. 2024 May 24;384(6698):eadh0829.

doi: 10.1126/science.adh0829. Epub 2024 May 24.

Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Cindy Wen^{1

2

3}, Michael Margolis^{2

3}, Rujia Dai⁴, Pan Zhang^{2

3}, Pawel F Przytycki⁵, Daniel D Vo^{2

3

6

7}, Arjun Bhattacharya^{8

9}, Nana Matoba^{10

11}, Miao Tang^{6

7}, Chuan Jiao^{4

12}, Minsoo Kim^{2

3}, Ellen Tsai^{2

3}, Celine Hoh^{2

3}, Nil Aygün^{10

11}, Rebecca L Walker^{1

2

3}, Christos Chatzinakos^{13

14

15}, Declan Clarke¹⁶, Henry Pratt¹⁷; PsychENCODE Consortium†; Mette A Peters¹⁸, Mark Gerstein^{16

19

20

21}, Nikolaos P Daskalakis^{13

14

15}, Zhiping Weng¹⁷, Andrew E Jaffe^{22

23

24

25

26

27

28}, Joel E Kleinman^{22

23}, Thomas M Hyde^{22

23

29}, Daniel R Weinberger^{22

23

24

25

29}, Nicholas J Bray³⁰, Nenad Sestan^{31

32}, Daniel H Geschwind^{3

33

34}, Kathryn Roeder^{35

36}, Alexander Gusev^{37

38

39

40}, Bogdan Pasaniuc^{1

3

8

34

41}, Jason L Stein^{10

11}, Michael I Love^{10

42}, Katherine S Pollard^{5

43

44}, Chunyu Liu^{4

45}, Michael J Gandal^{1

2

3

6

7}; PsychENCODE Consortium

Collaborators, Affiliations

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul A Bharadwaj, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-Fan Chien, Zhiyuan Chu, Ashley Clement, Leonardo Collado-Torres, Gregory M Cooper, Gregory E Crawford, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc Duong, Cagatay Dursun, Nicholas J Eagles, Jonathan Edelstein, Prashant S Emani, John F Fullard, Kiki Galani, Timur Galeev, Sophia Gaynor, Kiran Girdhar, Fernando S Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Gabriel E Hoffman, Yiling Huang, Louise A Huuki-Myers, Ahyeon Hwang, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Steven P Kleopoulos, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Shuang Liu, Shaoke Lou, Jacob M Loupe, Dan Lu, Shaojie Ma, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Samantha Mazariegos, Ran Meng, Richard M Myers, Courtney Micallef, Tatiana Mikhailova, Guo-Li Ming, Shahin Mohammadi, Emma Monte, Kelsey S Montgomery, Jill E Moore, Jennifer R Moran, Eran A Mukamel, Angus C Nairn, Charles B Nemeroff, Pengyu Ni, Scott Norton, Tomasz Nowakowski, Larsson Omberg, Stephanie C Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Alex Pollen, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Diana Quintero, Towfique Raj, Ananya S Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Panos Roussos, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nicholas Seyfried, Zhiping Shao, Nicole Shedd, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael Snyder, Ran Tao, Karen Therrien, Li-Huei Tsai, Alexander E Urban, Flora M Vaccarino, Harm van Bakel, Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Yu Wei, Annika K Weimer, Sean Whalen, Kevin P White, A Jeremy Willsey, Hyejung Won, Wing Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X Yap, Biao Zeng, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane R Zeier, Trisha M Zintel

Affiliations

¹ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
⁵ Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
⁶ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Lifespan Brain Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹¹ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Krebs, 75014 Paris, France.
¹³ Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
¹⁴ McLean Hospital, Belmont, MA 02478, USA.
¹⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁶ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
¹⁷ Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
¹⁸ CNS Data Coordination Group, Sage Bionetworks, Seattle, WA 98109, USA.
¹⁹ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
²⁰ Department of Computer Science, Yale University, New Haven, CT 06520, USA.
²¹ Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA.
²² Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
²³ Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁴ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁵ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁶ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
²⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
²⁸ Neumora Therapeutics, Watertown, MA 02472, USA.
²⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁰ MRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University School of Medicine, Cardiff CF24 4HQ, UK.
³¹ Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
³² Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
³³ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³⁴ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³⁵ Department of Statistics & Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³⁶ Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³⁷ Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³⁹ Harvard Medical School, Boston, MA 02215, USA.
⁴⁰ Division of Genetics, Brigham and Women's Hospital, Boston, MA 02215, USA.
⁴¹ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴² Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴³ Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴⁴ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁴⁵ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.

