| 1. |
- Cavalli, Marco, et al.
(författare)
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Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals
- 2016
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 107:6, s. 248-254
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) point to regions with associated genetic variants but rarely to a specific gene and therefore detailed knowledge regarding the genes contributing to complex traits and diseases remains elusive. The functional role of GWAS-SNPs is also affected by linkage disequilibrium with many variants on the same haplotype and sometimes in the same regulatory element almost equally likely to mediate the effect. Using ChIP-seq data on many transcription factors, we pinpointed genetic variants in HepG2 and HeLa-S3 cell lines which show a genome-wide significant difference in binding between alleles. We identified a collection of 3713 candidate functional regulatory variants many of which are likely drivers of GWAS signals or genetic difference in expression. A recent study investigated many variants before finding the functional ones at the GALNT2 locus, which we found in our genome-wide screen in HepG2. This illustrates the efficiency of our approach.
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| 2. |
- Cavalli, Marco, et al.
(författare)
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Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression
- 2016
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 135:5, s. 485-497
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.
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| 3. |
- Cavalli, Marco, et al.
(författare)
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Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK
- 2017
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Ingår i: Hepatology Research. - : Wiley. - 1386-6346 .- 1872-034X. ; 47:8, s. 826-830
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism.METHODS: We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays.RESULTS: Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor.CONCLUSIONS: Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.
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| 4. |
- Helgadottir, Hafdis, et al.
(författare)
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Somatic mutation that affects transcription factor binding upstream of CD55 in the temporal cortex of a late-onset Alzheimer disease patient
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 28:16, s. 2675-2685
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.
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