Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells.
Authors | |
Abstract | 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. |
Year of Publication | 2022
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Journal | Nat Genet
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Date Published | 2022 May 05
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ISSN | 1546-1718
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DOI | 10.1038/s41588-022-01056-5
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PubMed ID | 35513721
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Links | |
Grant list | F32AI129249 / 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)
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