Identifying the impact of intergenic variants from meta-GWAS of Rheumatoid Arthritis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE101812 | GEO | 2019/12/01
REPOSITORIES: GEO
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Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.
2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress
Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
2022-07-01 | GSE175457 | GEO
Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
2022-07-01 | GSE175458 | GEO
Project description:The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and a wide range of BP-related quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus.
2016-07-01 | GSE82042 | GEO
Project description:Background: Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetics variants that regulate protein expression in human livers. Results: We conducted a genome-wide pQTL study in 287 normal human liver samples and identified 900 local-pQTL variants and 4,026 distant-pQTL variants. We further discovered 53 genome hotspots of pQTL variants. Transcriptional region mapping analysis showed that 1,133 pQTL variants are in transcriptional regulatory regions. Genomic region enrichment analysis of the identified pQTL variants revealed 804 potential regulatory interactions among 595 regulators (e.g. non-coding RNAs) and 394 proteins. Moreover, pQTL variants and trait-variant integration analysis uncovered several novel mechanisms underlying the relationships between protein expression and liver diseases, such as alcohol dependence. Notably, over 2,000 of the identified pQTL variants have not been reported in previous eQTL studies, suggesting extensive involvement of genetic polymorphisms in post-transcriptional regulation of protein expression in human livers. Conclusions: We have partially established protein expression regulation networks in human livers and generated a wealth of pQTL data that could serve as a valuable resource for the scientific community.
2020-07-21 | PXD019169 | Pride
Project description:The nucleus is composed of membrane-less subnuclear compartments, containing intrinsically disordered proteins and RNAs that phase separate (PS) and contribute to specific nuclear reactions. However, whether and how different subnuclear compartments can intercommunicate remains elusive. Here we identified nuclear bodies with PS features composed of BAZ2A, a factor associating with active chromatin. BAZ2A-bodies depend on active transcription, RNAs, and the non-disordered BAZ2A RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space BAZ2A-bodies contact H3K27me3-bodies. Disruption of BAZ2A-bodies promotes BAZ2A invasion into H3K27me3-domains, causing H3K27me3-bodies loss, H3K27me3 decrease, and gene upregulation. BAZ2A-bodies formation is negatively regulated by the nuclear-speckles associated lncRNA Malat1 that interacts with BAZ2A and mediates BAZ2A association to chromatin at nuclear speckles, which do not contact BAZ2A-bodies. The results unravel how active compartments protect repressive compartments using PS mechanisms that are promoted or impaired according to the type of RNA interactions with RNA-binding proteins.
2024-04-09 | GSE225894 | GEO
Project description:The nucleus is composed of membrane-less subnuclear compartments, containing intrinsically disordered proteins and RNAs that phase separate (PS) and contribute to specific nuclear reactions. However, whether and how different subnuclear compartments can intercommunicate remains elusive. Here we identified nuclear bodies with PS features composed of BAZ2A, a factor associating with active chromatin. BAZ2A-bodies depend on active transcription, RNAs, and the non-disordered BAZ2A RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space BAZ2A-bodies contact H3K27me3-bodies. Disruption of BAZ2A-bodies promotes BAZ2A invasion into H3K27me3-domains, causing H3K27me3-bodies loss, H3K27me3 decrease, and gene upregulation. BAZ2A-bodies formation is negatively regulated by the nuclear-speckles associated lncRNA Malat1 that interacts with BAZ2A and mediates BAZ2A association to chromatin at nuclear speckles, which do not contact BAZ2A-bodies. The results unravel how active compartments protect repressive compartments using PS mechanisms that are promoted or impaired according to the type of RNA interactions with RNA-binding proteins.
2024-04-09 | GSE225895 | GEO
Project description:The nucleus is composed of membrane-less subnuclear compartments, containing intrinsically disordered proteins and RNAs that phase separate (PS) and contribute to specific nuclear reactions. However, whether and how different subnuclear compartments can intercommunicate remains elusive. Here we identified nuclear bodies with PS features composed of BAZ2A, a factor associating with active chromatin. BAZ2A-bodies depend on active transcription, RNAs, and the non-disordered BAZ2A RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space BAZ2A-bodies contact H3K27me3-bodies. Disruption of BAZ2A-bodies promotes BAZ2A invasion into H3K27me3-domains, causing H3K27me3-bodies loss, H3K27me3 decrease, and gene upregulation. BAZ2A-bodies formation is negatively regulated by the nuclear-speckles associated lncRNA Malat1 that interacts with BAZ2A and mediates BAZ2A association to chromatin at nuclear speckles, which do not contact BAZ2A-bodies. The results unravel how active compartments protect repressive compartments using PS mechanisms that are promoted or impaired according to the type of RNA interactions with RNA-binding proteins.
2024-04-09 | GSE225897 | GEO
Project description:The nucleus is composed of membrane-less subnuclear compartments, containing intrinsically disordered proteins and RNAs that phase separate (PS) and contribute to specific nuclear reactions. However, whether and how different subnuclear compartments can intercommunicate remains elusive. Here we identified nuclear bodies with PS features composed of BAZ2A, a factor associating with active chromatin. BAZ2A-bodies depend on active transcription, RNAs, and the non-disordered BAZ2A RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space BAZ2A-bodies contact H3K27me3-bodies. Disruption of BAZ2A-bodies promotes BAZ2A invasion into H3K27me3-domains, causing H3K27me3-bodies loss, H3K27me3 decrease, and gene upregulation. BAZ2A-bodies formation is negatively regulated by the nuclear-speckles associated lncRNA Malat1 that interacts with BAZ2A and mediates BAZ2A association to chromatin at nuclear speckles, which do not contact BAZ2A-bodies. The results unravel how active compartments protect repressive compartments using PS mechanisms that are promoted or impaired according to the type of RNA interactions with RNA-binding proteins.
2024-04-09 | GSE225896 | GEO
Project description:Genome-wide association studies (GWAS) have identified twenty melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with melanocyte-specific expression quantitative trait locus (eQTL) profiling. We identified thirty-nine candidate functional variants displaying allelic transcriptional activity, of which nine from four loci were also correlated with local gene expression in melanocytes (CTSS, CASP8, MX2, and MAFF). Among these, we further characterized the locus in MX2 gene on chromosome band Chr21q22.3 and validated a functional variant, rs398206. The functional variant mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation largely accounts for a significant cis-eQTL of the HIV-1 restriction gene, MX2, in primary melanocytes, where the melanoma risk-associated A allele is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated an accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we uncovered a pleiotropic function of MX2 in melanoma susceptibility.
2020-04-20 | GSE129242 | GEO