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Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex

Chengyu Deng, Sean Whalen, Marilyn Steyert, Ryan Ziffra, View ORCID ProfilePawel F. Przytycki, Fumitaka Inoue, Daniela A. Pereira, Davide Capauto, Scott Norton, Flora M. Vaccarino, View ORCID ProfileAlex Pollen, Tomasz J. Nowakowski, Nadav Ahituv, View ORCID ProfileKatherine S. Pollard
doi: https://doi.org/10.1101/2023.02.15.528663
Chengyu Deng
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA
2Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA
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Sean Whalen
3Gladstone Institutes; San Francisco, CA, USA
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Marilyn Steyert
4Department of Anatomy, University of California, San Francisco; San Francisco, CA, USA
5Department of Psychiatry, University of California, San Francisco; San Francisco, CA, USA
6Department of Neurological Surgery, University of California, San Francisco; San Francisco, CA, USA
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Ryan Ziffra
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA
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Pawel F. Przytycki
3Gladstone Institutes; San Francisco, CA, USA
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  • ORCID record for Pawel F. Przytycki
Fumitaka Inoue
7Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University; Kyoto, Japan
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Daniela A. Pereira
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA
2Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA
8Graduate Program of Genetics, Institute of Biological Sciences, Federal University of Minas Gerais; Belo Horizonte, Minas Gerais, Brazil
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Davide Capauto
9Child Study Center, Yale University; New Haven, CT, USA
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Scott Norton
9Child Study Center, Yale University; New Haven, CT, USA
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Flora M. Vaccarino
9Child Study Center, Yale University; New Haven, CT, USA
10Department of Neuroscience, Yale University; New Haven, CT, USA
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Alex Pollen
11Department of Neurology, University of California, San Francisco; San Francisco, CA, USA
12Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco; San Francisco, CA, USA
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  • ORCID record for Alex Pollen
Tomasz J. Nowakowski
4Department of Anatomy, University of California, San Francisco; San Francisco, CA, USA
5Department of Psychiatry, University of California, San Francisco; San Francisco, CA, USA
6Department of Neurological Surgery, University of California, San Francisco; San Francisco, CA, USA
12Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco; San Francisco, CA, USA
13Chan Zuckerberg Biohub, San Francisco; San Francisco, CA, USA
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Nadav Ahituv
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA
2Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA
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  • For correspondence: nadav.ahituv@ucsf.edu katherine.pollard@gladstone.ucsf.edu
Katherine S. Pollard
2Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA
3Gladstone Institutes; San Francisco, CA, USA
13Chan Zuckerberg Biohub, San Francisco; San Francisco, CA, USA
14Department of Epidemiology and Biostatistics, University of California, San Francisco; San Francisco, CA, USA
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  • ORCID record for Katherine S. Pollard
  • For correspondence: nadav.ahituv@ucsf.edu katherine.pollard@gladstone.ucsf.edu
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Abstract

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and disease. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 sequences, including differentially accessible cell-type specific regions in the developing cortex and single-nucleotide variants associated with psychiatric disorders. In primary cells, we identified 46,802 active enhancer sequences and 164 disorder-associated variants that significantly alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning, we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

One Sentence Summary We identify 46,802 enhancers and 164 psychiatric disorder variants with regulatory effects in the developing cortex and organoids.

Competing Interest Statement

NA is the cofounder and on the scientific advisory board of Regel Therapeutics and receives funding from BioMarin Pharmaceutical Incorporated.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted February 15, 2023.
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Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex
Chengyu Deng, Sean Whalen, Marilyn Steyert, Ryan Ziffra, Pawel F. Przytycki, Fumitaka Inoue, Daniela A. Pereira, Davide Capauto, Scott Norton, Flora M. Vaccarino, Alex Pollen, Tomasz J. Nowakowski, Nadav Ahituv, Katherine S. Pollard
bioRxiv 2023.02.15.528663; doi: https://doi.org/10.1101/2023.02.15.528663
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Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex
Chengyu Deng, Sean Whalen, Marilyn Steyert, Ryan Ziffra, Pawel F. Przytycki, Fumitaka Inoue, Daniela A. Pereira, Davide Capauto, Scott Norton, Flora M. Vaccarino, Alex Pollen, Tomasz J. Nowakowski, Nadav Ahituv, Katherine S. Pollard
bioRxiv 2023.02.15.528663; doi: https://doi.org/10.1101/2023.02.15.528663

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