Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution
Open accessAbstract
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).”
From Transcriptome-wide analysis of differential expression in perturbation atlases (2025) · cites this paper as [34]
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Transcriptome-wide analysis of differential expression in perturbation atlases
Nadig, A., Replogle, J. M., Pogson, A. N., Murthy, M., McCarroll, S. A., Weissman, J. S., Robinson, E. B., & O’Connor, L. J. (2025) · Nature Genetics · doi:10.1038/s41588-025-02169-3 · Cited by 70 · see citing works
Evaluating the Utilities of Foundation Models in Single‐Cell Data Analysis
Liu, T., Li, K., Wang, Y., Li, H., & Zhao, H. (2026) · Advanced Science · doi:10.1002/advs.202514490 · Cited by 76 · see citing works
Evaluating the Utilities of Foundation Models in Single-cell Data Analysis
Liu, T., Li, K., Wang, Y., Li, H., & Zhao, H. (2023) · doi:10.1101/2023.09.08.555192 · Cited by 62 · see citing works
Ennis, D., Shmorak, S., Jantscher‐Krenn, E., & Yassour, M. (2024) · Nature Communications · doi:10.1038/s41467-024-45209-y · Cited by 61 · see citing works
Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy
Ghodke‐Puranik, Y., Olferiev, M., & Crow, M. K. (2024) · Nature Reviews Rheumatology · doi:10.1038/s41584-024-01152-2 · Cited by 53 · see citing works
Exploring the HLA complex in autoimmunity: From the risk haplotypes to the modulation of expression
Sartoris, S., & Pozzo, G. D. (2024) · Clinical Immunology · doi:10.1016/j.clim.2024.110266 · Cited by 26 · see citing works
Single-cell analysis in rheumatic and allergic diseases: insights for clinical practice
Nishide, M., Shimagami, H., & Kumanogoh, A. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01043-3 · Cited by 25 · see citing works
SPLASH: A statistical, reference-free genomic algorithm unifies biological discovery
Chaung, K., Baharav, T. Z., Henderson, G., Zheludev, I. N., Wang, P. L., & Salzman, J. (2023) · Cell · doi:10.1016/j.cell.2023.10.028 · Cited by 23 · see citing works
The influence of HLA genetic variation on plasma protein expression
Krishna, C., Chiou, J., Sakaue, S., Kang, J. B., Christensen, S. M., Lee, I., Aksit, M. A., Kim, H. I., von Schack, D., Raychaudhuri, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50583-8 · Cited by 20 · see citing works
Self-citationIdentifying genetic variants that influence the abundance of cell states in single-cell data
Rumker, L., Sakaue, S., Reshef, Y., Kang, J. B., Yazar, S., Alquicira-Hernández, J., Valencia, C., Lagattuta, K. A., Mah-Som, A. Y., Nathan, A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01909-1 · Cited by 19 · see citing works
Self-citationPopp, J. M., Rhodes, K., Jangi, R., Li, M., Barr, K., Tayeb, K., Battle, A. J., & Gilad, Y. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100701 · Cited by 19 · see citing works
Historical perspective and future directions: computational science in immuno-oncology
Ricker, C. A., Meli, K., & Allen, E. M. V. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008306 · Cited by 13 · see citing works
Deciphering state-dependent immune features from multi-layer omics data at single-cell resolution
Edahiro, R., Sato, G. R., Naito, T., Shirai, Y., Saiki, R., Sonehara, K., Tomofuji, Y., Yamamoto, K., Namba, S., Sasa, N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02266-3 · Cited by 10 · see citing works
Ahlberg, E., Jenmalm, M. C., Karlsson, A., Karlsson, R., & Tingö, L. (2024) · Journal of Extracellular Biology · doi:10.1002/jex2.70020 · Cited by 8 · see citing works
Pahkuri, S., Katayama, S., Valta, M., Nygård, L., Knip, M., Kere, J., Ilonen, J., & Lempainen, J. (2024) · HLA · doi:10.1111/tan.15548 · Cited by 8 · see citing works
