Single-cell genomics and regulatory networks for 388 human brains
Prashant S. Emani(Yale University), Jason Liu(University of California, Los Angeles), Jason Liu(University of California, Los Angeles), Declan Clarke(Yale University), Matthew Jensen(Yale University), Jonathan Warrell(University of Wisconsin–Madison), Chirag Gupta(University of Wisconsin–Madison), Ran Meng(University of California, Irvine), Che-Yu Lee(University of California, Irvine), Siwei Xu(University of California, Irvine), Cagatay Dursun(Yale University), Shaoke Lou(Yale University), Yuhang Chen(Yale University), Zhiyuan Chu(Yale University), Timur R. Galeev(University of California, Irvine), Ahyeon Hwang(University of California, Irvine), Yunyang Li(Yale University), Pengyu Ni(Yale University), Xiao Zhou(Allen Institute for Brain Science), Trygve E. Bakken(Allen Institute for Brain Science), Jaroslav Bendl(Allen Institute for Brain Science), Lucy Bicks(University of California, Los Angeles), Tanima Chatterjee(Yale University), Lijun Cheng(University of California, Los Angeles), Yuyan Cheng(University of California, Los Angeles), Yi Dai(University of California, Irvine), Ziheng Duan(University of California, Irvine), Mary Flaherty(Allen Institute for Brain Science), John F. Fullard(Allen Institute for Brain Science), Michael Gancz(Yale University), Diego Garrido-Martín(Cornell University), Sophia C. Gaynor-Gillett(University of California, Los Angeles), Jennifer Grundman(University of California, Los Angeles), Natalie Hawken(University of California, Los Angeles), Ella Henry(Allen Institute for Brain Science), Gabriel E. Hoffman(Allen Institute for Brain Science), Ao Huang(Yale University), Yunzhe Jiang(University of Wisconsin–Madison), Ting Jin(Allen Institute for Brain Science), Nikolas L. Jorstad(Allen Institute for Brain Science), Riki Kawaguchi(University of Wisconsin–Madison), Saniya Khullar(University of Wisconsin–Madison), Jianyin Liu(University of California, Los Angeles), Jianyin Liu(University of Wisconsin–Madison), Junhao Liu(University of California, Los Angeles), Junhao Liu(University of California, Los Angeles), Shuang Liu(University of Wisconsin–Madison), Shaojie Ma(University of Massachusetts Chan Medical School), Michael Margolis(Tempus Labs (United States)), Samantha Mazariegos(University of California, Los Angeles), Jill E. Moore(University of Massachusetts Chan Medical School), Jennifer Moran(Allen Institute for Brain Science), Éric Nguyen(University of Massachusetts Chan Medical School), Nishigandha Phalke(University of California, Los Angeles), Milos Pjanic(Allen Institute for Brain Science), Henry Pratt(University of Massachusetts Chan Medical School), Diana Quintero(University of California, Los Angeles), Ananya S. Rajagopalan(Yale University), Tiernon R. Riesenmy(Yale University), Nicole Shedd(University of Massachusetts Chan Medical School), Manman Shi(Allen Institute for Brain Science), Megan Spector(University of California, Los Angeles), Rosemarie Terwilliger(Yale University), Kyle J. Travaglini(Allen Institute for Brain Science), Brie Wamsley(University of California, Los Angeles), Gaoyuan Wang(Yale University), Yan Xia(Yale University), Shaohua Xiao(Children's Hospital of Philadelphia), Andrew C. Yang(Allen Institute for Brain Science), Suchen Zheng(Allen Institute for Brain Science), Michael J. Gandal(Allen Institute for Brain Science), Donghoon Lee(Allen Institute for Brain Science), Ed S. Lein(Allen Institute for Brain Science), Panos Roussos(Allen Institute for Brain Science), Nenad Šestan(University of North Carolina at Chapel Hill), Zhiping Weng(University of Massachusetts Chan Medical School), Kevin P. White(National University of Singapore), Hyejung Won(University of North Carolina at Chapel Hill), Matthew J. Girgenti(University of California, Los Angeles), Jing Zhang(University of California, Irvine), Daifeng Wang(University of Wisconsin–Madison), Daniel H. Geschwind(University of California, Los Angeles), Mark Gerstein(Yale University), 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(Yale University), Frances A. Champagne(Tempus Labs (United States)), Chris Chatzinakos(Yale University), H. Isaac Chen, Lijun Cheng(Tempus Labs (United States)), Andrew Chess, Jo-fan Chien, Ashley Clement, Leonardo Collado‐Torres(University of Wisconsin–Madison), 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(Yale University), Duc M. Duong, Nicholas J. Eagles, Jonathan I. Edelstein, Kiki Galani, Kiran Girdhar, Fernando S. Goes, William J. Greenleaf, Hanmin Guo, Qiuyu Guo(University of California, Irvine), Yoav Hadas, Joachim Hallmayer(Yale University), Xikun Han, Vahram Haroutunian(Allen Institute for Brain Science), Chuan He(Allen Institute for Brain Science), Stephanie C. Hicks(University of Wisconsin–Madison), Marcus Ho, Li‐Lun Ho, Yi‐Ling Huang, Louise A. Huuki-Myers, Thomas M. Hyde, Artemis Iatrou(Yale University), Fumitaka Inoue(University of California, Irvine), Aarti Jajoo, Lihua Jiang, Peng Jin, Connor Jops, Alexandre Jourdon, Manolis Kellis, Joel E. Kleinman, Steven P. Kleopoulos, Alexey Kozlenkov, Arnold R. Kriegstein(University of California, Irvine), Anshul Kundaje(Allen Institute for Brain Science), Soumya Kundu(Allen Institute for Brain Science), Junhao Li(University of Wisconsin–Madison), Mingfeng Li(University of Wisconsin–Madison), Xiao Han Lin, Shuang Liu(University of Wisconsin–Madison), Chunyu Liu(Yale University), 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(University of California, Los Angeles), Carolin Purmann(Yale University), 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(University of California, Los Angeles), Robert Sebra, Nicholas T. Seyfried, Zhiping Shao, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Clara Snijders(Yale University), Hongjun Song, Matthew W. State, Jason L. Stein, Marilyn Steyert(Children's Hospital of Philadelphia), Sivan Subburaju(Tempus Labs (United States)), Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban(University of California, Los Angeles), Flora M. Vaccarino, Harm van Bakel(University of Wisconsin–Madison), Daniel Vo(University of Wisconsin–Madison), Georgios Voloudakis(University of Wisconsin–Madison), Tao Wang(University of California, Irvine), Sidney H. Wang, Yifan Wang, Wei Yu(University of Massachusetts Chan Medical School), Annika K. Weimer, Daniel R. Weinberger, Cindy Wen, Sean Whalen(University of California, Los Angeles), A. Jeremy Willsey, Wing Hung Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie(University of California, Irvine), Chloe X. Yap(University of California, Irvine), Biao Zeng(University of California, Irvine), Pan Zhang(University of California, Irvine), Chunling Zhang, Bin Zhang, Yanqiong Zhang, Ryan Ziffra, Zane Zeier, Trisha M. Zintel
Cited by 144Open Access
Abstract
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.