Peer-Reviewed Publication
Nature2026September 30, 2026Journal Article
Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.
Chun-Jie Guo1,2,3,4, Uma P Arora1,2,3,4, Xiaoheng Cheng1,2,3,4, Wanying Xu1,2,3,4, Liam D Cato1,2,3,4, Rick Li1,2,3,4, Henry Y Lu1,2,3,4, Andrew J Lee1,2,3,4, Fulong Yu1,2,3,4, Gaurav Agarwal1,2,3,4, Peng Lyu1,2,3,4, Tianyi Ye1,2,3,4, Mateusz Antoszewski1,2,3,4, Mariel Wissmann1,2,3,4, Baraka S Mkumbe5,6,7, Supachai Ekwattanakit8, Patrick Deelen9,10, Liberata Mwita11, Raphael Sangeda5,11, Thidarat Suksangpleng8, Suchada Riolueang8, Paola G Bronson12, Dirk S Paul13,14, Emily Kawabata13, William J Astle13,15,16,17, Francois Aguet4, Kristin Ardlie4, Aitzkoa Lopez de Lapuente Portilla18,19, Guolian Kang20, Yingze Zhang21, Seyed Mehdi Nouraie21, Victor R Gordeuk22, Mark T Gladwin23, Melanie E Garrett24, Allison Ashley-Koch24, Marilyn J Telen24, Brian Custer25,26, Shannon Kelly25,27, Carla Luana Dinardo28,29, Ester C Sabino29, Paula Loureiro30, Anna Bárbara Carneiro-Proietti31, Cláudia Maximo32, Adriana Méndez33, Angelika Hammerer-Lercher33, Julie Makani5,6, Vivien A Sheehan34, Mitchell J Weiss20, Lude Franke9,10, Björn Nilsson4,18,19, Adam S Butterworth13,14,15,35,36, Vip Viprakasit8,37, Siana Nkya5,6,38, Vijay G Sankaran39,40,41,42,43
1Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3Howard Hughes Medical Institute, Boston, MA, USA.
4Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
6Department of Biochemistry, Muhimbili University of Health and Allied Science, Dar es Salaam, Tanzania.
7Department of Artificial Intelligence and Innovative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
8Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
9Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
10Oncode Institute, Amsterdam, The Netherlands.
11Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
12R&D Translational Biology, Biogen, Cambridge, MA, USA.
13British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
14British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
15National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
16MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
17NHS Blood and Transplant, Cambridge, UK.
18Lund Stem Cell Center, Lund University, Lund, Sweden.
19Department of Laboratory Medicine, Lund University, Lund, Sweden.
20St. Jude Children's Research Hospital, Memphis, TN, USA.
21Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
22Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, IL, USA.
23Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
24Department of Medicine, Duke University Medical Center, Durham, NC, USA.
25Vitalant Research Institute, San Francisco, CA, USA.
26Department of Laboratory Medicine, UCSF, San Francisco, CA, USA.
27Division of Pediatric Hematology, UCSF Benioff Children's Hospital, Oakland, CA, USA.
28Fundacao Pro-Sangue Hemocentro de Sao Paulo, Sao Paulo, Brazil.
29Institute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
30Fundacao Hemope, Recife, Brazil.
31Fundacao Hemominas, Belo Horizonte, Brazil.
32Fundacao Hemorio, Rio de Janeiro, Brazil.
33Institute of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.
34Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta & Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
35Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
36Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
37Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
38Tanzania Human Genetics Organisation, Dar es Salaam, Tanzania.
39Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.
40Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.
41Howard Hughes Medical Institute, Boston, MA, USA. sankaran@broadinstitute.org.
42Broad Institute of MIT and Harvard, Cambridge, MA, USA. sankaran@broadinstitute.org.
43Harvard Stem Cell Institute, Cambridge, MA, USA. sankaran@broadinstitute.org.
Abstract
Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances1-8. Yet the mechanisms by which HbF expression is activated remain incompletely understood9. Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 individuals that identifies 91 conditionally independent associations…
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