{
  "abstract": "Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances 1–8 . Yet the mechanisms by which HbF expression is activated remain incompletely understood 9 . Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 individuals that identifies 91 conditionally independent associations across 12 genomic regions. In one previously uncharacterized associated region, the high-HbF-linked causal variant rs1010474-C reduces BACH2 expression and elevates HbF levels. Direct perturbation or inhibition of BACH2 likewise increases HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding γ-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the γ-globin genes. Although BACH2 and NRF2 binding motifs in the γ-globin promoters overlap, they can be selectively edited to activate or repress γ-globin, respectively, and do so independently of BCL11A. These findings illustrate how human genetic variation continues to advance our understanding of therapeutically relevant regulatory mechanisms underlying HbF expression.",
  "abstract_shown": true,
  "affiliations": [
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA",
    "Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA",
    "Howard Hughes Medical Institute, Boston, MA, USA",
    "Department of Artificial Intelligence and Innovative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan",
    "Department of Biochemistry, Muhimbili University of Health and Allied Science, Dar es Salaam, Tanzania",
    "Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania",
    "Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand",
    "Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands",
    "Oncode Institute, Amsterdam, The Netherlands",
    "Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania",
    "R&D Translational Biology, Biogen, Cambridge, MA, USA",
    "British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK",
    "British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK",
    "MRC Biostatistics Unit, University of Cambridge, Cambridge, UK",
    "NHS Blood and Transplant, Cambridge, UK",
    "National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK",
    "Department of Laboratory Medicine, Lund University, Lund, Sweden",
    "Lund Stem Cell Center, Lund University, Lund, Sweden",
    "St. Jude Children's Research Hospital, Memphis, TN, USA",
    "Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA",
    "Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, IL, USA",
    "Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA",
    "Department of Medicine, Duke University Medical Center, Durham, NC, USA",
    "Department of Laboratory Medicine, UCSF, San Francisco, CA, USA",
    "Vitalant Research Institute, San Francisco, CA, USA",
    "Division of Pediatric Hematology, UCSF Benioff Children's Hospital, Oakland, CA, USA",
    "Fundacao Pro-Sangue Hemocentro de Sao Paulo, Sao Paulo, Brazil",
    "Institute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil",
    "Fundacao Hemope, Recife, Brazil",
    "Fundacao Hemominas, Belo Horizonte, Brazil",
    "Fundacao Hemorio, Rio de Janeiro, Brazil",
    "Institute of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland",
    "Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta & Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA",
    "Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK",
    "Heart and Lung Research Institute, University of Cambridge, Cambridge, UK",
    "Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand",
    "Tanzania Human Genetics Organisation, Dar es Salaam, Tanzania",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA. sankaran@broadinstitute.org",
    "Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 54,
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      "name": "C. Guo",
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      "name": "Uma P. Arora",
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      "name": "Xiaoheng Cheng",
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      "name": "Suchada Riolueang"
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      "name": "Paola G. Bronson",
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      "name": "Dirk S. Paul",
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      "name": "Emily Kawabata",
      "orcid": "0000-0003-4178-5513"
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      "name": "William John Astle",
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      "name": "François Aguet",
      "orcid": "0000-0001-9414-300X"
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      "name": "Kristin Ardlie",
      "orcid": "0000-0003-4272-6283"
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      "name": "Aitzkoa Lopez de Lapuente Portilla",
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      "name": "Guolian Kang",
      "orcid": "0000-0002-6102-0115"
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      "name": "Yingze Zhang",
      "orcid": "0000-0001-6947-2901"
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        20
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      "name": "Mehdi syed Nouraie",
      "orcid": "0000-0001-7465-0581"
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      "name": "Victor R. Gordeuk",
      "orcid": "0000-0003-4725-7295"
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      "name": "Mark T. Gladwin",
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      "name": "Melanie E. Garrett",
      "orcid": "0000-0003-2302-6150"
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      "name": "Allison E. Ashley‐Koch",
      "orcid": "0000-0001-5409-9155"
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      "name": "Marilyn J. Telen",
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      "name": "Brian Custer",
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      "name": "Shannon Kelly",
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      "name": "Carla Luana Dinardo",
      "orcid": "0000-0002-0453-7863"
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      "name": "Éster Cerdeira Sabino",
      "orcid": "0000-0003-2623-5126"
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      "name": "Paula Rodrigues Andrade da Cunha Loureiro",
      "orcid": "0000-0003-1849-0047"
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        30
      ],
      "name": "Anna Bárbara Carneiro-Proietti"
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      "name": "Cláudia Maximo"
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      "name": "Adriana Mendez",
      "orcid": "0000-0003-0418-9608"
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      ],
      "name": "Angelika Hammerer‐Lercher",
      "orcid": "0000-0002-9762-827X"
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        5,
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      "name": "Julie Makani"
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      "name": "Vivien Sheehan",
      "orcid": "0000-0003-2837-2255"
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      "name": "Mitchell J. Weiss",
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      "name": "Lude Franke",
      "orcid": "0000-0002-5159-8802"
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      "name": "Björn Nilsson",
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      "name": "Adam S. Butterworth",
      "orcid": "0000-0002-6915-9015"
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      "name": "Vip Viprakasit",
      "orcid": "0000-0003-3162-1849"
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      "name": "Siana Watoky Nkya",
      "orcid": "0000-0001-7576-6279"
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      "name": "Vijay G. Sankaran",
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  ],
  "bibtex": "https://research.draconitic.com/paper/46859cxc3vk6w.bib",
  "cited_by": 11,
  "doi": "10.1038/s41586-026-11113-2",
  "fulltext_url": null,
  "id": "46859cxc3vk6w",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-11113-2",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2716|Hemoglobinopathies and Related Disorders"
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  "pdf_url": "https://www.nature.com/articles/s41586-026-11113-2.pdf",
  "pmcid": "PMC10055601",
  "pmid": "36993312",
  "published": "2026-09-30",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/46859cxc3vk6w.ris",
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    {
      "first_seen": "2026-11-04T13:21:15Z",
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      "url": "https://doi.org/10.1038/s41586-026-11113-2"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Hemoglobinopathies and Related Disorders",
      "subfield": "human-genetics"
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  ],
  "title": "Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation",
  "title_text": "Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:39Z",
  "url": "https://research.draconitic.com/paper/46859cxc3vk6w",
  "venue": "Nature",
  "versions": []
}