Genetic regulation of fetal hemoglobin across global populations
Genetic regulation of fetal hemoglobin across global populations
1. Abstract Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.
Lopez de Lapuente Portilla Aitzkoa、Ardlie Kristin、Kang Guolian、Zhang Yingze、Gordeuk Victor R.、Ashley-Koch Allison、Custer Brian、Dinardo Carla Luana、Sheehan Vivien A.、Cato Liam D.、Wissman Mariel、Ekwattanakit Supachai、Sangeda Raphael、Nilsson Bj?rn、Nkya Siana、Paul Dirk S.、Sabino Ester C.、Maximo Cl¨￠udia、NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium、M¨|ndez Adriana、Li Rick、Viprakasit Vip、Weiss Mitchell J.、Riolueang Suchada、Hammerer-Lercher Angelika、Mkumbe Baraka S.、Deelen Patrick、Astle William J.、Lu Henry Y.、Suksangpleng Thidarat、Nouraie Seyed Mehdi、Garrett Melanie E.、Sankaran Vijay G.、Kelly Shannon、Butterworth Adam S.、Loureiro Paula、Aguet Francois、Carneiro-Proietti Anna B¨￠rbara、Franke Lude、Kawabata Emily、BIOS Consortium、Telen Marilyn J.、Yu Fulong、Mwita Liberata、Gladwin Mark T.、Bronson Paola G.
Lund Stem Cell Center, Lund University||Department of Laboratory Medicine, Lund UniversityBroad Institute of MIT and HarvardSt. Jude Children?ˉs Research HospitalDepartment of Medicine, School of Medicine, University of PittsburghDivision of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at ChicagoDepartment of Medicine, Duke University Medical Center, DurhamVitalant Research Institute, San Francisco||Department of Laboratory Medicine, UCSFFundacao Pro-Sangue Hemocentro de Sao Paulo||Institute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao PauloAflac Cancer & Blood Disorders Center, Children?ˉs Healthcare of Atlanta & Department of Pediatrics, Emory University School of MedicineDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and HarvardDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and HarvardSiriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol UniversitySickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences||Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied SciencesBroad Institute of MIT and Harvard||Lund Stem Cell Center, Lund University||Department of Laboratory Medicine, Lund UniversitySickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences||Department of Biochemistry, Muhimbili University of Health and Allied Science||Tanzania Human Genetics OrganisationBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||British Heart Foundation Centre of Research Excellence, University of CambridgeInstitute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao PauloFundacao HemorioThe TOPMed ConsortiumInstitute of Laboratory Medicine, Cantonal Hospital AarauDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and HarvardSiriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University||Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol UniversitySt. Jude Children?ˉs Research HospitalSiriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol UniversityInstitute of Laboratory Medicine, Cantonal Hospital AarauSickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences||Department of Biochemistry, Muhimbili University of Health and Allied Science||Department of Artificial Intelligence and Innovative Medicine, Graduate School of Medicine, Tohoku UniversityDepartment of Genetics, University of Groningen, University Medical Center Groningen||Oncode InstituteBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge||MRC Biostatistics Unit, University of Cambridge||NHS Blood and TransplantDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and HarvardSiriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol UniversityDepartment of Medicine, School of Medicine, University of PittsburghDepartment of Medicine, Duke University Medical Center, DurhamDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and Harvard||Harvard Stem Cell Institute||Department of Biochemistry, Muhimbili University of Health and Allied ScienceVitalant Research Institute, San Francisco||Division of Pediatric Hematology, UCSF Benioff Children?ˉs HospitalBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||British Heart Foundation Centre of Research Excellence, University of Cambridge||National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||Heart and Lung Research Institute, University of CambridgeFundacao HemopeBroad Institute of MIT and HarvardFundacao HemominasOncode Institute||Department of Genetics, University of Groningen, University Medical Center GroningenBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of CambridgeBIOS ConsortiumDepartment of Medicine, Duke University Medical Center, DurhamDivision of Hematology/Oncology, Boston Children?ˉs Hospital, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Broad Institute of MIT and HarvardDepartment of Pharmaceutical Microbiology, Muhimbili University of Health and Allied SciencesDepartment of Medicine, University of Maryland School of MedicineR&D Translational Biology
遗传学基础医学分子生物学
Lopez de Lapuente Portilla Aitzkoa,Ardlie Kristin,Kang Guolian,Zhang Yingze,Gordeuk Victor R.,Ashley-Koch Allison,Custer Brian,Dinardo Carla Luana,Sheehan Vivien A.,Cato Liam D.,Wissman Mariel,Ekwattanakit Supachai,Sangeda Raphael,Nilsson Bj?rn,Nkya Siana,Paul Dirk S.,Sabino Ester C.,Maximo Cl¨￠udia,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,M¨|ndez Adriana,Li Rick,Viprakasit Vip,Weiss Mitchell J.,Riolueang Suchada,Hammerer-Lercher Angelika,Mkumbe Baraka S.,Deelen Patrick,Astle William J.,Lu Henry Y.,Suksangpleng Thidarat,Nouraie Seyed Mehdi,Garrett Melanie E.,Sankaran Vijay G.,Kelly Shannon,Butterworth Adam S.,Loureiro Paula,Aguet Francois,Carneiro-Proietti Anna B¨￠rbara,Franke Lude,Kawabata Emily,BIOS Consortium,Telen Marilyn J.,Yu Fulong,Mwita Liberata,Gladwin Mark T.,Bronson Paola G..Genetic regulation of fetal hemoglobin across global populations[EB/OL].(2025-03-28)[2025-08-02].https://www.medrxiv.org/content/10.1101/2023.03.24.23287659.点此复制
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