E. Jaffe, Amanda J. Price, Nikolay A. Ivanov, Leonardo Collado‐Torres, Thomas M. Hyde, Emily E. Burke, Joel E. Kleiman, Ran Tao, Joo Heon Shin, Kiran Girdhar, Yan Jiang, Marija Kundaković, Leanne Brown, Jennifer Wiseman, Elizabeth Zharovsky, Rivka Jacobov, Olivia Devillers, Elie Flatow, Gabriel E. Hoffman, Judson Belmont, Diane M. Del Valle, Nancy Francoeur, Evi Hadjimichael, Dalila Pinto, Harm van Bakel, Panos Roussos, John F. Fullard, Jaroslav Bendl, Mads E. Hauberg, Alexander W. Charney, Vahram Haroutunian, Barbara K. Lipska, David A. Lewis, Chang-Gyu Hahn, Lara M. Mangravite, Mette A. Peters, Yooree Chae, Junmin Peng, Mingming Niu, Xusheng Wang, Maree J. Webster, Thomas G. Beach, Chao Chen, Yi Jiang, Rujia Dai, Yongjun Wang, Yan Xia, Annie W. Shieh, Chunyu Liu, Kay Grennan, Ramu Vadukapuram, Gina Giase, Dominic Fitzgerald, Lijun Cheng, Miguel Brown, Mimi Brown, Tonya M. Brunetti, Thomas Goodman, Majd Alsayed, Kevin P. White, Mohana Ray, Damon Polioudakis, Brie Wamsley, Jiani Yin, Luis de la Torre-Ubieta, Michael J. Gandal, Vivek Swarup, Stephan Sanders, Matthew W. State, Donna M. Werling, Joon‐Yong An, Brooke Sheppard, A. Jeremy Willsey, Amira Kefi, Eugenio Mattei, Michael Purcaro, Zhiping Weng, J. Russell Moore, Henry Pratt, Jack Huey
Abstract
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.