The genetic basis of autoimmunity seen through the lens of T cell functional traits
Lagattuta, K. A., Park, H. L., Rumker, L., Ishigaki, K., Nathan, A., & Raychaudhuri, S. (2024) · Nature Communications · doi:10.1038/s41467-024-45170-w · Cited by 7 · see citing works
Self-citationEvaluating the Utilities of Large Language Models in Single-cell Data AnalysisPreprint
Zhao, H., Liu, T., Li, K., Wang, Y., & Li, H. (2023) · Research Square · doi:10.21203/rs.3.rs-3376641/v1 · Cited by 7 · see citing works
Lundtoft, C., Knight, A., Meadows, J., Karlsson, Å., Rantapää-Dahlqvist, S., Berglin, E., Palm, Ø., Haukeland, H., Gunnarsson, I., Bruchfeld, A., et al. (2024) · RMD Open · doi:10.1136/rmdopen-2023-004039 · Cited by 6 · see citing works
Modeling heterogeneity in single-cell perturbation states enhances detection of response eQTLs
Valencia, C., Nathan, A., Kang, J. B., Rumker, L., Lee, H., & Raychaudhuri, S. (2025) · Nature Genetics · doi:10.1038/s41588-025-02344-6 · Cited by 6 · see citing works
Self-citationZhang, H., Fan, K., Zhang, Z., Guo, Y., & Mo, X. (2024) · Autoimmunity · doi:10.1080/08916934.2024.2419117 · Cited by 5 · see citing works
Understanding rheumatic disease through continuous cell state analysis
Marshall, L. M., Raychaudhuri, S., & Viatte, S. (2025) · Nature Reviews Rheumatology · doi:10.1038/s41584-025-01253-6 · Cited by 5 · see citing works
Self-citationAbe, H., Lin, P. C., Zhou, D., Ruderfer, D. M., & Gamazon, E. R. (2024) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2024.100397 · Cited by 5 · see citing works
Zhang, L., Cai, S., Teng, A., Lin, L., Han, F., Yan, H., Hong, S., Pizza, F., Plazzi, G., Morandi, L., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2513989122 · Cited by 4 · see citing works
Zhang, H., Zhang, Z., Fan, K., Chen, H., Guo, Y., & Mo, X. (2024) · Immunogenetics · doi:10.1007/s00251-024-01350-y · Cited by 4 · see citing works
Evolution of the tuberculin skin test reveals generalisable Mtb-reactive T cell metaclones
Turner, C. T., Tiffeau-Mayer, A., Rosenheim, J., Chandran, A., Saxena, R., Zhang, P., Jiang, J., Berkeley, M. I. K., Pang, F., Uddin, I., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68678-9 · Cited by 3 · see citing works
Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome
Vollger, M. R., Swanson, E. G., Neph, S. J., Mallory, B. J., Dubocanin, D., Ho, C., Cheng, Y.-H. H., Ranchalis, J., Munson, K. M., Sedeño-Cortés, A. E., et al. (2026) · Cell · doi:10.1016/j.cell.2026.09.034 · Cited by 37 · see citing works
Zhang, H., Zhang, Z., Fan, K., Chen, Y., Xu, P., Guo, Y., & Mo, X. (2024) · Molecular Immunology · doi:10.1016/j.molimm.2024.10.005 · Cited by 3 · see citing works
A single-cell genetic colocalization test improves power and resolves disease-mediating cell typesPreprint
Mitchel, J., Nazeen, S., Wang, X., Patnaik, P. K., Morrow, A. R., Nasir, H., Strom, R., Ritter, D., Studer, L., Chun, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.10.681685 · Cited by 3 · see citing works
Early and late RNA eQTL are driven by different genetic mechanisms
Sakaue, S., Accelerating Medicines Partnership®: RA/SLE Network, Anolik, J. H., Apruzzese, W., Arazi, A., Barnas, J. L., Belmont, H. M., Berthier, C. C., Buyon, J. P., Curtis, M., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-72139-8 · Cited by 2 · see citing works
Self-citationExploring the shared genetic architecture between periodontitis and cardiovascular disease
Jin, T., Lin, J., Zhang, P., Lu, Y., Chen, S., & Lin, H. (2026) · BDJ Open · doi:10.1038/s41405-026-00421-4 · Cited by 2 · see citing works
