Connecting GWAS SNPs to Target Genes in primary human immune cell types

Abstract

Abstract Expression quantitative trait loci (eQTLs) studies have provided associations with gene expression for many non-coding genetic variants associated with human disease and evolution. However, they fail to pinpoint the functionally important eQTLs or provide mechanistic insights. Also, most eQTL discovery studies restrict analysis to SNPs within ±1 Mb of the TSS of the gene tested to minimize corrections for multiple association tests. Using proximity ligation-assisted H3K27ac ChIP-seq (HiChIP) assays, here we mapped eQTLs that overlap active cis-regulatory elements and interact with their target gene promoters (promoter-interacting eQTLs, pieQTLs) in five common immune cell types. This allowed us to narrow down functionally important eQTLs and show mechanisms that explain their cell type restriction. A subset of the identified pieQTLs overlapped non-transcribed promoters, which interact with their target gene promoters and function as enhancers as validated by CRISPRi. In addition, we devised a novel approach to eQTL discovery that relied on HiChIP-based promoter interaction maps as a structural framework for deciding what SNPs to test for association with gene expression. We discovered ultralong distance pieQTLs (>1Mb from target gene), including several disease-risk variants and new eGenes such as FHIT for which we validated the role of an ultralong distance pieQTL by CRISPRi. Our study provides insights into cell-specific gene regulatory mechanisms and highlights the potentially functional non-coding variants (pieQTLs) linked to human diseases.