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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 [Expt2] |
| 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 Note that while paired-end sequencing was technically performed, only read 1 (i.e., the barcode-spanning read) of each pair was utilized for analysis, and thus only read 1 files are provided. (fastq files are processed as plain text using string-matching for stringent barcode identification, so header inconsistencies regarding single/paired end read design should not cause issues using our pipeline; however, if read 2 files are required to perform your own form of analysis, contact mulveyb@wustl.edu ; we are happy to provide them.)
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| Overall design |
n=6 replicates each of plasmid-transfected N2A cells, treated in culture with either 20µM all-trans retinoic acid (ATRA) or vehicle (100% DMSO).
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 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F30 MH116654 |
Identification and characterization of common, noncoding regulatory variants associated with Major Depressive Disorder. |
WASHINGTON UNIVERSITY |
Bernard John Mulvey |
| R01 MH116999 |
Highly parallel analysis of 5' and 3' UTR variants in Autism Spectrum Disorders |
WASHINGTON UNIVERSITY |
JOSEPH D DOUGHERTY |
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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
|
| Organization name |
Washington University in St. Louis
|
| Department |
Genetics
|
| Lab |
Dougherty
|
| Street address |
660 S Euclid Ave, Campus Box 8232
|
| City |
St. Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL25368 |
Illumina NovaSeq 6000 (Escherichia coli) |
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| Samples (13)
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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 |
PRJNA704847 |
| SRA |
SRP308183 |
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