Study of the Rheumatoid Arthritis genetic component from multiplex families
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2000
ORGANISM(S): Homo Sapiens
SUBMITTER: GenHotel
PROVIDER: PRJEB57722 | EVA | 2022-11-24
REPOSITORIES: EVA
Dataset's files
Items per page: 5 1 - 5 of 6 |
Similar Datasets
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:Beckwith–Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies. We identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID. Our data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling.
2022-06-02 | GSE195873 | GEO
Project description:Interventions: The aim of this research is to find the undiscovered gene or genes responsible for hereditary colorectal cancer, and to understand how the gene(s) cause colorectal cancer. One of the best approaches used to find the answers to these questions is to study families where there are several family members affected with colorectal cancer.
Case probands and their relatives (affected and unaffected) will be recruited
(20 ml) of blood will be obtained on one occasion from each participant
Where tissues from affected family members have already been obtained (paraffin embedded tumour tissue in blocks) we will seek permission to access this material for DNA extraction. The duration of study will be approximately 48 months.
Primary outcome(s): To identify molecular markers of potential value in understanding predisposition to CRC by their association with gene variants that increase the risk of CRC.
The study will be a family based analysis of SNP genotypes for cases and controls within families and between families. Transmission of disease associated SNPs will be assessed to determine within-family association and linkage and then to calculate across-family associations.[2-3 blood samples per week over 36 months approx]
Study Design: Purpose: Natural history;Duration: Cross-sectional;Selection: Defined population;Timing: Both
| 2452082 | ecrin-mdr-crc
Project description:Background: Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have focussed attention on the role of non-sequence-based genomic variation in health and disease. Although a better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches. Results: We performed a multi-stage epigenome-wide association study (EWAS), quantifying genome-wide patterns of DNA methylation in a total of 1,801 individuals from three independent sample cohorts. We identified multiple differentially methylated positions (DMPs) and region (DMRs) associated with schizophrenia, independently of important confounders such as smoking, with consistent effects across the three independent cohorts. We also show that polygenic burden for schizophrenia is associated with epigenetic variation at multiple loci across the genome, independently of loci implicated in the analysis of diagnosed schizophrenia. Finally, we show how DNA methylation quantitative trait loci (mQTL) analyses can be used to annotate the extended genomic regions nominated by genetic studies of schizophrenia, with Bayesian co-localization analyses highlighting potential regulatory variation causally involved in disease. Conclusion: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological pipeline that can be used to inform EWAS analyses of other complex traits and diseases. We demonstrate the utility of using polygenic risk score (PRS) for identifying molecular variation associated with etiological variation, and mQTLs for refining the functional/regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. 675 whole blood derived DNA samples (353 schizophrenia cases and 322 controls) representing phase 1 of our meta-analysis. Bisulfite converted DNA from these samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip v1.0.
2016-08-01 | E-GEOD-80417 | biostudies-arrayexpress
Project description:To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five new histotype-specific EOC risk regions (P-value < 5 x 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (P-value < 10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue data sets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (FDR < 0.05). Finally, by integrating genome-wide HiChIP interactome analysis with TWAS, variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8 and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by GWAS.
2024-03-27 | GSE255142 | GEO
Project description:Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and SNP arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g. PARP1, CDKN2A) or co-segregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare co-segregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
2016-12-01 | GSE85010 | GEO
Project description:To efficiently identify genetic susceptibility variants for gastric cancer, including rare coding variants, we performed an exome chip-based array study. We found that a linkage disequilibrium (LD) block containing 2 significant variants in PSCA gene increased the risk and two blocks that included 15 suggested variants including TRIM31, TRIM 40, TRIM 10, and TRIM26 regions, and included one suggested variant and OR2H2 gene showed protective associations with gastric cancer susceptibility. In addition, the PLEC region (rs200893203), FBLN2 region (rs201192415), and EPHA2 region (rs3754334) were associated with increased susceptibility We performed an exome chip-based array study in 329 gastric cancer cases and 683 controls.
2014-06-11 | E-GEOD-58356 | biostudies-arrayexpress
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:Abstract Background: Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have focussed attention on the role of non-sequence-based genomic variation in health and disease. Although a better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches. Results: We performed a multi-stage epigenome-wide association study (EWAS), quantifying genome-wide patterns of DNA methylation in a total of 1,801 individuals from three independent sample cohorts. We identified multiple differentially methylated positions (DMPs) and region (DMRs) associated with schizophrenia, independently of important confounders such as smoking, with consistent effects across the three independent cohorts. We also show that polygenic burden for schizophrenia is associated with epigenetic variation at multiple loci across the genome, independently of loci implicated in the analysis of diagnosed schizophrenia. Finally, we show how DNA methylation quantitative trait loci (mQTL) analyses can be used to annotate the extended genomic regions nominated by genetic studies of schizophrenia, with Bayesian co-localization analyses highlighting potential regulatory variation causally involved in disease. Conclusion: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological pipeline that can be used to inform EWAS analyses of other complex traits and diseases. We demonstrate the utility of using polygenic risk score (PRS) for identifying molecular variation associated with etiological variation, and mQTLs for refining the functional/regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. 847 whole blood derived DNA samples (414 schizophrenia cases and 433 controls) representing phase 2 of our meta-analysis. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.
2016-08-01 | E-GEOD-84727 | biostudies-arrayexpress