Mapping the dynamic genetic regulatory architecture of <i>HLA</i> genes at single-cell resolution

Abstract

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in <i>HLA</i> genes has been extensively documented, regulatory genetic variation modulating <i>HLA</i> expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical <i>HLA</i> genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific <i>cis</i>-eQTLs for every classical <i>HLA</i> gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. <i>HLA-DQ</i> genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic <i>HLA</i> regulation may underlie important interindividual variability in immune responses.