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Nat Genet DOI:10.1038/s41588-022-01056-5

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

Publication TypeJournal Article
Year of Publication2022
AuthorsMouri, K, Guo, MH, de Boer, CG, Lissner, MM, Harten, IA, Newby, GA, DeBerg, HA, Platt, WF, Gentili, M, Liu, DR, Campbell, DJ, Hacohen, N, Tewhey, R, Ray, JP
JournalNat Genet
Date Published2022 May 05

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.


Alternate JournalNat Genet
PubMed ID35513721
Grant ListF32AI129249 / / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) /
K22 AI153648 / AI / NIAID NIH HHS / United States
ALTF 486-2018 / / European Molecular Biology Organization (EMBO) /
CRI2993 / / Cancer Research Institute (CRI) /