Single-cell genomics and regulatory networks for 388 human brains

Authors: Prashant S. Emani, Jason Liu, Jason Liu, Declan Clarke, Matthew Jensen, Jonathan Warrell, Chirag Gupta, Ran Meng, Che-Yu Lee, Siwei Xu, Cagatay Dursun, Shaoke Lou, Yuhang Chen, Zhiyuan Chu, Timur R. Galeev, Ahyeon Hwang, Yunyang Li, Pengyu Ni, Xiao Zhou, Trygve E. Bakken, Jaroslav Bendl, Lucy Bicks, Tanima Chatterjee, Lijun Cheng, Yuyan Cheng, Yi Dai, Ziheng Duan, Mary Flaherty, John F. Fullard, Michael Gancz, Diego Garrido-Martín, Sophia C. Gaynor-Gillett, Jennifer Grundman, Natalie Hawken, Ella Henry, Gabriel E. Hoffman, Ao Huang, Yunzhe Jiang, Ting Jin, Nikolas L. Jorstad, Riki Kawaguchi, Saniya Khullar, Jianyin Liu, Jianyin Liu, Junhao Liu, Junhao Liu, Shuang Liu, Shaojie Ma, Michael Margolis, Samantha Mazariegos, Jill E. Moore, Jennifer Moran, Éric Nguyen, Nishigandha Phalke, Milos Pjanic, Henry Pratt, Diana Quintero, Ananya S. Rajagopalan, Tiernon R. Riesenmy, Nicole Shedd, Manman Shi, Megan Spector, Rosemarie Terwilliger, Kyle J. Travaglini, Brie Wamsley, Gaoyuan Wang, Yan Xia, Shaohua Xiao, Andrew C. Yang, Suchen Zheng, Michael J. Gandal, Donghoon Lee, Ed S. Lein, Panos Roussos, Nenad Šestan, Zhiping Weng, Kevin P. White, Hyejung Won, Matthew J. Girgenti, Jing Zhang, Daifeng Wang, Daniel H. Geschwind, Mark Gerstein, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Sabina Berretta, Rahul Bharadwaj, Arjun Bhattacharya, Kristen Brennand, Davide Capauto, Frances A. Champagne, Chris Chatzinakos, H. Isaac Chen, Lijun Cheng, Andrew Chess, Jo-fan Chien, Ashley Clement, Leonardo Collado‐Torres, Gregory M. Cooper, Gregory E. Crawford, Rujia Dai, Nikolaos P. Daskalakis, José Dávila-Velderrain, Amy Deep‐Soboslay, Chengyu Deng, Christopher P. DiPietro, Stella Dracheva, Shiron Drusinsky, Duc M. Duong, Nicholas J. Eagles, Jonathan I. Edelstein, Kiki Galani, Kiran Girdhar, Fernando S. Goes, William J. Greenleaf, Hanmin Guo, Qiuyu Guo, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Chuan He, Stephanie C. Hicks, Marcus Ho, Li‐Lun Ho, Yi‐Ling Huang, Louise A. Huuki-Myers, Thomas M. Hyde, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Lihua Jiang, Peng Jin, Connor Jops, Alexandre Jourdon, Manolis Kellis, Joel E. Kleinman, Steven P. Kleopoulos, Alexey Kozlenkov, Arnold R. Kriegstein, Anshul Kundaje, Soumya Kundu, Junhao Li, Mingfeng Li, Xiao Han Lin, Shuang Liu, Chunyu Liu, Jacob M. Loupe, Dan Lü, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R. Maynard, R Myers, Courtney Micallef, Tatiana Mikhailova, Guo‐li Ming, Shahin Mohammadi, Emma Monte, Kelsey S. Montgomery, Eran A. Mukamel, Angus C. Nairn, Charles B. Nemeroff, Scott Norton, Tomasz J. Nowakowski, Larsson Omberg, Stephanie C. Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Mette A. Peters, Dalila Pinto, Sirisha Pochareddy, Katherine S. Pollard, Alex A. Pollen, Pawel F. Przytycki, Carolin Purmann, Zhaohui Qin, Pingping Qu, Towfique Raj, Sarah Reach, Thomas Reimonn, Kerry J. Ressler, D Ross, Joel Rozowsky, M Hall Ruth, W. Brad Ruzicka, Stephan Sanders, Juliane M. Schneider, Soraya Scuderi, Robert Sebra, Nicholas T. Seyfried, Zhiping Shao, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Clara Snijders, Hongjun Song, Matthew W. State, Jason L. Stein, Marilyn Steyert, Sivan Subburaju, Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban, Flora M. Vaccarino, Harm van Bakel, Daniel Vo, Georgios Voloudakis, Tao Wang, Sidney H. Wang, Yifan Wang, Wei Yu, Annika K. Weimer, Daniel R. Weinberger, Cindy Wen, Sean Whalen, A. Jeremy Willsey, Wing Hung Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Chloe X. Yap, Biao Zeng, Pan Zhang, Chunling Zhang, Bin Zhang, Yanqiong Zhang, Ryan Ziffra, Zane Zeier, Trisha M. Zintel - Science 2024 cited by 149

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.