PMID: 38781368
DOI: 10.1126/science.adh0829

Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Cindy Wen et al. Science. 2024.

. 2024 May 24;384(6698):eadh0829.

doi: 10.1126/science.adh0829. Epub 2024 May 24.

Authors

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul A Bharadwaj, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-Fan Chien, Zhiyuan Chu, Ashley Clement, Leonardo Collado-Torres, Gregory M Cooper, Gregory E Crawford, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc Duong, Cagatay Dursun, Nicholas J Eagles, Jonathan Edelstein, Prashant S Emani, John F Fullard, Kiki Galani, Timur Galeev, Sophia Gaynor, Kiran Girdhar, Fernando S Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Gabriel E Hoffman, Yiling Huang, Louise A Huuki-Myers, Ahyeon Hwang, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Steven P Kleopoulos, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Shuang Liu, Shaoke Lou, Jacob M Loupe, Dan Lu, Shaojie Ma, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Samantha Mazariegos, Ran Meng, Richard M Myers, Courtney Micallef, Tatiana Mikhailova, Guo-Li Ming, Shahin Mohammadi, Emma Monte, Kelsey S Montgomery, Jill E Moore, Jennifer R Moran, Eran A Mukamel, Angus C Nairn, Charles B Nemeroff, Pengyu Ni, Scott Norton, Tomasz Nowakowski, Larsson Omberg, Stephanie C Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Alex Pollen, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Diana Quintero, Towfique Raj, Ananya S Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Panos Roussos, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nicholas Seyfried, Zhiping Shao, Nicole Shedd, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael Snyder, Ran Tao, Karen Therrien, Li-Huei Tsai, Alexander E Urban, Flora M Vaccarino, Harm van Bakel, Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Yu Wei, Annika K Weimer, Sean Whalen, Kevin P White, A Jeremy Willsey, Hyejung Won, Wing Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X Yap, Biao Zeng, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane R Zeier, Trisha M Zintel

Affiliations

¹ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
⁵ Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
⁶ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Lifespan Brain Institute, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹¹ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Krebs, 75014 Paris, France.
¹³ Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
¹⁴ McLean Hospital, Belmont, MA 02478, USA.
¹⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁶ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
¹⁷ Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
¹⁸ CNS Data Coordination Group, Sage Bionetworks, Seattle, WA 98109, USA.
¹⁹ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
²⁰ Department of Computer Science, Yale University, New Haven, CT 06520, USA.
²¹ Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA.
²² Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
²³ Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁴ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁵ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁶ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
²⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
²⁸ Neumora Therapeutics, Watertown, MA 02472, USA.
²⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁰ MRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University School of Medicine, Cardiff CF24 4HQ, UK.
³¹ Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
³² Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
³³ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³⁴ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³⁵ Department of Statistics & Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³⁶ Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³⁷ Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³⁹ Harvard Medical School, Boston, MA 02215, USA.
⁴⁰ Division of Genetics, Brigham and Women's Hospital, Boston, MA 02215, USA.
⁴¹ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴² Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴³ Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴⁴ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁴⁵ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.

PMID: 38781368
DOI: 10.1126/science.adh0829

Abstract

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

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Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain.
Wen C, Margolis M, Dai R, Zhang P, Przytycki PF, Vo DD, Bhattacharya A, Matoba N, Jiao C, Kim M, Tsai E, Hoh C, Aygün N, Walker RL, Chatzinakos C, Clarke D, Pratt H, Consortium P, Peters MA, Gerstein M, Daskalakis NP, Weng Z, Jaffe AE, Kleinman JE, Hyde TM, Weinberger DR, Bray NJ, Sestan N, Geschwind DH, Roeder K, Gusev A, Pasaniuc B, Stein JL, Love MI, Pollard KS, Liu C, Gandal MJ. Wen C, et al. medRxiv [Preprint]. 2023 Mar 6:2023.03.03.23286706. doi: 10.1101/2023.03.03.23286706. medRxiv. 2023. Update in: Science. 2024 May 24;384(6698):eadh0829. doi: 10.1126/science.adh0829. PMID: 36945630 Free PMC article. Updated. Preprint.

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Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

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Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

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