Cited by 50Genetic Associations and EpidemiologySingle-cell and spatial transcriptomicsGenomics and Chromatin Dynamics

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

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Kang, Joyce B., Shen, Amber Z., Gurajala, Saisriram, Nathan, Aparna, Rumker, Laurie, Aguiar, Vitor R. C., Valencia, Cristian, Lagattuta, Kaitlyn A. +98 more·2023·Nature Genetics

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.

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  • Compared to Euclidean distance, TI produced a more coherent cell-type hierarchy of PBMCs in OneK1K.

    “Indeed, we found that compared to Euclidean distance, transcriptome-wide impact produced a more coherent cell-type hierarchy of peripheral blood mononuclear cells in the OneK1K dataset33,34 (Methods; Supplementary Fig. 26; Supplementary Table 19).”

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  1. [58]Janeway CA, Travers P, Walport M & Shlomchik MJ Immunobiology (CRC Press, 2001).

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Authors
Kang, J. B., Shen, A. Z., Gurajala, S., Nathan, A., Rumker, L., Aguiar, V. R. C., Valencia, C., Lagattuta, K. A., Zhang, F., Jonsson, A. H., Yazar, S., Alquicira-Hernandez, J., Khalili, H., Ananthakrishnan, A. N., Jagadeesh, K., Dey, K., Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Albrecht, J., Apruzzese, W., Banda, N., Barnas, J. L., Bathon, J. M., Ben-Artzi, A., Boyce, B. F., Boyle, D. L., Bridges, S. L., Bykerk, V. P., Campbell, D., Carr, H. L., Ceponis, A., Chicoine, A., Cordle, A., Curtis, M., Deane, K. D., DiCarlo, E., Dunn, P., Filer, A., Firestein, G. S., Forbess, L., Geraldino-Pardilla, L., Goodman, S. M., Gravallese, E. M., Gregersen, P. K., Guthridge, J. M., Holers, V. M., Horowitz, D., Hughes, L. B., Ishigaki, K., Ivashkiv, L. B., James, J. A., Keras, G., Korsunsky, I., Lakhanpal, A., Lederer, J. A., Lewis, M., Li, Z. J., Li, Y., Liao, K. P., Mandelin, A. M., Mantel, I., Marks, K. E., Maybury, M., McDavid, A., McGeachy, M. J., Mears, J., Meednu, N., Millard, N., Moreland, L. W., Nayar, S., Nerviani, A., Orange, D. E., Perlman, H., Pitzalis, C., Rangel-Moreno, J., Raza, K., Reshef, Y., Ritchlin, C., Rivellese, F., Robinson, W. H., Sahbudin, I., Singaraju, A., Seifert, J. A., Slowikowski, K., Smith, M. H., Tabechian, D., Scheel-Toellner, D., Utz, P. J., Watts, G. F. M., Wei, K., Weinand, K., Weisenfeld, D., Weisman, M. H., Wyse, A., Xiao, Q., Zhu, Z., Daly, M. J., Xavier, R. J., Donlin, L. T., Anolik, J. H., Powell, J. E., Rao, D. A., Brenner, M. B., Gutierrez-Arcelus, M., Luo, Y., Sakaue, S., & Raychaudhuri, S.
Affiliations
  • Broad Institute (US)
  • Brigham and Women's Hospital (US)
  • Garvan Institute of Medical Research (AU)
  • Harvard University (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Rochester Medicine (US)
  • Cedars-Sinai Medical Center (US)
  • Hospital for Special Surgery (US)
  • Queen Elizabeth Hospital Birmingham (GB)
  • National Institutes of Health (US)
  • University of California San Diego (US)
  • Columbia University (US)
  • Northwell Health (US)
  • Oklahoma Medical Research Foundation (US)
  • Northwestern University (US)
  • University of Pittsburgh (US)
  • Queen Mary University of London (GB)
  • Humanitas University (IT)
  • Stanford Medicine (US)
Corresponding author
Raychaudhuri, Soumya
Venue
Nature Genetics
Published
2023-11-30
Volume
55
Issue
12
Pages
2255-2268
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W4389174580
Cited by
49
References
79
Citations by year
2026: 17 · 2025: 11 · 2024: 17 · 2023: 4
FWCI
8.13
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (U01HG012009, UC2AR081023, R01AR063759, F30AI172238, T32GM144273, T32HG002295, T32AR007530, F30AI157385)
  • MGH Center for the Study of Inflammatory Bowel Disease
  • Fok Foundation
  • Arthritis National Research Foundation
  • Gilead Sciences
  • Lupus Research Alliance
  • Kennedy Trust KTRR Senior Research Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
HLA locus, HLA gene expression, expression quantitative trait loci, cis-eQTL, single-cell transcriptomics, HLA-DQA1, HLA-DQ, cytotoxic T lymphocytes, myeloid cells, B cells

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