System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Preprint Journal Article Epublish 9 citations

PubMed: 36993312 DOI: 10.1101/2023.03.24.23287659

Genetic regulation of fetal hemoglobin across global populations.

medRxiv

Authors: Liam D Cato, Rick Li, Henry Y Lu, Fulong Yu, Mariel Wissman, Baraka S Mkumbe, Supachai Ekwattanakit, Patrick Deelen, Liberata Mwita, Raphael Sangeda, Thidarat Suksangpleng, Suchada Riolueang, Paola G Bronson, Dirk S Paul, Emily Kawabata, William J Astle, Francois Aguet, Kristin Ardlie, Aitzkoa Lopez de Lapuente Portilla, Guolian Kang, Yingze Zhang, Seyed Mehdi Nouraie, Victor R Gordeuk, Mark T Gladwin, Melanie E Garrett, Allison Ashley-Koch, Marilyn J Telen, Brian Custer, Shannon Kelly, Carla Luana Dinardo, Ester C Sabino, Paula Loureiro, Anna Bárbara Carneiro-Proietti, Cláudia Maximo, Adriana Méndez, Angelika Hammerer-Lercher, Vivien A Sheehan, Mitchell J Weiss, Lude Franke, Björn Nilsson, Adam S Butterworth, Vip Viprakasit, Siana Nkya, Vijay G Sankaran

Affiliations

  • 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.
  • 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.
  • 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, Massachusetts, 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.
  • 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.
  • Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
  • Department of Laboratory Medicine, Lund University, 221 84 Lund, Sweden.
  • St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Division of Hematology and Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois, USA.
  • Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
  • Vitalant Research Institute, San Francisco, California, USA.
  • Department of Laboratory Medicine, UCSF, San Francisco, California, USA.
  • Division of Pediatric Hematology, UCSF Benioff Children's Hospital, Oakland, California, 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, Pernambuco, Brazil.
  • Fundacao Hemominas, Belo Horizonte, Brazil.
  • Fundacao Hemorio, Rio de Janeiro, Brazil.
  • Institute of Laboratory Medicine, Cantonal Hospital Aarau, 5000 Aarau, Switzerland.
  • Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta & Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, 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, Tanzania.
  • Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
  • Department of Biochemistry, Muhimbili University of Health and Allied Science.

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.

MeSH

Therapeutics, Genome-Wide Association Study, Genetic Variation, Genes, Fetal Hemoglobin, Hemoglobins