Functional characterization of gene regulatory elements and neuropsychiatric disease-associated risk loci in iPSCs and iPSC-derived neurons
Open accessAbstract
Genome-wide association studies (GWAS) have identified thousands of non-coding variants that contribute to psychiatric disease risks, likely by perturbing cis -regulatory elements (CREs). However, our ability to interpret and explore their mechanisms of action is hampered by a lack of annotation of functional CREs (fCREs) in neural cell types. Here, through genome-scale CRISPR screens of 22,000 candidate CREs (cCREs) in human induced pluripotent stem cells (iPSCs) undergoing differentiation to excitatory neurons, we identify 2,847 and 5,540 fCREs essential for iPSC fitness and neuronal differentiation, respectively. These fCREs display dynamic epigenomic features and exhibit increased numbers and genomic spans of chromatin interactions following terminal neuronal differentiation. Furthermore, fCREs essential for neuronal differentiation show significantly greater enrichment of genetic heritability for neurodevelopmental diseases including schizophrenia (SCZ), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) than cCREs. Using high-throughput prime editing screens we experimentally confirm 45 SCZ risk variants that act by affecting the function of fCREs. The extensive and in-depth functional annotation of cCREs in neuronal types therefore provides a crucial resource for interpreting non-coding risk variants of neuropsychiatric disorders.
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iPSCs have already been employed in large-scale CRISPR screens.
“iPSCs have already been employed in large-scale CRISPR screens, suggesting that similar strategies could be adapted and integrated into future MAVE experimental designs (75, 76, 77).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [77]
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Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
- Authors
- Yang, X., Jones, I. R., Chen, P. B., Yang, H., Ren, X., Zheng, L., Li, B., Li, Y. E., Sun, Q., Wen, J., Beaman, C., Cui, X., Li, Y., Wang, W., Hu, M., Ren, B., & Shen, Y.
- Affiliations
- University of California, San Francisco (US)
- Agency for Science, Technology and Research (SG)
- University of California San Diego (US)
- University of North Carolina at Chapel Hill (US)
- Cleveland Clinic (US)
- Corresponding author
- Ren, Bing
- Shen, Yin
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-08-30
- OpenAlex
- W4386309504
- Cited by
- 10
- References
- 11
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 1 · 2022: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- cis-regulatory elements, non-coding variants, induced pluripotent stem cells, iPSC-derived neurons, neuronal differentiation, CRISPR screen, prime editing, schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorder, neurodevelopmental disorders, chromatin interactions, epigenomics, heritability
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