Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
22 07 2021
22 07 2021
Historique:
received:
15
03
2021
accepted:
16
06
2021
revised:
02
06
2021
entrez:
23
7
2021
pubmed:
24
7
2021
medline:
3
8
2021
Statut:
epublish
Résumé
Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters) based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients and promote depressive-like behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, selecting SNPs based on overlap with predicted regulatory features-including expression quantitative trait loci (eQTL) and histone marks-from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs), with additional allelic differences unmasked by treatment with all-trans retinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting an in vivo site of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional-regulatory program across loci, a component of which is unmasked by retinoids.
Identifiants
pubmed: 34294677
doi: 10.1038/s41398-021-01493-6
pii: 10.1038/s41398-021-01493-6
pmc: PMC8298436
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
403Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : 1F30MH1116654
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : 1R01MH116999
Organisme : Simons Foundation
ID : 571009
Organisme : NIMH NIH HHS
ID : R01 MH116999
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103525
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Informations de copyright
© 2021. The Author(s).
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