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Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Escherichia coli

PROVIDER: GSE167519 | GEO | 2021/06/30

REPOSITORIES: GEO

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Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays.

Project description: Not available

| S-EPMC8298436 | biostudies-literature

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt2]

Project description: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.)

2021-06-30 | GSE167518 | GEO

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt1]

2021-06-30 | GSE167517 | GEO

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays

Project description:Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays

| PRJNA704843 | ENA

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt1]

Project description:Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt1]

| PRJNA704846 | ENA

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt2]

Project description:Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt2]

| PRJNA704847 | ENA

Massively Parallel Reporter Assays: Defining Functional Psychiatric Genetic Variants Across Biological Contexts.

Project description: Not available

| S-EPMC7938388 | biostudies-literature

Massively parallel reporter assays with multi-layer annotation identified cell-type-specific functional variants and genes associated with melanoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-28 | GSE210356 | GEO

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma.

Project description: Not available

| S-EPMC7264232 | biostudies-literature

Massively parallel reporter assays with multi-layer annotation identified cell-type-specific functional variants and genes associated with melanoma (MPRA)

Project description:The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRA) using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRA, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (QTLs) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRA along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional.

2022-11-28 | GSE210354 | GEO

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