PMID- 38036787 OWN - NLM STAT- MEDLINE DCOM- 20231216 LR - 20240508 IS - 1546-1718 (Electronic) IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 55 IP - 12 DP - 2023 Dec TI - Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution. PG - 2255-2268 LID - 10.1038/s41588-023-01586-6 [doi] AB - 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. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature America, Inc. FAU - Kang, Joyce B AU - Kang JB AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Shen, Amber Z AU - Shen AZ AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Gurajala, Saisriram AU - Gurajala S AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Nathan, Aparna AU - Nathan A AUID- ORCID: 0000-0002-5975-2851 AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Rumker, Laurie AU - Rumker L AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Aguiar, Vitor R C AU - Aguiar VRC AUID- ORCID: 0000-0002-4137-9518 AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Valencia, Cristian AU - Valencia C AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Lagattuta, Kaitlyn A AU - Lagattuta KA AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Zhang, Fan AU - Zhang F AUID- ORCID: 0000-0002-6102-2970 AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Division of Rheumatology and the Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA. FAU - Jonsson, Anna Helena AU - Jonsson AH AUID- ORCID: 0000-0002-9558-2474 AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Yazar, Seyhan AU - Yazar S AD - Garvan Institute of Medical Research, Sydney, New South Wales, Australia. FAU - Alquicira-Hernandez, Jose AU - Alquicira-Hernandez J AD - Garvan Institute of Medical Research, Sydney, New South Wales, Australia. FAU - Khalili, Hamed AU - Khalili H AD - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Ananthakrishnan, Ashwin N AU - Ananthakrishnan AN AD - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Jagadeesh, Karthik AU - Jagadeesh K AUID- ORCID: 0000-0002-0957-812X AD - Harvard T. H. Chan School of Public Health, Boston, MA, USA. FAU - Dey, Kushal AU - Dey K AUID- ORCID: 0000-0002-3520-2345 AD - Harvard T. H. Chan School of Public Health, Boston, MA, USA. AD - Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, NY, USA. CN - Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network FAU - Daly, Mark J AU - Daly MJ AD - Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. AD - The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. AD - Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. FAU - Xavier, Ramnik J AU - Xavier RJ AD - Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. AD - Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Donlin, Laura T AU - Donlin LT AD - Hospital for Special Surgery, New York, NY, USA. AD - Weill Cornell Medicine, New York, NY, USA. FAU - Anolik, Jennifer H AU - Anolik JH AD - Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. FAU - Powell, Joseph E AU - Powell JE AUID- ORCID: 0000-0002-5070-4124 AD - Garvan Institute of Medical Research, Sydney, New South Wales, Australia. FAU - Rao, Deepak A AU - Rao DA AUID- ORCID: 0000-0001-9672-7746 AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Brenner, Michael B AU - Brenner MB AUID- ORCID: 0000-0001-6202-8445 AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Gutierrez-Arcelus, Maria AU - Gutierrez-Arcelus M AUID- ORCID: 0000-0001-7898-7691 AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Luo, Yang AU - Luo Y AUID- ORCID: 0000-0001-7385-6166 AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. FAU - Sakaue, Saori AU - Sakaue S AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Raychaudhuri, Soumya AU - Raychaudhuri S AUID- ORCID: 0000-0002-1901-8265 AD - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. soumya@broadinstitute.org. AD - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. soumya@broadinstitute.org. AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. LA - eng GR - P01 AI148102/AI/NIAID NIH HHS/United States GR - P30 DK043351/DK/NIDDK NIH HHS/United States GR - T32 AR007530/AR/NIAMS NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - T32 GM144273/GM/NIGMS NIH HHS/United States GR - UH2 AR067677/AR/NIAMS NIH HHS/United States GR - U01 HG012009/HG/NHGRI NIH HHS/United States GR - F30 AI172238/AI/NIAID NIH HHS/United States GR - MR/M007669/1/MRC_/Medical Research Council/United Kingdom GR - F30 AI157385/AI/NIAID NIH HHS/United States GR - R56 HG013083/HG/NHGRI NIH HHS/United States GR - P30 AR070253/AR/NIAMS NIH HHS/United States GR - UC2 AR081023/AR/NIAMS NIH HHS/United States GR - T32 HG002295/HG/NHGRI NIH HHS/United States GR - T32 GM007753/GM/NIGMS NIH HHS/United States GR - R01 AR063759/AR/NIAMS NIH HHS/United States GR - MR/P021220/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20231130 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 SB - IM UOF - medRxiv. 