<i>motifbreakR</i>: an R/Bioconductor package for predicting variant effects at transcription factor binding sites

Coetzee, Simon; Coetzee, Gerhard A.; Hazelett, Dennis J.

doi:10.1093/bioinformatics/btv470

Cited by 252 publications

(254 citation statements)

References 15 publications

(16 reference statements)

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“…The combinations of these histone modifications were used to segment the genome in these ENCODE cell lines into active and poised promoter regions with or without DNase I hypersensitivity, active and poised enhancer regions with or without DNase I hypersensitivity, putative regulatory sites with open chromatin, and CTCF bound sites outside promoters and enhancers. SNPs that could be mapped to core regions (DNase hypersensitive sites) of putative non-coding regulatory regions (enhancers and promoters) were further subjected to analysis of transcription factor binding site disruptiveness using the R/Bioconductor package motifbreakR (24). To define other physical map features (transcription start sites, 5′ UTR, 3′UTR) we downloaded annotations from the February 2009 release of the human genome (GRCh37/hg19) available from the UCSC genome browser (25).…”

Section: Methodsmentioning

confidence: 99%

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Rand

Song

Déan

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma (MM). Methods We performed association testing of common variation in eight regions in 1,264 MM patients and 1,479 controls of European ancestry (EA) and 1,305 MM patients and 7,078 controls of African ancestry (AA) and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (p<0.05) associated with MM risk in AAs and EAs and the variant in 3p22.1 was associated in EAs only. In a combined AA-EA meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically signficantly associated with MM risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR=1.32, p=2.93×10−7) in TNFRSF13B, encodes a lymphocyte-specific protein in the tumor necrosis factor receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions We found that reported MM susceptibility regions contain risk variants important across populations supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact A subset of reported risk loci for multiple myeloma have consistent affects across populations and are likely to be functional.

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Section: Methodsmentioning

confidence: 99%

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Rand

Song

Déan

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…S5). To gain insight into the molecular pathways regulating RNASET2 expression and prioritize the number of candidate functional SNPs, we performed motif analysis to predict TF motif disruptions 22 across all SNPs which were associated with eQTL/mQTL. We then selected variants disrupting motifs of TFs expressed in T cells and focused on candidate variants in LD with the RNASET2 disease index SNP rs1819333.…”

Section: Resultsmentioning

confidence: 99%

“…22 Only T cell specific TFs identified as being expressed using RNA-seq data from CD patients, were carried forward. Candidate regulatory SNPs were then analyzed for potential functionality based on Roadmap Epigenomics Mapping Consortium (REMC) data.…”

Section: Methodsmentioning

confidence: 99%

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

et al. 2017

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Background & Aims Variants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel diseases (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression. We investigated T-cell gene expression patterns to determine the mechanisms by which TL1A regulates cytokine production, and whether these associate with outcomes of patients with Crohn’s disease (CD). Methods Peripheral T cells isolated from normal donors were cultured with TL1A. We performed gene expression profile analysis, by RNA sequencing, of subsets of interferon gamma (IFNG)-producing and non-producing cells, purified by flow cytometry. Unsupervised hierarchical clustering analysis was used to identify gene expression differences between these subsets. Ribonuclease T2 gene (RNASET2) expression and methylation were assessed by quantitative trait loci analyses. Clinical characteristics of patients (complications, resistance to therapy, recurrence time) were associated with single nucleotide polymorphisms in RNASET2. We performed motif screening to identify polymorphisms that disrupt transcription factor binding sites. Levels of RNASET2 were knocked down with small interfering RNA in CD4+ T cells and the effect on protein expression was determined by proteomic analysis and cytokine production. Cell aggregation was measured by flow cytometry. Results We identified 764 genes with at least a 2-fold difference in TL1A-mediated expression between IFNG-secreting and non-secreting T cells (P<1 × 10−5). Many of these genes were located near IBD susceptibility variants. RNASET2 was the only IBD risk-associated gene with greater than 5-fold downregulation in the IFNG-secreting subset. RNASET2 disease risk variants were associated with decreased expression in peripheral and mucosal tissues and DNA hypermethylation in CD patients requiring surgical intervention. RNASET2 disease risk variants were associated in CD patients with more complicated disease or resistance to therapy, defined in part by failed response to treatment, increased length of intestinal resection, shorter time to repeat surgery, and high Rutgeerts score (>2) in post-operative endoscopy. The RNASET2 variant rs2149092 was predicted to disrupt a consensus binding site for the transcription factor ETS within an enhancer region. Expression of RNASET2 correlated with expression of ETS. RNASET2 knockdown in T cells increased expression of IFNG and ICAM1 and induced T cells aggregation. A blocking antibody against LFA1, disrupting the LFA1-ICAM1 interaction, reduced T-cell production of IFNG. Conclusions We identified decreased expression of RNASET2 as a component of TL1A-mediated increase in production of IFNG and as a potential biomarker for patients with severe CD. Further study of the role of RNASET2 in regulating mucosal inflammation may lead to development of novel therapeutic targets.

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“…We used motifbreakR (38) to search for transcription factor motifs that bind to each variant (39–43). Chromatin features that overlapped variants and motifs that significantly altered binding (using the default setting with the score threshold, 0.9) are summarized in Supplementary Table S3.…”

Section: Methodsmentioning

confidence: 99%

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

Feng

Rhie

Huo

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Genome-wide association studies have identified ~100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Due to different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER and ROOT). Results Fifty-four of the 74 variants (73%) were found to have odds ratios that were directionally consistent with those previously reported, of which twelve were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13) we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3) we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions Through fine-mapping of known susceptibility regions we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry.

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motifbreakR: an R/Bioconductor package for predicting variant effects at transcription factor binding sites

Cited by 252 publications

References 15 publications

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

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