Fine Mapping of Eight Psoriasis Susceptibility Loci
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA375837 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:<p>Psoriasis is a common immune-mediate disease identified through scaly patches of the skin. In this study we collected genotype information on 5,067 samples of European ancestry as a follow-up study of our initial GWAS (<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=19169254">Nair et al. 2009</a>). We designed an Illumina iSelect custom genotyping array with 2,269 tagging SNPs in the eight known psoriasis susceptibility regions (<a href="https://www.ncbi.nlm.nih.gov/gene/3107">MHC</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/3593">IL12B</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/149233">IL23R</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/51561">IL23A</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/7128">TNFAIP3</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/3596">IL13</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/55905">RNF114</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/10318">TNIP1</a>). The custom array also included 5,463 SNPs outside the eight known susceptibility regions, which were selected based on their association p-values in a meta-analysis of HapMap-imputed genotypes of two published GWAS-CASP (<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=19169254">Nair et al. 2009</a>) and (<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=20953188">Ellinghaus et al. 2010</a>). After quality control we analyzed 4,806 samples (2,699 cases and 2,107 controls). </p> <p>Please note: The accession number for this dbGaP study was incorrectly listed in the relevant publication (<a href="https://www.ncbi.nlm.nih.gov/pubmed/25182136">Das et al.</a>, 2015, Eur. J. Hum. Genet 23:844-853) as phs000019.v1.p1.</p>
| phs001298 | dbGaP
Project description:Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49?239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.
| S-EPMC4795047 | biostudies-literature
Project description:CIDR_NCI_Validation and Fine Scale Mapping of Pancreatic Cancer Susceptibility Loci
| PRJNA214445 | ENA
Project description:Fine Mapping of Eight Psoriasis Susceptibility Loci
| PRJNA375838 | ENA
Project description:Background: Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA, and instead are enriched in cell type and stimulation-specific gene regulatory regions. Results: Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (>500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis associated enhancer upregulates known genes in the KLF4 pathway, specific to skin cells and apoptosis. Conclusions: Taken together, our study design provides a robust pipeline to follow up GWAS disease associated variants and implicate the causal genes, cell types, direction of effect and consequences, which are vital next steps for the functional translation of genetic findings into clinical benefit.
2020-04-10 | GSE137906 | GEO
Project description:Genome-wide association studies of type 2 diabetes have been extremely successful in discovering loci that contribute genetic effects to susceptibility to the disease. However, at the vast majority of these loci, the variants and transcripts through which these effects on type 2 diabetes are mediated are unknown, limiting progress in defining the pathophysiological basis of the disease. In this review, we will describe available approaches for assaying genetic variation across loci and discuss statistical methods to determine the most likely causal variants in the region. We will consider the utility of trans-ethnic meta-analysis for fine mapping by leveraging the differences in the structure of linkage disequilibrium between diverse populations. Finally, we will discuss progress in fine-mapping type 2 diabetes susceptibility loci to date and consider the prospects for future efforts to localise causal variants for the disease.
| S-EPMC4169615 | biostudies-literature
Project description:Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31
| PRJNA573841 | ENA
Project description:2,981 primary biliary cirrhosis (PBC) cases were collected by the UK PBC Consortium and genotyped on the Illumina Immunochip where 2,861 passed quality control. These cases were then compared to a UK population control to identify novel PBC risk loci and fine-map association signals. (Liu & Almarri et al., Nat Genet, 2012)
| EGAS00001001837 | EGA
Project description:Most psoriasis-related genes or loci identified through genome-wide association studies (GWASs) represent common clusters and are located in non-coding regions of the human genome, providing only limited evidence for the role of coding variants in psoriasis. Two exome-wide case-control genotyping data sets were obtained from our previous study. Quality control was established for each data set, and the remaining markers in each were annotated using ANNOVAR. Gene-based analysis was performed on the annotation results. A total of 250 and 35 genes in the Exome_Fine and Exome_Asian Array cohorts, respectively, exceeded the threshold (P < 4.43 × 10-6). Merged gene-based analysis was then conducted on the same set of SNPs from seven genes common to both arrays, and the chi-square test was used to confirm all gene-based results. Ultimately, four new susceptibility genes were identified: BBS7 (Pcombine = 1.38 × 10−29), GSTCD (Pcombine = 8.35 × 10−47), LIPK (Pcombine = 1.02 × 10−19) and PPP4R3B (Pcombine = 1.79 × 10−33). This study identified four new susceptibility genes for psoriasis through a gene-based method using rare variants, contributing to our understanding of the pathogenesis of psoriasis.
2019-05-24 | GSE131663 | GEO
Project description:Coronary artery disease (CAD) is the leading cause of mortality and morbidity driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with CAD and myocardial infarction (MI) susceptibility in multi-ethnic populations. The majority of these variants reside in non-coding regulatory regions and are co-inherited with hundreds of candidate regulatory SNPs. Herein, we use integrative genomic, epigenomic, and transcriptomic fine-mapping in human coronary artery smooth muscle cells (HCASMC) and tissues to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps we prioritize 65 candidate variants and perform allele-specific binding and expression analyses on 7 top candidates. We validate our findings in two independent cohorts of diseased human arterial expression quantitative trait loci (eQTL), which together demonstrate fundamental links between CAD associations and regulatory function in the appropriate disease context.
2016-07-06 | GSE72696 | GEO