Turner, C. T., Tiffeau-Mayer, A., Rosenheim, J., Chandran, A., Saxena, R., Zhang, P., Jiang, J., Berkeley, M. I. K., Pang, F., Uddin, I., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.12.648537 · Cited by 2 · see citing works
Sobczyk, M. K., & Gaunt, T. R. (2026) · Scientific Reports · doi:10.1038/s41598-026-41818-3 · Cited by 2 · see citing works
Taming the HLA for single-cell genomics
Kelly, J. A., Tessneer, K. L., & Gaffney, P. M. (2023) · Nature Genetics · doi:10.1038/s41588-023-01590-w · Cited by 1 · see citing works
Lin, Y.-M., Li, X., Fang, J., Zeng, Q., Cheng, D., Wang, G.-F., Shi, R.-L., Luo, Y., Ma, Y., Li, M., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112070 · Cited by 1 · see citing works
Self-citationBondeelle, L., Bezrukov, F., Berra, G., Chalandon, Y., Gensous, C., Loison, S., Giannotti, F., Messe, R., LeGoff, J., Clément, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.26.696372 · Cited by 1 · see citing works
SPLASH: a statistical, reference-free genomic algorithm unifies biological discoveryPreprint
Chaung, K., Baharav, T. Z., Henderson, G., Zheludev, I. N., Wang, P. L., & Salzman, J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.17.549408
Quantifying HLA transcripts by genotype in chimeric mixtures at single-cell resolutionPreprint
Kanaan, S. B., Underwood, J. G., Gladden, R. G., Fan, E., Bhise, S. S., Thakar, M. S., Jaeger-Ruckstuhl, C. A., Stevens, J., Gray, A., Riddell, S. R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.12.675951
Liu, X., Yuan, P.-Y., Zhang, G.-H., Bu, L.-H., Jin-li, H., Deng, F., Wu, H., & Lei, S. (2025) · Clinical Rheumatology · doi:10.1007/s10067-025-07729-w
scHG: a supercell framework with high-order graph learning enables hyper-fast multi-omics analysisPreprint
Huang, Y., Gan, Y., & Gong, X. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.19.695346
Gozzard, M., Sonehara, K., Ly, K. C. H., Rupall, T. S., Ke, Z., Ibarra-Soria, X., Lotfollahi, M., Soskic, B., Jones, C. P., Bakker, O. B., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.22.707277
scHG: A supercell framework with high-order graph learning enables scalable multi-omics analysis
Huang, Y., Gan, Y., & Gong, X. (2026) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1013851
Zhang, J., Qin, Y., Chen, N., & Wang, J. (2026) · International Journal of General Medicine · doi:10.2147/ijgm.s601076
Decoding Immune Regulation: From Genetic Variation to Mechanism Through Single-Cell Genomics
Koh, J. H., & Ye, C. (2026) · Immune Network · doi:10.4110/in.2026.26.e24
Geniş, E. Ç., & Çam, F. S. (2026) · Immunogenetics · doi:10.1007/s00251-026-01407-0
Zhou, Q.-Q., & Peng, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1889678
Tomofuji, Y., Mu, Z., Mire, H. M., Zhao, Y., Liu, C.-J., Jayanthi, V., Sugiarto, N. W., Accelerating Medicines Partnership: RA/SLE Network, Sparks, J. A., & Raychaudhuri, S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.29.741564
Self-citationRheumatoid Arthritis in Adults
Smolen, J. S., Kerschbaumer, A., Aletaha, D., & Robinson, W. H. (2026) · JAMA · doi:10.1001/jama.2026.15455 · Cited by 1 · see citing works
Self-citationCao, C. Q., Maher, M., Hu, J., Keating, B. J., Burwick, R. M., Karumanchi, S. A., Maxwell, G. L., Powe, C. E., McElrath, T. F., Cantonwine, D. E., et al. (2026) · HLA · doi:10.1111/tan.70970
Sex-stratified and interaction multi-omics analysis of DNA methylation and gene expression in asthmaPreprint
Dessie, E. Y., Gautam, Y., Rosen, B. H., Mendy, A., Kang, M., & Baye, T. M. (2026) · medRxiv · doi:10.64898/2026.10.19.26365928
Daldoul, A., & Almawi, W. Y. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1918845
- 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
- ORCID
- Kang, Joyce B.
