Abstract Text: Autoimmune diseases have complex genetic inheritance patterns making their genetic origins difficult to determine. Genome-wide association studies have identified thousands of variants associated with autoimmune diseases, but the causal variants for >99% of these trait associations have yet to be identified and functionally validated. Thus, there continues to be a lack of understanding of the mechanisms that promote genetic risk for these complex traits. As part of our efforts to connect non-coding variants to an effect on cellular function, we targeted >1000 variants in T cell cis-regulatory regions that associate with multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, and type 1 diabetes using genome-wide CRISPR-interference screens in primary human T cells. We defined >50 variants that were in regulatory regions that control T cell proliferation in activated Th0 cells and >30 variant regulatory regions that control IFNg secretion in differentiated Th1 cells. We connected each regulatory region to putative target genes, identifying 124 gene candidates, which significantly enrich for T cell proliferation and immune dysfunction pathways. Many gene candidates are previously unknown to affect T cell proliferation or cytokine secretion. Variant regulatory regions acted at an average distance of 106 kb from their putative target genes with a range of 1 bp to 1 Mbp, suggesting that enhancers play a major role in regulating T cell phenotypes and that variants perturb T cell functions from distal parts of the genome. This work represents a crucial step to define the effects of risk variants on disease-relevant cellular functions.
