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Series GSE117877 Query DataSets for GSE117877
Status Public on Jul 28, 2021
Title A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Bipolar disorder is a highly heritable mental illness, but the relevant genetic variants and molecular mechanisms are largely unknown. Recent GWASs have identified an intergenic region associated with both cognitive performance and bipolar disorder. This region contains dozens of putative fetal brain-specific enhancers and is located ~0.7 Mb upstream of the neuronal transcription factor POU3F2. We identified a candidate causal variant, rs77910749, that falls within a highly conserved putative enhancer, LC1. This human-specific variant is a single-base deletion in a PAX6 binding site and is predicted to be functional. We hypothesized that rs77910749 alters LC1 activity and hence POU3F2 expression during neurodevelopment. Indeed, transgenic reporter mice demonstrated LC1 activity in the developing cerebral cortex and amygdala. Furthermore, ex vivo reporter assays in embryonic mouse brain and human iPSC-derived cerebral organoids revealed increased enhancer activity conferred by the variant. To probe the in vivo function of LC1, we deleted the orthologous mouse region, which resulted in amygdala-specific changes in Pou3f2 expression. Lastly, ‘humanized’ rs77910749 knock-in mice displayed behavioral defects in sensory gating, an amygdala-dependent endophenotype seen in patients with bipolar disorder. Our study suggests a molecular mechanism underlying the long-speculated link between enhanced cognitive performance and neuropsychiatric disease.
Overall design mRNA-seq in mouse brain
Contributor(s) Shen SQ, Corbo JC
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Submission date Jul 30, 2018
Last update date Oct 27, 2021
Contact name Joseph C Corbo
Organization name Washington University School of Medicine
Street address 660 S. Euclid Ave.
City St. Louis
State/province MO
ZIP/Postal code 63110
Country USA
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (12)
GSM3314407 6-LC1_WT
GSM3314408 7-LC1_KO
GSM3314409 22-LC1_KO
BioProject PRJNA483474
SRA SRP155753

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE117877_DE_genes_LC1KOvsWT.txt.gz 2.2 Mb (ftp)(http) TXT
GSE117877_DE_genes_RKIWTvshomozygous.txt.gz 2.2 Mb (ftp)(http) TXT
GSE117877_DE_transcripts_LC1KOvsWT.txt.gz 5.7 Mb (ftp)(http) TXT
GSE117877_DE_transcripts_RKIWTvshomozygous.txt.gz 6.2 Mb (ftp)(http) TXT
GSE117877_all.gene_RPKM_annot.txt.gz 2.7 Mb (ftp)(http) TXT
GSE117877_all.gene_counts_annot.txt.gz 1.6 Mb (ftp)(http) TXT
GSE117877_all.transcript_RPKM_annot.txt.gz 5.8 Mb (ftp)(http) TXT
GSE117877_all.transcript_counts_annot.txt.gz 5.8 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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