Abstract
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.
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