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

Sool Lee; Jessica C McAfee; Jiseok Lee; Alejandro Gomez; Austin T Ledford; Declan Clarke; Hyunggyu Min; Mark B Gerstein; Alan P Boyle; Patrick F Sullivan; Adriana S Beltran; Hyejung Won

doi:10.1016/j.cell.2024.12.022

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

Cell. 2025 Jan 20:S0092-8674(24)01435-1. doi: 10.1016/j.cell.2024.12.022. Online ahead of print.

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: [email protected].

PMID: 39848247
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.