Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

Abstract

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. Naive 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.

Functional Characterization of Genetic Variant Effects on Expression

“…Because of linkage disequilibrium (LD) between variants, multiple variants in a region may show statistically significant associations even if only one has a true functional effect, and the lead variant may not always be a causal variant. Adding to this complexity, recent massively parallel reporter assay (MPRA)-based studies have suggested that many associated loci (estimates range from 17% to 40% of tested loci) may have multiple functional variants in high LD (65,66). Statistical fine-mapping approaches attempt to address the issue of LD by assigning a causal probability to the lead variant of the association or by narrowing the potential causal variants to a small set, although they cannot differentiate between multiple putatively causal variants in high LD.…”