Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells.
Nat Genet 2022 May; 54(5):603-612
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.
Mouri, Kousuke; Guo, Michael H; de Boer, Carl G; Lissner, Michelle M; Harten, Ingrid A; Newby, Gregory A; DeBerg, Hannah A; Platt, Winona F; Gentili, Matteo; Liu, David R; Campbell, Daniel J; Hacohen, Nir; Tewhey, Ryan; and Ray, John P, "Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells." (2022). Faculty Research 2022. 58.