. 2024 May 24;384(6698):eadi5199.

doi: 10.1126/science.adi5199. Epub 2024 May 24.

Single-cell genomics and regulatory networks for 388 human brains

Prashant S Emani^#^{1

2}, Jason J Liu^#^{1

2}, Declan Clarke^#^{1

2}, Matthew Jensen^#^{1

2}, Jonathan Warrell^#^{1

2}, Chirag Gupta^#^{3

4}, Ran Meng^#^{1

2}, Che Yu Lee^#⁵, Siwei Xu^#⁵, Cagatay Dursun^#^{1

2}, Shaoke Lou^#^{1

2}, Yuhang Chen^{1

2}, Zhiyuan Chu¹, Timur Galeev^{1

2}, Ahyeon Hwang^{5

6}, Yunyang Li^{2

7}, Pengyu Ni^{1

2}, Xiao Zhou^{1

2}; PsychENCODE Consortium‡; Trygve E Bakken⁸, Jaroslav Bendl^{9

10

11

12}, Lucy Bicks¹³, Tanima Chatterjee^{1

2}, Lijun Cheng¹⁴, Yuyan Cheng^{13

15}, Yi Dai⁵, Ziheng Duan⁵, Mary Flaherty¹⁴, John F Fullard^{9

10

11

12}, Michael Gancz^{1

2}, Diego Garrido-Martín¹⁶, Sophia Gaynor-Gillett^{14

17}, Jennifer Grundman¹³, Natalie Hawken¹³, Ella Henry^{1

2}, Gabriel E Hoffman^{9

10

11

12

18

19}, Ao Huang¹, Yunzhe Jiang^{1

2}, Ting Jin^{3

4}, Nikolas L Jorstad⁸, Riki Kawaguchi^{13

20}, Saniya Khullar^{3

4}, Jianyin Liu¹³, Junhao Liu⁵, Shuang Liu⁴, Shaojie Ma^{21

22}, Michael Margolis, Samantha Mazariegos¹³, Jill Moore²³, Jennifer R Moran¹⁴, Eric Nguyen^{1

2}, Nishigandha Phalke²³, Milos Pjanic^{9

10

11

12}, Henry Pratt²³, Diana Quintero¹³, Ananya S Rajagopalan⁷, Tiernon R Riesenmy²⁴, Nicole Shedd²³, Manman Shi¹⁴, Megan Spector¹⁴, Rosemarie Terwilliger²⁵, Kyle J Travaglini⁸, Brie Wamsley¹³, Gaoyuan Wang^{1

2}, Yan Xia^{1

2}, Shaohua Xiao¹³, Andrew C Yang^{1

2}, Suchen Zheng^{1

2}, Michael J Gandal^{26

27

28

29

30}, Donghoon Lee^{9

10

11

12}, Ed S Lein^{8

31

32}, Panos Roussos^{9

10

11

12

18

19}, Nenad Sestan²¹, Zhiping Weng²³, Kevin P White³³, Hyejung Won³⁴, Matthew J Girgenti^{25

35

36}, Jing Zhang⁵, Daifeng Wang^{3

4

37}, Daniel Geschwind^{13

20

27

28

38}, Mark Gerstein^{1

2

7

24

39}; PsychENCODE Consortium

Collaborators, Affiliations

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Sabina Berretta, Rahul A 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, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Duc Duong, Nicholas J Eagles, Jonathan Edelstein, Kiki Galani, Kiran Girdhar, Fernando S Goes, William Greenleaf, Hanmin Guo, Qiuyu Guo, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Chuan He, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Yiling 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, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Chunyu Liu, Jacob M Loupe, Dan Lu, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Richard M 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 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 Pollen, Pawel F Przytycki, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Towfique Raj, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nicholas Seyfried, Zhiping Shao, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Jason Stein, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael 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, Yu Wei, Annika K Weimer, Daniel R Weinberger, Cindy Wen, Sean Whalen, A Jeremy Willsey, Wing 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 R Zeier, Trisha M Zintel

Affiliations

¹ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
² Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
³ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Department of Computer Science, University of California, Irvine, CA 92697, USA.
⁶ Mathematical, Computational and Systems Biology, University of California, Irvine, CA 92697, USA.
⁷ Department of Computer Science, Yale University, New Haven, CT 06520, USA.
⁸ Allen Institute for Brain Science, Seattle, WA 98109, USA.
⁹ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹³ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁴ Tempus Labs, Chicago, IL 60654, USA.
¹⁵ Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona 08028, Spain.
¹⁷ Department of Biology, Cornell College, Mount Vernon, IA 52314, USA.
¹⁸ Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
¹⁹ Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
²⁰ Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, CA 90095, USA.
²¹ Department of Neuroscience, Yale University, New Haven, CT 06510, USA.
²² Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
²³ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
²⁴ Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA.
²⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
²⁶ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles CA, 90095, USA.
²⁷ Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁹ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³⁰ Lifespan Brain Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³¹ Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA.
³² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
³³ Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
³⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³⁵ Wu Tsai Institute, Yale University, New Haven, CT 06520, USA.
³⁶ Clinical Neuroscience Division, National Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA.
³⁷ Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
³⁸ Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
³⁹ Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA.

