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

Nat Genet. 2022 May;54(5):603-612. doi: 10.1038/s41588-022-01056-5. Epub 2022 May 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Autoimmune Diseases* / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study* / methods
  • Mice
  • Polymorphism, Single Nucleotide / genetics
  • Regulatory Sequences, Nucleic Acid
  • T-Lymphocytes