PMID- 36993194 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231211 DP - 2023 Mar 20 TI - Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution. LID - 2023.03.14.23287257 [pii] LID - 10.1101/2023.03.14.23287257 [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, using personalized reference genomes to mitigate technical confounding. 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. Dynamic HLA regulation may underlie important interindividual variability in immune responses. 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 - 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 - Luo, Yang AU - Luo Y 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 - 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 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 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 AU - Lagattuta K 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 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 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, NSW, Australia. FAU - Alquicira-Hernandez, Jose AU - Alquicira-Hernandez J AD - Garvan Institute of Medical Research, Sydney, NSW, Australia. FAU - Khalili, Hamed AU - Khalili H AD - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. FAU - Ananthakrishnan, Ashwin N AU - Ananthakrishnan AN AD - Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. FAU - Jagadeesh, Karthik AU - Jagadeesh K AD - Harvard T. H. Chan School of Public Health, Boston, MA, USA. FAU - Dey, Kushal AU - Dey K AD - Harvard T. H. Chan School of Public Health, Boston, MA, 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 AD - Garvan Institute of Medical Research, Sydney, NSW, Australia. FAU - Rao, Deepak A AU - Rao DA 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 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 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 - Raychaudhuri, Soumya AU - Raychaudhuri 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. LA - eng GR - P30 DK043351/DK/NIDDK NIH HHS/United States GR - T32 HG002295/HG/NHGRI NIH HHS/United States GR - T32 AR007530/AR/NIAMS NIH HHS/United States GR - T32 GM144273/GM/NIGMS NIH HHS/United States GR - R01 AR063759/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 - F30 AI157385/AI/NIAID NIH HHS/United States GR - UC2 AR081023/AR/NIAMS NIH HHS/United States PT - Preprint DEP - 20230320 PL - United States TA - medRxiv JT - medRxiv : the preprint server for health sciences JID - 101767986 UIN - Nat Genet. 2023 Dec;55(12):2255-2268. PMID: 38036787 PMC - PMC10055604 EDAT- 2023/03/31 06:00 MHDA- 2023/03/31 06:01 PMCR- 2023/03/29 CRDT- 2023/03/30 02:51 PHST- 2023/03/31 06:00 [pubmed] PHST- 2023/03/31 06:01 [medline] PHST- 2023/03/30 02:51 [entrez] PHST- 2023/03/29 00:00 [pmc-release] AID - 2023.03.14.23287257 [pii] AID - 10.1101/2023.03.14.23287257 [doi] PST - epublish SO - medRxiv [Preprint]. 2023 Mar 20:2023.03.14.23287257. doi: 10.1101/2023.03.14.23287257.