Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies

Yang, Tsun-Po; Beazley, Claude; Montgomery, Stephen B.; Dimas, Antigone S.; Gutiérrez‐Arcelus, María; Stranger, Barbara Elaine; Deloukas, Panos; Dermitzakis, Emmanouil T.

doi:10.1093/bioinformatics/btq452

Cited by 275 publications

(237 citation statements)

References 16 publications

(24 reference statements)

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“…We then used the Ensembl Variant Effect Predictor web tool to annotate these variants for predicted functional consequences (http://www.ensembl.org/info/docs/tools/vep/index.html) and used Genevar 12, seeQTL (http://www.bios.unc.edu/research/genomic_software/seeQTL/) 13, and the University of Chicago eQTL browser (http://eqtl.uchicago.edu/cgi‐bin/gbrowse/eqtl/) to identify eQTLs.…”

Section: Methodsmentioning

confidence: 99%

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Merkel

Xie

Monach

et al. 2017

Arthritis & Rheumatology

134

154

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ObjectiveTo identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).MethodsA genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.ResultsAmong the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.ConclusionThis study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

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Section: Methodsmentioning

confidence: 99%

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Merkel

Xie

Monach

et al. 2017

Arthritis & Rheumatology

134

154

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“…15 The Expression Quantitative Trait Locus (eQTL) analysis of SNP--gene relations was based on the HapMap3 study. 16 rESuLtS On the basis of the present in-silico analysis, the computationally identified variants that may affect the regulation of gene expression, and thus the existence of disease through changes within miRNA binding sites, are herein specified.…”

Section: Methodsmentioning

confidence: 99%

In‑silico identification of cardiovascular disease‑related SNPs affecting predicted microRNA target sites

Kamiński¹,

Kamińska²,

Skorupa³

et al. 2013

Polish Archives of Internal Medicine

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IntroductIon MicroRNAs (miRNAs) are small RNAs that play an important role in the regulation of gene expression. miRNA dysregulation has been associated with phenotypic changes, including cardiovascular diseases (CVDs).objEctIvES The aim of the study was to obtain a list of single nucleotide polymorphisms (SNPs) related to CVDs, with computationally predicted effect on miRNA binding sites, which would verify the hypothesis that miRNA dysregulation can lead to the development of CVDs. MAtErIALS And MEthodSSNPs, CVDs, and miRNAs were the 3 factors subjected to analysis. Based on the publicly available databases, we created a set of SNPs associated with the phenotype of interest and of SNPs located in known miRNA binding sites. We then merged the records assigned by the same SNP, which allowed us to indicate miRNA target sites, whose variants may be associated with CVDs. The results were supplemented with the additional data such as miRNA and mRNA coexpression, differences in the expression between various tissues, and Expression Quantitative Trait Locus analysis. Only in-silico methods, on the basis of publically available information tools and databases, were used. rESuLtS We obtained a list of 47 entries, constituting unique miRNA-SNP allele-phenotype linkages. concLuSIonS Computational approach supports the hypothesis of the linkage between alterations in miRNA function and numerous CVDs. Given the high frequency of SNP incidence, this pathomechanism may be common in the population. Although the obtained results need to be further experimentally validated, limiting the number of interactions to the most probable ones will facilitate the identification of clinically significant associations. potential therapeutic agents for the treatment of CVDs has been proposed. 6 Although genome-wide association studies (GWAS) indicate numerous connections between single nucleotide polymorphisms (SNPs) and phenotypes, leading to the conclusion that these genetic variants are able to significantly affect the course of CVD, 7 they do not provide direct information on the possible mechanisms by which these modulations occur. Given the association of multiple polymorphisms with CVDs, the presence of functional SNPs in noncoding intron sequences, 8 and the effect of miRNAs on gene transcription, we hypothesize that SNPs within miRNA binding site, by destroying the existing or creating novel target sites or by changing miRNA binding strength, may change its effects on gene expression, which results in the onset or change in the course of CVD. In this paper, based on an in-silico analysis, we would like to determine whether there exist miRNAs associated with CVDs by the coexistence of SNPs interfering with their function, and, if so, to indicate the specific ones. KEy WordSIn silico is, apart from in vivo or in vitro, one of the experimental techniques. It represents a modern approach to research, based on the use of computing power to perform mathematical analyses of a large amount of data and the creation of complex datab...

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“…Although some eQTL datasets are publicly available (e.g., http://www. sanger.ac.uk/resources/software/genevar/; Yang et al 2010a), few are from primary cell types, and available datasets may not be relevant to some traits or diseases, and few studies have performed both complex trait GWAS and eQTL mapping in the same individuals. To provide the scientific community with a resource to facilitate large-scale analyses, the National Institutes of Health recently launched the Genotype-Tissue Expression (GTeX) project (http:/ /nihroadmap.nih.gov/GTEx/ index.asp) to provide a publicly available catalog of tissuespecific gene expression profiles and eQTL.…”

Section: The Promise Of Gwas-systems Genetics Of Complex Traitsmentioning

confidence: 99%

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

2011

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Enormous progress in mapping complex traits in humans has been made in the last 5 yr. There has been early success for prevalent diseases with complex phenotypes. These studies have demonstrated clearly that, while complex traits differ in their underlying genetic architectures, for many common disorders the predominant pattern is that of many loci, individually with small effects on phenotype. For some traits, loci of large effect have been identified. For almost all complex traits studied in humans, the sum of the identified genetic effects comprises only a portion, generally less than half, of the estimated trait heritability. A variety of hypotheses have been proposed to explain why this might be the case, including untested rare variants, and gene-gene and gene-environment interaction. Effort is currently being directed toward implementation of novel analytic approaches and testing rare variants for association with complex traits using imputed variants from the publicly available 1000 Genomes Project resequencing data and from direct resequencing of clinical samples. Through integration with annotations and functional genomic data as well as by in vitro and in vivo experimentation, mapping studies continue to characterize functional variants associated with complex traits and address fundamental issues such as epistasis and pleiotropy. This review focuses primarily on the ways in which genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics.M ANY phenotypes are quantitative in nature, and complex in etiology, with multiple environmental and genetic causes. The observation that complex traits cluster in relation to genetic relatedness suggests heritability, and advances in theoretical and experimental genetics, combined with analytical developments and high-throughput genomics, have provided an unprecedented view into the mode of inheritance and genetic architecture of complex traits.

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Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies

Cited by 275 publications

References 16 publications

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

In‑silico identification of cardiovascular disease‑related SNPs affecting predicted microRNA target sites

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

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