- Shen, Amber Z.
- Nathan, Aparna
- Rumker, Laurie
- Aguiar, Vitor R. C.
- Valencia, Cristian
- Lagattuta, Kaitlyn A.
- Zhang, Fan
- Jonsson, Anna Helena
- Yazar, Seyhan
- Khalili, Hamed
- Ananthakrishnan, Ashwin N.
- Jagadeesh, Karthik
- Dey, Kushal
- Apruzzese, William
- Banda, Nirmal
- Barnas, Jennifer L.
- Bathon, Joan M.
- Boyce, Brendan F.
- Boyle, David L.
- Bridges, S. Louis
- Bykerk, Vivian P.
- Carr, Hayley L.
- Cordle, Andrew
- Curtis, Michelle
- Deane, Kevin D.
- DiCarlo, Edward
- Dunn, Patrick
- Filer, Andrew
- Firestein, Gary S.
- Geraldino-Pardilla, Laura
- Goodman, Susan M.
- Gravallese, Ellen M.
- Gregersen, Peter K.
- Guthridge, Joel M.
- Holers, V. Michael
- Ishigaki, Kazuyoshi
- Ivashkiv, Lionel B.
- James, Judith A.
- Keras, Gregory
- Korsunsky, Ilya
- Lakhanpal, Amit
- Lederer, James A.
- Lewis, Myles
- Li, Yuhong
- Liao, Katherine P.
- Mandelin, Arthur M.
- Mantel, Ian
- Marks, Kathryne E.
- Maybury, Mark
- McDavid, Andrew
- McGeachy, Mandy J.
- Mears, Joseph
- Meednu, Nida
- Millard, Nghia
- Moreland, Larry W.
- Nayar, Saba
- Nerviani, Alessandra
- Orange, Dana E.
- Perlman, Harris
- Pitzalis, Costantino
- Raza, Karim
- Reshef, Yakir
- Ritchlin, Christopher
- Rivellese, Felice
- Robinson, William H.
- Sahbudin, Ilfita
- Singaraju, Anvita
- Seifert, Jennifer A.
- Slowikowski, Kamil
- Smith, Melanie H.
- Utz, Paul J.
- Wei, Kevin
- Weinand, Kathryn
- Weisenfeld, Dana
- Weisman, Michael H.
- Wyse, Aaron
- Xiao, Qian
- Zhu, Zhu
- Daly, Mark J.
- Xavier, Ramnik J.
- Donlin, Laura T.
- Anolik, Jennifer H.
- Powell, Joseph E.
- Rao, Deepak A.
- Brenner, Michael B.
- Gutierrez-Arcelus, Maria
- Luo, Yang
- Sakaue, Saori
- Raychaudhuri, Soumya
- Venue
- Nature Genetics
- Published
- 2023-11-30
- Volume
- 55
- Issue
- 12
- Pages
- 2255-2268
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC10787945
- 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
- green
- doi.org
- Licence
- 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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