Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Program in Computational Biology & Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Department of Statistics & Data Science, Yale University, New Haven, CT 06520, USA; Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Human Pluripotent Cell Core, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: hyejung_won@med.unc.edu.

PMID: 39848247
PMCID: PMC11890967 (available on 2026-03-06)
DOI: 10.1016/j.cell.2024.12.022

Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Sool Lee et al. Cell. 2025.

. 2025 Mar 6;188(5):1409-1424.e21.

doi: 10.1016/j.cell.2024.12.022. Epub 2025 Jan 22.

Authors

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Program in Computational Biology & Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Department of Statistics & Data Science, Yale University, New Haven, CT 06520, USA; Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Human Pluripotent Cell Core, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: hyejung_won@med.unc.edu.

PMID: 39848247
PMCID: PMC11890967 (available on 2026-03-06)
DOI: 10.1016/j.cell.2024.12.022

Abstract

A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches and CRISPR perturbation. In vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve the regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.

Keywords: CROP-seq; GWAS; MPRA; cross-disorder; fine-mapping; functional validation; pleiotropy; psychiatric disorders; variant-gene mapping.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Global Burden of Disease Study 2019 (GBD 2019) Data Resources | GHDx. https://ghdx.healthdata.org/gbd-2019.
1. King BH (2016). Psychiatric comorbidities in neurodevelopmental disorders. Curr. Opin. Neurol 29, 113–117. 10.1097/WCO.0000000000000299. - DOI - PubMed
1. Brainstorm Consortium, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, Escott-Price V, Falcone GJ, Gormley P, et al. (2018). Analysis of shared heritability in common disorders of the brain. Science 360. 10.1126/science.aap8757. - DOI - PMC - PubMed
1. Sullivan PF, Agrawal A, Bulik CM, Andreassen OA, Børglum AD, Breen G, Cichon S, Edenberg HJ, Faraone SV, Gelernter J, et al. (2018). Psychiatric genomics: an update and an agenda. Am. J. Psychiatry 175, 15–27. 10.1176/appi.ajp.2017.17030283. - DOI - PMC - PubMed
1. Cross-Disorder Group of the Psychiatric Genomics Consortium. (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell 179, 1469–1482.e11. 10.1016/j.cell.2019.11.020. - DOI - PMC - PubMed

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Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Affiliations

Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials