Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.
Kang JB., Shen AZ., Gurajala S., Nathan A., Rumker L., Aguiar VRC., Valencia C., Lagattuta KA., Zhang F., Jonsson AH., Yazar S., Alquicira-Hernandez J., Khalili H., Ananthakrishnan AN., Jagadeesh K., Dey K., Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network ., Daly MJ., Xavier RJ., Donlin LT., Anolik JH., Powell JE., Rao DA., Brenner MB., Gutierrez-Arcelus M., Luo Y., Sakaue S., Raychaudhuri S.
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 HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.