The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria

Oyesola O Ojewunmi, Titilope A Adeyemo, Ajoke I Oyetunji, Bassey Inyang, Afolashade Akinrindoye, Baraka S Mkumbe, Kate Gardner, Helen Rooks, John Brewin, Hamel Patel, Sang Hyuck Lee, Raymond Chung, Sara Rashkin, Guolian Kang, Reuben Chianumba, Raphael Sangeda, Liberata Mwita, Hezekiah Isa, Uche-Nnebe Agumadu, Rosemary EkongJamilu A Faruk, Bello Y Jamoh, Niyi M Adebiyi, Ismail A Umar, Abdulaziz Hassan, Christopher Grace, Anuj Goel, Baba P D Inusa, Mario Falchi, Siana Nkya, Julie Makani, Hafsat R Ahmad, Obiageli Nnodu, John Strouboulis, Stephan Menzel

Research output: Contribution to journalArticlepeer-review


The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, β = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, β = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.

Original languageEnglish
Pages (from-to)919-929
Number of pages11
JournalHuman Molecular Genetics
Issue number10
Early online date10 Feb 2024
Publication statusPublished - 4 May 2024


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