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

被引：4

作者：

Lee, Sool ^{[1
,2
]}

Mcafee, Jessica C.

Lee, Jiseok ^{[1
,2
]}

Gomez, Alejandro ^{[1
,2
]}

Ledford, Austin T. ^{[1
,2
]}

Clarke, Declan ^{[3
,4
,5
]}

Min, Hyunggyu ^{[1
,8
]}

Gerstein, Mark B. ^{[3
,4
,5
,6
,7
]}

Boyle, Alan P. ^{[9
,10
]}

Sullivan, Patrick F. ^{[1
,11
,12
]}

Beltran, Adriana S. ^{[1
,13
,14
]}

Won, Hyejung ^{[1
,2
]}

机构：

[1] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA

[2] Univ North Carolina Chapel Hill, Neurosci Ctr, Chapel Hill, NC 27599 USA

[3] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA

[4] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA

[5] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA

[6] Yale Univ, Dept Stat & Data Sci, New Haven, CT 06520 USA

[7] Yale Univ, Dept Biomed Informat & Data Sci, New Haven, CT 06520 USA

[8] Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC 27599 USA

[9] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[11] Univ North Carolina Chapel Hill, Dept Psychiat, Chapel Hill, NC 27599 USA

[12] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[13] Univ North Carolina Chapel Hill, Human Pluripotent Cell Core, Chapel Hill, NC 27599 USA

[14] Univ North Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

来源：

CELL | 2025年 / 188卷 / 05期

关键词：

CELL-TYPES; R PACKAGE; TRANSCRIPTION; SYSTEM;

D O I：

10.1016/j.cell.2024.12.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1409 / 1424.e21

页数：38

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