CIDR_NCI_Validation and Fine Scale Mapping of Pancreatic Cancer Susceptibility Loci
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PROVIDER: PRJNA214445 | ENA |
REPOSITORIES: ENA
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Project description:Fine Mapping of Eight Psoriasis Susceptibility Loci
| PRJNA375837 | ENA
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: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: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: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
Project description:We present a Bayesian, Markov-chain Monte Carlo method for fine-scale linkage-disequilibrium gene mapping using high-density marker maps. The method explicitly models the genealogy underlying a sample of case chromosomes in the vicinity of a putative disease locus, in contrast with the assumption of a star-shaped tree made by many existing multipoint methods. Within this modeling framework, we can allow for missing marker information and for uncertainty about the true underlying genealogy and the makeup of ancestral marker haplotypes. A crucial advantage of our method is the incorporation of the shattered coalescent model for genealogies, allowing for multiple founding mutations at the disease locus and for sporadic cases of disease. Output from the method includes approximate posterior distributions of the location of the disease locus and population-marker haplotype proportions. In addition, output from the algorithm is used to construct a cladogram to represent genetic heterogeneity at the disease locus, highlighting clusters of case chromosomes sharing the same mutation. We present detailed simulations to provide evidence of improvements over existing methodology. Furthermore, inferences about the location of the disease locus are shown to remain robust to modeling assumptions.
| S-EPMC384946 | biostudies-other
Project description:We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ?14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-?, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
| S-EPMC4406292 | biostudies-literature
Project description:CIDR_NCI_Validation and Fine Scale Mapping of Pancreatic Cancer Susceptibility Loci
| PRJNA214446 | ENA
Project description:We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P<5×10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2>0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.
| S-EPMC3459817 | biostudies-literature
Project description:African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women's Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.
| S-EPMC6202164 | biostudies-literature