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

ABSTRACT: 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

ORGANISM(S): Mus musculus Escherichia coli

PROVIDER: GSE167517 | GEO | 2021/06/30

REPOSITORIES: GEO

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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

Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association.

Project description:The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work. Gene expression data was determined of peripheral blood samples (n=705) from InChianti cohort.

2013-06-21 | E-GEOD-48152 | biostudies-arrayexpress

Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association.

2013-06-21 | GSE48152 | GEO

Integrative high-throughput enhancer surveying and functional verifying divulges YY2 condensed regulatory axis conferring risk for osteoporosis

Project description:The precise roles of chromatin organizations at osteoporosis risk loci remains largely elusive. Here we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated SNPs. We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) which linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs, and prevailing osteoporosis-relevant regulatory roles for their chromatin interacted genes. Further motif enrichment and network mapping prioritized several putative key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected on top ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underlined roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help better understand the intricate molecular regulatory mechanisms underlying osteoporosis-risk loci.

2023-12-29 | GSE231932 | GEO

Global discovery of SLE genetic risk variant allelic enhancer activity

Project description:Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assays (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into Epstein-Barr virus-transformed B cell line GM12878 revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Combined with allelic enhancer activity analyses in Jurkat cell line, we identified shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around 51 allelic variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.

2021-01-31 | GSE143792 | GEO

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes

Project description:The majority of single nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to systematically detect regulatory activity of 5,987 noncoding GWASs SNPs in three IR-relevant cell lines. We identified 876 SNPs with biased allelic enhancer activity across 133 loci, and further uncovered the genetic regulatory mechanisms underlying functional SNPs through integrating multi-omics analyses.

2023-07-28 | GSE198047 | GEO

Differential allelic expression in normal breast tissue

Project description:Most loci contributing to breast cancer susceptibility identified by the recent genome-wide association studies (GWAS) are predicted to have a regulatory function. Additionally, the early phases of the GWAS studies have generated long lists of possible candidates that need to be prioritised for follow-up studies. Integration of allelic expression mapping and disease association data should enable the identification of those GWAS hits with higher cis-regulatory potential. Our aims are (1) to assess how well functional data and disease risk are correlated and (2) to help prioritise and select the strongest candidates from the GWAS scan for further follow-up and functional analysis. We are performing genome-wide differential allelic expression (DAE) analysis to identify loci with cis-regulatory potential in sixty-four normal breast tissue samples. Using the Illumina Exon510S-Duo BeadChips, we have identified 34K informative SNPs of which approximately 8K (23.5%) displayed DAE. Two SNPs showed monoallelic expression suggesting possible new imprinted loci. We are mapping the cis-regulatory loci by fitting a linear regression model with permutations to DAE ratios vs genotype at SNPs within ±250kb of the RefSeq gene corresponding to the DAE SNP. We will combine our data with the UK GWAS1 and GWAS2 studies for breast cancer susceptibility, to generate a list of genes that show regulatory variation for further evaluation as candidates. This is the first genome-wide differential allelic expression study in normal breast tissue, and one of the first in a primary tissue. We predict that this will be a powerful approach to validate/identify susceptibility loci and to unravel some of the biology underlying breast cancer susceptibility. Allelic gene expression of normal breast sample from healthy controls.

2012-05-02 | E-GEOD-35023 | biostudies-arrayexpress

Multiple causal variants underlie genetic associations in humans

Project description:We applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTLs) assessed for colocalization across 114 traits.

2021-05-24 | GSE174534 | GEO

Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci

Project description:Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. Here, we comprehensively map eQTLs in the human colon, assess their relevance for GWAS of colonic diseases and provide functional characterization.

2014-04-15 | GSE56789 | GEO

Differential allelic expression in normal breast tissue

2012-05-03 | GSE35023 | GEO

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