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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2255-2268 |
| Number of pages | 14 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2023 |
Funding
We thank A. Dobin, H. Randolph, H. Lau, C. Stevens and members of the Raychaudhuri Lab, in particular A. Gupta and Y. Baglaenko, for their helpful input and discussions. This work was funded by the National Institutes of Health grants T32GM007753 and T32GM144273 (J.B.K., L.R. and K.A.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S. and L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.) and UC2AR081023 (S.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project also received funding from the MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), a fellowship from the Fok Foundation (J.E.P.), the Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), Lupus Research Alliance (M.G.-A.) and a Kennedy Trust KTRR Senior Research Fellowship (KENN202109) (Y.L). We thank A. Dobin, H. Randolph, H. Lau, C. Stevens and members of the Raychaudhuri Lab, in particular A. Gupta and Y. Baglaenko, for their helpful input and discussions. This work was funded by the National Institutes of Health grants T32GM007753 and T32GM144273 (J.B.K., L.R. and K.A.L.), F30AI172238 (J.B.K.), T32HG002295 (A.Z.S. and L.R.), T32AR007530 (A.N.), F30AI157385 (L.R.), R01AR063759 (S.R.), U01HG012009 (S.R.) and UC2AR081023 (S.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project also received funding from the MGH Center for the Study of Inflammatory Bowel Disease grant DK-43351 (R.J.X.), a fellowship from the Fok Foundation (J.E.P.), the Arthritis National Research Foundation (M.G.-A.), Gilead Sciences Research Scholar grant (M.G.-A.), Lupus Research Alliance (M.G.-A.) and a Kennedy Trust KTRR Senior Research Fellowship (KENN202109) (Y.L).
ASJC Scopus subject areas
- Genetics