2023 Mar 20;:. PMID: 36993194 MH - Humans MH - *Gene Expression Regulation/genetics MH - *Quantitative Trait Loci/genetics MH - Genome-Wide Association Study MH - Polymorphism, Single Nucleotide PMC - PMC10787945 MID - NIHMS1954699 FIR - Albrecht, Jennifer IR - Albrecht J FIR - Apruzzese, William IR - Apruzzese W FIR - Banda, Nirmal IR - Banda N FIR - Barnas, Jennifer L IR - Barnas JL FIR - Bathon, Joan M IR - Bathon JM FIR - Ben-Artzi, Ami IR - Ben-Artzi A FIR - Boyce, Brendan F IR - Boyce BF FIR - Boyle, David L IR - Boyle DL FIR - Bridges, S Louis Jr IR - Bridges SL Jr FIR - Bykerk, Vivian P IR - Bykerk VP FIR - Campbell, Debbie IR - Campbell D FIR - Carr, Hayley L IR - Carr HL FIR - Ceponis, Arnold IR - Ceponis A FIR - Chicoine, Adam IR - Chicoine A FIR - Cordle, Andrew IR - Cordle A FIR - Curtis, Michelle IR - Curtis M FIR - Deane, Kevin D IR - Deane KD FIR - DiCarlo, Edward IR - DiCarlo E FIR - Dunn, Patrick IR - Dunn P FIR - Filer, Andrew IR - Filer A FIR - Firestein, Gary S IR - Firestein GS FIR - Forbess, Lindsy IR - Forbess L FIR - Geraldino-Pardilla, Laura IR - Geraldino-Pardilla L FIR - Goodman, Susan M IR - Goodman SM FIR - Gravallese, Ellen M IR - Gravallese EM FIR - Gregersen, Peter K IR - Gregersen PK FIR - Guthridge, Joel M IR - Guthridge JM FIR - Holers, V Michael IR - Holers VM FIR - Horowitz, Diane IR - Horowitz D FIR - Hughes, Laura B IR - Hughes LB FIR - Ishigaki, Kazuyoshi IR - Ishigaki K FIR - Ivashkiv, Lionel B IR - Ivashkiv LB FIR - James, Judith A IR - James JA FIR - Keras, Gregory IR - Keras G FIR - Korsunsky, Ilya IR - Korsunsky I FIR - Lakhanpal, Amit IR - Lakhanpal A FIR - Lederer, James A IR - Lederer JA FIR - Lewis, Myles IR - Lewis M FIR - Li, Zhihan J IR - Li ZJ FIR - Li, Yuhong IR - Li Y FIR - Liao, Katherine P IR - Liao KP FIR - Mandelin, Arthur M 2nd IR - Mandelin AM 2nd FIR - Mantel, Ian IR - Mantel I FIR - Marks, Kathryne E IR - Marks KE FIR - Maybury, Mark IR - Maybury M FIR - McDavid, Andrew IR - McDavid A FIR - McGeachy, Mandy J IR - McGeachy MJ FIR - Mears, Joseph IR - Mears J FIR - Meednu, Nida IR - Meednu N FIR - Millard, Nghia IR - Millard N FIR - Moreland, Larry W IR - Moreland LW FIR - Nayar, Saba IR - Nayar S FIR - Nerviani, Alessandra IR - Nerviani A FIR - Orange, Dana E IR - Orange DE FIR - Perlman, Harris IR - Perlman H FIR - Pitzalis, Costantino IR - Pitzalis C FIR - Rangel-Moreno, Javier IR - Rangel-Moreno J FIR - Raza, Karim IR - Raza K FIR - Reshef, Yakir IR - Reshef Y FIR - Ritchlin, Christopher IR - Ritchlin C FIR - Rivellese, Felice IR - Rivellese F FIR - Robinson, William H IR - Robinson WH FIR - Sahbudin, Ilfita IR - Sahbudin I FIR - Singaraju, Anvita IR - Singaraju A FIR - Seifert, Jennifer A IR - Seifert JA FIR - Slowikowski, Kamil IR - Slowikowski K FIR - Smith, Melanie H IR - Smith MH FIR - Tabechian, Darren IR - Tabechian D FIR - Scheel-Toellner, Dagmar IR - Scheel-Toellner D FIR - Utz, Paul J IR - Utz PJ FIR - Watts, Gerald F M IR - Watts GFM FIR - Wei, Kevin IR - Wei K FIR - Weinand, Kathryn IR - Weinand K FIR - Weisenfeld, Dana IR - Weisenfeld D FIR - Weisman, Michael H IR - Weisman MH FIR - Wyse, Aaron IR - Wyse A FIR - Xiao, Qian IR - Xiao Q FIR - Zhu, Zhu IR - Zhu Z EDAT- 2023/12/01 00:43 MHDA- 2023/12/17 09:43 PMCR- 2024/02/01 CRDT- 2023/11/30 23:50 PHST- 2023/03/31 00:00 [received] PHST- 2023/10/19 00:00 [accepted] PHST- 2023/12/17 09:43 [medline] PHST- 2023/12/01 00:43 [pubmed] PHST- 2023/11/30 23:50 [entrez] PHST- 2024/02/01 00:00 [pmc-release] AID - 10.1038/s41588-023-01586-6 [pii] AID - 10.1038/s41588-023-01586-6 [doi] PST - ppublish SO - Nat Genet. 2023 Dec;55(12):2255-2268. doi: 10.1038/s41588-023-01586-6. Epub 2023 Nov 30.