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. 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.