Hi-C dataset for testicular germ cell tumour GWAS risk loci, as described in the Oncoarray Litchfield et al. 2016 paper.
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001001930 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.
| EGAS00001001836 | EGA
Project description:Genome wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify further SNPs associated with TGCT we conducted a multistage GWAS with a combined dataset of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P = 1.5 x 10-9), 11q14.1 (rs7107174, GAB2, P = 9.7 x 10-11), 16p13.13 (rs4561483, GSPT1, P = 1.6 x 10-8) and 16q24.2 (rs55637647, ZFPM1, P = 3.4 x 10-9). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development.
| EGAS00001001302 | EGA
Project description:Genome-wide association studies (GWAS) have identified multiple lung cancer risk loci including those that are distinct in the major histological types. However, most of these loci have not been functionally characterized. Here we employed massively parallel reporter assays (MPRA) to assess allelic transcriptional activity of risk-associated variants en masse. We tested 2,245 variants in 42 loci from 3 recent GWASs of East Asian and European populations in the context of lung adenocarcinoma and squamous cell carcinoma cells while incorporating exposure to a tobacco-smoke carcinogen, benzo[a]pyrene. At FDR < 0.01, we identified 844 MPRA-significant variants with allelic transcriptional activity across 88% of lung cancer loci. Further variant scoring using lung-specific epigenomic annotation demonstrated that 63% of the loci harbored multiple equally functional variants in linkage disequilibrium. Cell-type-specific variants were observed in 72% of the loci, a subset of which aligned with histology-specific association in the GWAS. Distinct subsets of transcription factors were predicted to bind to cell-type-specific variants and those affecting multiple GWAS loci in trans. Linking MPRA-significant variants to target genes based on four different approaches identified candidate susceptibility genes including essential genes for lung cancer cell growth. CRISPR-interference of a high-scoring MPRA-significant variant validated multiple variant-gene connections from different datasets, including RTEL1, SOX18, and ARFRP1. Our data provide a comprehensive catalog of functional characterization of lung cancer GWAS loci and the molecular basis of heterogeneity and polygenicity of lung cancer susceptibility.
2024-05-16 | GSE245699 | GEO
Project description:Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for chronic and inflammatory disease phenotypes in humans. There is increasing evidence that chronic inflammation is a crucial driver in the pathogenesis of cardiovascular diseases (CVD), which may be genetically determined. To understand the genetic architecture underlying chronic inflammation and CVD we performed a systematic analysis of (1) common risk alleles coming from published GWAS, (2) of protein-protein interaction (PPI) networks informed by (3) gene expression data with a defined molecular target involved in the inflammatory processes promoting CVD, MRP8. (4) through analysis of integrated haplotype scores (iHS) and FST values in HapMap phase 2 data, we investigated whether recent selection pressure acting upon inflammatory genes affected CVD susceptibility loci. Our findings provide significant evidence for a PPI network, which connects inflammatory and cardiovascular susceptibility genes, and establish a genetic framework of inflammatory CVD. 41.59% of PPI genes are associated with immune functions. 28.3% of integrated genes can be linked to both, an inflammatory and cardiovascular disease phenotype. Interestingly, CDKN2B, and CELSR2/PSRC1/MYBPHL/SORT1, unequivocally replicated CVD loci, are integrated within this network as are several SNPs located in transcription factor recognition sequences, i.e. NFKB1, STAT3, which are key factors in inflammation. Finally, we observed a significant enrichment of inflammatory variants within CVD cluster loci that are targets of selection. Overall, 32 genes exhibit traces of selection, 16 of which are part of the PPI, further suggesting that recent selective sweeps may have affected the genomic architecture underlying CVD. 6 samples, no replicates.
2015-09-01 | E-GEOD-54989 | biostudies-arrayexpress
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
Project description:Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR)<1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus.
2021-03-30 | GSE171077 | GEO
Project description:Malignant (type II) testicular germ cell tumors (TGCT) are considered tumors of embryonic germ cell ancestry that diverge morphologically as seminoma (SE), and nonseminomas (NS), the latter including embryonal carcinoma (EC), teratoma (TE), yolk sac tumor (YS) and choriocarcinoma. We have analyzed the genomes and epigenomes of pure histological forms of TGCT (n=130) and 128 matched adjacent normal testicular tissues for TGCT core and subtype-specific DNA methylome profiles and somatic copy number aberrations (SCNA). Original data were compared with published data sets focused on differentiated and pluripotent states. First, we identified pan-TGCT recurrent erasure of maternal and paternal germline imprints and DPPA3 (STELLA), consistent with an embryonic germ cell ancestry. Beyond these conserved properties, we identified TGCT subtype-dependent epigenomic congruency with pluripotent versus somatic reference lineages, thereby establishing competency for lineage-conforming methylation reprogramming in the multi-potent common ancestor of TGCT. Notable subtype programming distinctions are as follows: the SE methylome reflects a ground-state of germ cell erasure; EC is found to harbor pervasive embryonic stem cell (ESC)-like CpH (non-CpG) methylation, absent in other TGCT and non-germ cell tumors and differentiated tissues. EC was further distinguished by ESC-like hypomethylation of NANOG, contrasting with NANOG methylation in TE, YS, and somatic tissues. Thus, EC methylomes present a novel mixed ESC/embryonic germ cell epigenomic state. TE global methylation was most convergent with somatic tissue; however, and unique among TGCT subtypes, TE manifested hypermethylation of the H19 paternal germline DMR. The YS methylome most closely resembled extra-embryonic trophoblast. The total set of findings provides evidence for a multi-potent TGCT stem cell whose progeny may harbor pluripotent, primordial germ/gonocyte, and somatic lineage-defining methylation marks. Despite such competency, no TGCT subtype restored erased parental germline imprints. TE is the exception, with H19 hypermethylation. Benign testis adjacent to TGCT exhibited a bimodal epigenotype distribution determined by spermatogenesis and significantly associated with high versus low Johnsen score. Overall, TGCT methylomes are trapped in a core embryonic germ cell-like state of DPPA3/STELLA and imprint erasure, while differential somatic and pluripotent reprogramming profiles are otherwise established.
2016-09-15 | GSE74104 | GEO
Project description:Background: Recent genome-wide association studies (GWAS) have identified more than 100 loci associated with increased risk of prostate cancer, most of which are in non-coding regions of the genome. Understanding the function of these non-coding risk loci is critical to elucidate the genetic susceptibility to prostate cancer. Results: We generated genome-wide regulatory element maps and performed genome-wide chromosome confirmation capture assays (in situ Hi-C) in normal and tumorigenic prostate cells. Using this information, we annotated the regulatory potential of 2,181 fine-mapped PCa risk-associated SNPs and predicted a set of target genes that are regulated by PCa risk-related H3K27Ac-mediated loops. We next identified PCa risk-associated CTCF sites involved in long-range chromatin loops. We used CRISPR-mediated deletion to remove PCa risk-associated CTCF anchor regions and the CTCF anchor regions looped to the PCa risk-associated CTCF sites; we observed up to 100 fold increases in expression of genes within the loops when the PCa risk-associated CTCF anchor regions were deleted. Conclusions: We have identified GWAS risk loci involved in long-range loops that function to repress gene expression within chromatin loops. Our studies provide new insights into the genetic susceptibility to prostate cancer.
2018-08-15 | GSE118514 | 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