FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries
Known fetal haemoglobin (HbF)-modulating loci explain 10-24% variation of HbF level in Africans with Sickle Cell Disease (SCD), compared to 50% among Europeans. Here, we report fourteen candidate loci from a genome-wide association study (GWAS) of HbF level in patients with SCD from Cameroon, Tanzania, and the United States of America. We present results of cell-based experiments for FLT1 candidate, demonstrating expression in early haematopoiesis and a possible involvement in hypoxia associated HbF induction. Our study employed genotyping arrays that capture a broad range of African and non-African genetic variation and replicated known loci (BCL11A and HBS1L-MYB). We estimated the heritability of HbF level in SCD at 94%, higher than estimated in unselected Europeans, and suggesting a robust capture of HbF-associated loci by these arrays. Our approach, which involved genotype imputation against six reference haplotype panels and association analysis with each of the panels, proved superior over selecting a best-performing panel, evidenced by a substantial proportion of panel-specific (up to 18%) and a low proportion of shared (28%) imputed variants across the panels.
Authors
- Jonathan Yen (ORCID: https://orcid.org/0000-0002-9432-9450)
- Rachel M. Levine (ORCID: https://orcid.org/0000-0002-3684-2950)
- Khuthala Mnika (ORCID: https://orcid.org/0000-0002-8461-1372)
- James F. Casella (ORCID: https://orcid.org/0000-0002-2846-9420)
- Ambroise Wonkam (ORCID: https://orcid.org/0000-0003-1420-9051)
- Gregory A. Newby (ORCID: https://orcid.org/0000-0001-7869-2615)
- Siana Watoky Nkya (ORCID: https://orcid.org/0000-0001-7576-6279)
- Julie Makani (ORCID: https://orcid.org/0000-0002-4801-6250)
- Raphael Zozimus Sangeda (ORCID: https://orcid.org/0000-0002-6574-5308)
- Dan E. Arking (ORCID: https://orcid.org/0000-0001-8980-8695)
- Daiana Drehmer (ORCID: https://orcid.org/0000-0002-7329-2425)
- Erin Dempsey (ORCID: https://orcid.org/0009-0000-2512-0939)
- Nikitha Nimmagadda (ORCID: https://orcid.org/0000-0003-1648-6335)
- Emile R. Chimusa (ORCID: https://orcid.org/0000-0001-8846-2047)
- Victoria Nembaware (ORCID: https://orcid.org/0000-0001-7966-4042)
- Martin H. Steinberg (ORCID: https://orcid.org/0000-0001-8800-8020)
- M Beer (ORCID: https://orcid.org/0000-0001-9955-3809)
- Kevin Esoh (ORCID: https://orcid.org/0000-0002-4024-5681)
- Valentina Josiane Ngo Bitoungui (ORCID: https://orcid.org/0000-0002-2845-8879)
- Rachel Latanich
- Guillaume Lettre (ORCID: https://orcid.org/0000-0002-7740-3399)
- Nicola Mulder (ORCID: https://orcid.org/0000-0003-4905-0941)
- Stylianos E. Antonarakis (ORCID: https://orcid.org/0000-0001-8907-5823)
- Fujr Osman Ibrahim Osman (ORCID: https://orcid.org/0000-0003-4993-996X)
- Jack Morrice
Institutions
- Boston University (US)
- University of Geneva (CH)
- St. Jude Children's Research Hospital (US)
- Johns Hopkins University (US)
- Muhimbili University of Health and Allied Sciences (TZ)
- University of Cape Town (ZA)
- Université de Dschang (CM)
- Johns Hopkins Medicine (US)
- Montreal Heart Institute (CA)
- Northumbria University (GB)
- Wellcome Centre for Infectious Diseases Research in Africa (ZA)
- Imperial College London (GB)
- Université de Montréal (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1038/s41467-025-57413-5
- Citations
- 5
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 8.13
Funders
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Human Genome Research Institute