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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Escherichia coli Mus musculus Homo sapiens

PROVIDER: GSE197539 | GEO | 2022/02/28

REPOSITORIES: GEO

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [BaseEditing]

Project description:Determining causal variants for autoimmune disease is an enormous challenge - 90% of autoimmune disease-associated variants are non-coding and there are often 10s-100s are in tight linkage disequilibrium with the causal variant(s), making identification of the true causal variants difficult. Using massively parallel reporter assays in a T cell line, we prioritized variants that enriched highly for likely causal variants according to statistical fine-mapping. We followed up on one of the prioritized variants, rs72928038 in the BACH2 locus, which had a high effect size, finding that it regulates Bach2 expression in a human T cell line. We created mice containing a small deletion over this non-coding variant, and have tested mutant vs. WT antigen-specific T cells for their responses during acute viral infection. In the context of rs72928038-deleted mice (termed Bach218del), we found an increase in effector T cell differentiation, which highlights a potential role for rs72928038 in modulating effector T cell differentiation in the context of autoimmune disease.

2022-03-02 | GSE197537 | GEO

Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [MPRA]

2022-03-02 | GSE197538 | GEO

Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [scRNA-seq]

2022-03-02 | GSE194424 | GEO

Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

Project description:Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [BaseEditing]

Project description:Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [BaseEditing]

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [MPRA]

Project description:Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [MPRA]

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [scRNA-seq]

Project description:Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells [scRNA-seq]

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cepip: context-dependent epigenomic weighting for prioritization of regulatory variants and disease-associated genes.

Project description:It remains challenging to predict regulatory variants in particular tissues or cell types due to highly context-specific gene regulation. By connecting large-scale epigenomic profiles to expression quantitative trait loci (eQTLs) in a wide range of human tissues/cell types, we identify critical chromatin features that predict variant regulatory potential. We present cepip, a joint likelihood framework, for estimating a variant's regulatory probability in a context-dependent manner. Our method exhibits significant GWAS signal enrichment and is superior to existing cell type-specific methods. Furthermore, using phenotypically relevant epigenomes to weight the GWAS single-nucleotide polymorphisms, we improve the statistical power of the gene-based association test.

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Context-specific effects of genetic variants associated with autoimmune disease.

Project description:Autoimmune diseases such as rheumatoid arthritis and coeliac disease are typical examples of complex genetic diseases caused by a combination of genetic and non-genetic risk factors. Insight into the genetic risk factors (single nucleotide polymorphisms (SNPs)) has increased since genome-wide association studies (GWAS) became possible in 2007 and, for individual diseases, SNPs can now explain some 15-50% of genetic risk. GWAS have also shown that some 50% of the genetic risk factors for individual autoimmune diseases overlap between different diseases. Thus, shared risk factors may converge to pathways that, when perturbed by genetic variation, predispose to autoimmunity in general. This raises the question of what determines disease specificity, and suggests that identical risk factors may have different effects in various autoimmune diseases. Addressing this question requires translation of genetic risk factors to causal genes and then to molecular and cellular pathways. Since?>90% of the genetic risk factors are found in the non-coding part of the genome (i.e. outside the exons of protein-coding genes) and can have an impact on gene regulation, there is an urgent need to better understand the non-coding part of the genome. Here, we will outline the methods being used to unravel the gene regulatory networks perturbed in autoimmune diseases and the importance of doing this in the relevant cell types. We will highlight findings in coeliac disease, which manifests in the small intestine, to demonstrate how cell type and disease context can impact on the consequences of genetic risk factors.

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Identification of <i>ATP2B4</i> Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria.

Project description:Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.

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