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Status |
Public on Jun 30, 2021 |
Title |
Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt1] |
Organisms |
Escherichia coli; Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1,000 SNPs, prioritized from 39 neuropsychiatric trait/disease GWAS loci based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. Using mouse neuroblastoma Neuro2a (N2a) cells, we identify over 100 SNPs with allelic effects on expression. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs); with additional allelic differences unmasked in cells treated with all-trans retinoic acid (ATRA). Motifs overrepresented at functional SNPs corresponded to a set of TFs highly specific to serotonergic neurons and collectively downregulated in schizophrenia. Our application of MPRAs to screen MDD-associated SNPs suggested a shared transcriptional regulatory program across loci, a subset of which are unmasked by retinoids. Additional code and results corresponding to this GEO submission can be found at https://bitbucket.org/jdlabteam/n2a_atra_mdd_mpra_paper/src
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Overall design |
n=6 replicates of plasmid-transfected N2A cells, plated at 2 different densities at the time of transfection (linear regression showed that this had no effect on expression of any barcode set). Grants: 1. 5F30MH116654 - Bernard Mulvey - Identification and characterization of common, noncoding regulatory variants associated with Major Depressive Disorder - NIMH
2. 1R01MH116999 - Joseph Dougherty - Highly parallel analysis of 5' and 3' UTR variants in Autism Spectrum Disorders - NIMH
3. 571009 - Joseph Dougherty - Simons Foundation
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Contributor(s) |
Mulvey B, Dougherty JD |
Citation(s) |
34294677 |
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Submission date |
Feb 25, 2021 |
Last update date |
Aug 11, 2021 |
Contact name |
Joseph Dougherty |
E-mail(s) |
mulveyb@wustl.edu, jdougherty@wustl.edu, berniejmulvey@gmail.com
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Organization name |
Washington University in St. Louis
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Department |
Genetics
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Lab |
Dougherty
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Street address |
660 S Euclid Ave, Campus Box 8232
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City |
St. Louis |
State/province |
MO |
ZIP/Postal code |
63110 |
Country |
USA |
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Platforms (2) |
GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
GPL18133 |
Illumina HiSeq 2500 (Escherichia coli) |
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Samples (7)
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This SubSeries is part of SuperSeries: |
GSE167519 |
Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays |
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Relations |
BioProject |
PRJNA704846 |
SRA |
SRP308182 |