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

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

PROVIDER: PRJNA810855 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR17486809.fastq.gz	Fastqsanger.gz
	SRR17486810.fastq.gz	Fastqsanger.gz
	SRR17486811.fastq.gz	Fastqsanger.gz
	SRR17486812.fastq.gz	Fastqsanger.gz

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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 [MPRA]

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.

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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.

Project description:Genome-wide association studies (GWASs) have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variants within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness and, upon acute viral infection, displayed greater propensity to become effector T cells. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

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

Project description:This SuperSeries is composed of the SubSeries listed below.

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Genetic Risk Variants for Autoimmune Diseases that Influence Gene Expression in Thymus

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