Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells
Nat Genet. 2022-05-01;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.
- Consortium data used in this publication
- Data generated in this study from all manuscript figures are available in NCBI GEO (GSE197539). The 1000 Genomes Phase 3 reference panel was obtained from ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/. DHS data across 733 samples were obtained from https://zenodo.org/record/3838751#.X_IA7-lKg6U. Histone chromatin immunoprecipitation sequencing data were downloaded from ENCODE (encodeproject.org); the specific files utilized are listed in Supplementary Table 20. CAGE-based enhancer annotations were downloaded from https://fantom.gsc.riken.jp/5/datafiles/latest/extra/Enhancers/. ChromHMM was obtained from https://egg2.wustl.edu/roadmap/data/byFileType/chromhmmSegmentations/ChmmModels/core_K27ac/jointModel/final/. HOCOMOCO TF position-weighted matrices were obtained from https://hocomoco11.autosome.ru/downloads_v10. ATAC-seq allelic skew data were obtained from Calderon et al. (https://www.nature.com/articles/s41588-019-0505-9; Supplementary Table 1, “significant_ASCs” tab). Chromatin accessibility QTLs were downloaded from Gate et al. (https://www.nature.com/articles/s41588-018-0156-2; Supplementary Table 6). DeltaSVM precomputed weights for naive CD4 T cells and Jurkat cells were obtained from http://www.beerlab.org/deltasvm_models/downloads/deltasvm_models_e2e.tar.gz. The EMBL GWAS catalog (https://www.ebi.ac.uk/gwas/) was accessed on 10 August 2020. T1D GWAS fine-mapping results were obtained from Onengut-Gumuscu et al. (https://www.nature.com/articles/ng.3245; Supplementary Table 1). pcHiC data were obtained from Javierre et al. (https://osf.io/u8tzp/). The ImmunoSigDB immunologic signatures database (v7.2) was downloaded from http://www.gsea-msigdb.org/gsea/msigdb/. Tscm Bach2 guide RNA perturbed mouse RNA-seq data were obtained from NCBI GEO (GSE152379). The GRCm38 mouse transcriptome index for Kallisto RNA-seq alignments were obtained from https://github.com/pachterlab/kallisto-transcriptome-indices/releases. The Bach218del (stock 35028) mouse strain is available at The Jackson Laboratory.