Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks [MPRA]
Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here, we tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4+ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for probable causal variants, are mediated by common upstream pathways, and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk. Overall design: This project contains MPRA data of 18,312 variants identified from 578 GWAS index variants (representing 531 distinct GWAS loci) associated with autoimmune disease in which T-cells are known to play a role. Additonally, it includes and 91 positive enhancer controls and 506 negative controls. The dataset includes 5 samples of plasmid DNA barcode sequencing and 7 samples of mRNA barcode sequencing read replicates from human primary T cells.