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| Status |
Public on Feb 10, 2023 |
| Title |
Extensive sex differences in depression-linked variants functionally assayed in mouse brain [Hippocampus II] |
| Organisms |
Mus musculus; Adeno-associated virus 9 |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Here, we selected >1000 variants from over 30 depression-associated loci using brain epigenomic data, and functionally assayed them using in vivo functional assays in the mouse brain to examine sex-by-genotype interactions. We identify extensive sex-by-allele effects in mature hippocampus, suggesting genetic risk and thus disease mechanisms may be distinct between the sexes. Unbiased informatics approaches indicated a role for nuclear hormone receptors, which was supported by . Further, comparative analysis of allelic function in the neonatal mouse brain, during a key between developmental neonates during the masculinizing testosterone surge, and in the adult hippocampus—a region of interest in depression pathology—but not at 10 days old, a older hormonally quiescent developmental stage juveniles. Our study provides novel insights into depression genetics as influenced by age, biological sex, and cell type, and provides a framework for in vivo parallel assays at a scale not previously shown possible to functionally define interactions between sex and disease variation.
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| Overall design |
n=5-6 replicates each of AAV9-transduced adult mouse brain tissues (replication experiment): male total hippocampus, ovaries-intact female total hippocampus, ovariectomized female total hippocampus, male Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction, intact female Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction, ovariectomized female Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction.
Adult mice, all B6 background, were injected with AAV9 28 days before tissue collection for MPRA via TRAP and RNA-sequencing. Female mice also underwent either sham surgery or ovariectomy during the same surgical session as AAV9 administration.
Additional grant information: 571009 - Joseph Dougherty - Simons Foundation
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| Contributor(s) |
Mulvey B, Dougherty JD, Selmanovic D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 MH116999 |
Highly parallel analysis of 5' and 3' UTR variants in Autism Spectrum Disorders |
WASHINGTON UNIVERSITY |
JOSEPH D DOUGHERTY |
| F30 MH116654 |
Identification and characterization of common, noncoding regulatory variants associated with Major Depressive Disorder. |
WASHINGTON UNIVERSITY |
Bernard John Mulvey |
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| Submission date |
Jan 04, 2023 |
| Last update date |
Feb 10, 2023 |
| 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) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL30885 |
Illumina NovaSeq 6000 (Adeno-associated virus 9) |
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| Samples (38)
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| Relations |
| BioProject |
PRJNA918422 |
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