PT  - JOURNAL ARTICLE
AU  - Kousuke Mouri
AU  - Michael H. Guo
AU  - Carl G. de Boer
AU  - Gregory A. Newby
AU  - Matteo Gentili
AU  - David R. Liu
AU  - Nir Hacohen
AU  - Ryan Tewhey
AU  - John P. Ray
TI  - Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells
AID  - 10.1101/2021.05.30.445673
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.30.445673
4099  - http://biorxiv.org/content/early/2021/05/30/2021.05.30.445673.short
4100  - http://biorxiv.org/content/early/2021/05/30/2021.05.30.445673.full
AB  - 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. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.Competing Interest StatementG.A.N. and D.R.L have filed patent applications on genome editing agents. D.R.L. is a consultant and equity owner of Beam Therapeutics, Prime Medicine, and Pairwise Plants, companies that use genome editing. NH holds equity in BioNTech and consults for Related Sciences. Other authors have no conflicts of interest.