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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE194424 | GEO | 2022/03/02

REPOSITORIES: GEO

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Project description:Background: The identification of causal variants responsible for disease associations from genome-wide association studies (GWAS) facilitates functional understanding of the disease mechanisms implicated by GWAS. One of the earliest GWAS associations to COPD spans an intragenic region within FAM13A, but the causal variants at this loci have not yet been identified. Massively parallel reporter assays (MPRA) can be used to prioritize functional regulatory variants in a high-throughput manner. Methods: We used an integrated approach using fine-mapping in over 10,000 subjects from COPD GWAS studies, two MPRA experiments, traditional reporter assays, chromatin conformation capture, and CRISPR-based gene editing to characterize COPD-associated regulatory variants in FAM13A in human bronchial epithelial cell lines. Results: Conditional genetic association and fine mapping analyses identified two independent COPD association signals in FAM13A. MPRA identified 45 common functional regulatory variants, and six COPD-associated putative functional variants were prioritized for further functional investigation. Three variants demonstrated significant activity in traditional reporter assays, and one variant, rs2013701, was selected for further testing in the endogenous genomic context based on a direction of effect consistent with postulated mechanisms of FAM13A-mediated COPD susceptibility. CRISPR-based genome editing for this variant confirmed allele-specific effects on FAM13A expression and altered rates of cellular proliferation, providing multiple levels of functional characterization for this COPD-associated variant. Conclusions: Comprehensive screening for regulatory variants near FAM13A identified the presence of extensive functional regulatory variation within a 250kb window of FAM13A in HBECs. Focused functional evaluation of the COPD-associated functional variants in LD with the two independent association signals in this region prioritized the common variant rs2013701, for which multiple parallel lines of functional evidence confirm allelic effects on FAM13A regulation.

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

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