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Cell, January 22, 2025 | https://doi.org/10.1016/j.cell.2024.12.022
Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders
Sool Lee,1,2,15 Jessica C. McAfee,1,2,15 Jiseok Lee,1,2,15 Alejandro Gomez,1,2 Austin T. Ledford,1,2 Declan Clarke,3,4,5,6,7 Hyunggyu Min,1,8 Mark B. Gerstein,3,4,5,6,7 Alan P. Boyle,9,10 Patrick F. Sullivan,1,11,12 Adriana S. Beltran,1,13,14 and Hyejung Won 1,2,16,*
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3Program in Computational Biology & Bioinformatics, Yale University, New Haven, CT 06520, USA
4Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA
5Department of Computer Science, Yale University, New Haven, CT 06520, USA
6Department of Statistics & Data Science, Yale University, New Haven, CT 06520, USA
7Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA
8Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
9Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
10Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
11Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA
12Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
13Human Pluripotent Cell Core, University of North Carolina, Chapel Hill, NC 27599, USA
14Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
15These authors contributed equally
16Lead contact
2Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3Program in Computational Biology & Bioinformatics, Yale University, New Haven, CT 06520, USA
4Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA
5Department of Computer Science, Yale University, New Haven, CT 06520, USA
6Department of Statistics & Data Science, Yale University, New Haven, CT 06520, USA
7Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA
8Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
9Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
10Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
11Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA
12Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
13Human Pluripotent Cell Core, University of North Carolina, Chapel Hill, NC 27599, USA
14Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
15These authors contributed equally
16Lead contact
*Corresponding author: correspondence to Hyejung Won
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.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-02-07)
- 국외 연구진
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