^# Contributed equally.

PMID: 38781369
DOI: 10.1126/science.adi5199

Single-cell genomics and regulatory networks for 388 human brains

Prashant S Emani et al. Science. 2024.

. 2024 May 24;384(6698):eadi5199.

doi: 10.1126/science.adi5199. Epub 2024 May 24.

Authors

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Sabina Berretta, Rahul A 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, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Duc Duong, Nicholas J Eagles, Jonathan Edelstein, Kiki Galani, Kiran Girdhar, Fernando S Goes, William Greenleaf, Hanmin Guo, Qiuyu Guo, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Chuan He, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Yiling 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, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Chunyu Liu, Jacob M Loupe, Dan Lu, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Richard M 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 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 Pollen, Pawel F Przytycki, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Towfique Raj, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nicholas Seyfried, Zhiping Shao, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Jason Stein, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael 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, Yu Wei, Annika K Weimer, Daniel R Weinberger, Cindy Wen, Sean Whalen, A Jeremy Willsey, Wing 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 R Zeier, Trisha M Zintel

Affiliations

¹ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
² Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
³ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Department of Computer Science, University of California, Irvine, CA 92697, USA.
⁶ Mathematical, Computational and Systems Biology, University of California, Irvine, CA 92697, USA.
⁷ Department of Computer Science, Yale University, New Haven, CT 06520, USA.
⁸ Allen Institute for Brain Science, Seattle, WA 98109, USA.
⁹ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹³ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁴ Tempus Labs, Chicago, IL 60654, USA.
¹⁵ Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona 08028, Spain.
¹⁷ Department of Biology, Cornell College, Mount Vernon, IA 52314, USA.
¹⁸ Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
¹⁹ Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
²⁰ Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, CA 90095, USA.
²¹ Department of Neuroscience, Yale University, New Haven, CT 06510, USA.
²² Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
²³ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
²⁴ Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA.
²⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
²⁶ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles CA, 90095, USA.
²⁷ Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁹ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³⁰ Lifespan Brain Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³¹ Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA.
³² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
³³ Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
³⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³⁵ Wu Tsai Institute, Yale University, New Haven, CT 06520, USA.
³⁶ Clinical Neuroscience Division, National Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA.
³⁷ Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
³⁸ Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
³⁹ Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA.

^# Contributed equally.

PMID: 38781369
DOI: 10.1126/science.adi5199

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.

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Single-cell genomics and regulatory networks for 388 human brains.
Emani PS, Liu JJ, Clarke D, Jensen M, Warrell J, Gupta C, Meng R, Lee CY, Xu S, Dursun C, Lou S, Chen Y, Chu Z, Galeev T, Hwang A, Li Y, Ni P, Zhou X; PsychENCODE Consortium; Bakken TE, Bendl J, Bicks L, Chatterjee T, Cheng L, Cheng Y, Dai Y, Duan Z, Flaherty M, Fullard JF, Gancz M, Garrido-Martín D, Gaynor-Gillett S, Grundman J, Hawken N, Henry E, Hoffman GE, Huang A, Jiang Y, Jin T, Jorstad NL, Kawaguchi R, Khullar S, Liu J, Liu J, Liu S, Ma S, Margolis M, Mazariegos S, Moore J, Moran JR, Nguyen E, Phalke N, Pjanic M, Pratt H, Quintero D, Rajagopalan AS, Riesenmy TR, Shedd N, Shi M, Spector M, Terwilliger R, Travaglini KJ, Wamsley B, Wang G, Xia Y, Xiao S, Yang AC, Zheng S, Gandal MJ, Lee D, Lein ES, Roussos P, Sestan N, Weng Z, White KP, Won H, Girgenti MJ, Zhang J, Wang D, Geschwind D, Gerstein M. Emani PS, et al. bioRxiv [Preprint]. 2024 Mar 30:2024.03.18.585576. doi: 10.1101/2024.03.18.585576. bioRxiv. 2024. Update in: Science. 2024 May 24;384(6698):eadi5199. doi: 10.1126/science.adi5199. PMID: 38562822 Free PMC article. Updated. Preprint.

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Single-cell genomics and regulatory networks for 388 human brains

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Single-cell genomics and regulatory networks for 388 human brains

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