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

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. Overall design: This project contains MPRA data of 18,312 variants identified from 578 GWAS index variants (representing 531 distinct GWAS loci) associated with autoimmune disease in which T-cells are known to play a role. Additonally, it includes and 91 positive enhancer controls and 506 negative controls. The dataset includes 5 samples of plasmid DNA barcode sequencing and 3 samples of mRNA barcode sequencing read replicates.