Promoter-Interacting Expression Quantitative Trait Loci (pieQTLs) in Human Immune Cell Types

Expression quantitative trait loci (eQTLs) studies provide associations of genetic variants with gene expression but fall short of pinpointing functionally important eQTLs or providing mechanistic insights. Using proximity ligation-assisted H3K27ac ChIP-seq (HiChIP/PLAC-seq) 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 to a small minority and show mechanisms that explain their cell type restriction. We demonstrated genotype-dependent correlation between frequency of pieQTL interactions and gene expression. In addition, we discovered ultralong distance pieQTLs including several disease-risk variants, and new eGenes such as FHIT for which we validated the functional role of an eQTL-overlapping cis-regulatory element located >1Mb away from its promoter by CRISPRi assays. Our study provides insights into cell-specific gene regulation and highlights the potentially functional non-coding variants (pieQTLs) linked to human diseases.