BRBseq of Naïve T cells from Bach2_18del and WT controls

Genome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) 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. Naïve 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. Naïve CD4 and CD8 T cells were sorted from spleens by using 150 days old three homozygous of Bach2<18del> (The Jackson Laboratory #35028) and three wild type littermates.