Genetic regulation of fetal hemoglobin across global populations.

Journal

medRxiv : the preprint server for health sciences
Titre abrégé: medRxiv
Pays: United States
ID NLM: 101767986

Informations de publication

Date de publication:
28 Mar 2023
Historique:
pubmed: 31 3 2023
medline: 31 3 2023
entrez: 30 3 2023
Statut: epublish

Résumé

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

Identifiants

DOI: 10.1101/2023.03.24.23287659 PMID: 36993312 PMC: PMC10055601
pubmed: 36993312
doi: 10.1101/2023.03.24.23287659
pmc: PMC10055601
pii:
doi:

Types de publication

Preprint

Langues

eng

Auteurs

Liam D Cato (LD)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Rick Li (R)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Henry Y Lu (HY)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Fulong Yu (F)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Mariel Wissman (M)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Baraka S Mkumbe (BS)

Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Department of Biochemistry, Muhimbili University of Health and Allied Science, Dar es Salaam, Tanzania.
Department of Artificial Intelligence and Innovative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Supachai Ekwattanakit (S)

Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Patrick Deelen (P)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Oncode Institute, Amsterdam, the Netherlands.

Liberata Mwita (L)

Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.

Raphael Sangeda (R)

Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.

Thidarat Suksangpleng (T)

Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Suchada Riolueang (S)

Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Paola G Bronson (PG)

R&D Translational Biology, Biogen, Cambridge, Massachusetts, USA.

Dirk S Paul (DS)

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.

Emily Kawabata (E)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

William J Astle (WJ)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
NHS Blood and Transplant, Cambridge, UK.

Francois Aguet (F)

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Kristin Ardlie (K)

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Aitzkoa Lopez de Lapuente Portilla (AL)

Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
Department of Laboratory Medicine, Lund University, 221 84 Lund, Sweden.

Guolian Kang (G)

St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Yingze Zhang (Y)

Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Seyed Mehdi Nouraie (SM)

Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Victor R Gordeuk (VR)

Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois, USA.

Mark T Gladwin (MT)

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Melanie E Garrett (ME)

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Allison Ashley-Koch (A)

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Marilyn J Telen (MJ)

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Brian Custer (B)

Vitalant Research Institute, San Francisco, California, USA.
Department of Laboratory Medicine, UCSF, San Francisco, California, USA.

Shannon Kelly (S)

Vitalant Research Institute, San Francisco, California, USA.
Division of Pediatric Hematology, UCSF Benioff Children's Hospital, Oakland, California, USA.

Carla Luana Dinardo (CL)

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.

Ester C Sabino (EC)

Institute of Tropical Medicine, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.

Paula Loureiro (P)

Fundacao Hemope, Recife, Pernambuco, Brazil.

Anna Bárbara Carneiro-Proietti (AB)

Fundacao Hemominas, Belo Horizonte, Brazil.

Cláudia Maximo (C)

Fundacao Hemorio, Rio de Janeiro, Brazil.

Adriana Méndez (A)

Institute of Laboratory Medicine, Cantonal Hospital Aarau, 5000 Aarau, Switzerland.

Angelika Hammerer-Lercher (A)

Institute of Laboratory Medicine, Cantonal Hospital Aarau, 5000 Aarau, Switzerland.

Vivien A Sheehan (VA)

Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta & Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

Mitchell J Weiss (MJ)

St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Lude Franke (L)

Oncode Institute, Amsterdam, the Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Björn Nilsson (B)

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
Department of Laboratory Medicine, Lund University, 221 84 Lund, Sweden.

Adam S Butterworth (AS)

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.
National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.

Vip Viprakasit (V)

Siriraj Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Siana Nkya (S)

Sickle Cell Program, Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Department of Biochemistry, Muhimbili University of Health and Allied Science, Dar es Salaam, Tanzania.
Tanzania Human Genetics Organisation, Tanzania.

Vijay G Sankaran (VG)

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Department of Biochemistry, Muhimbili University of Health and Allied Science.

Classifications MeSH