TY - JOUR
T1 - The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria
AU - Ojewunmi, Oyesola O
AU - Adeyemo, Titilope A
AU - Oyetunji, Ajoke I
AU - Inyang, Bassey
AU - Akinrindoye, Afolashade
AU - Mkumbe, Baraka S
AU - Gardner, Kate
AU - Rooks, Helen
AU - Brewin, John
AU - Patel, Hamel
AU - Lee, Sang Hyuck
AU - Chung, Raymond
AU - Rashkin, Sara
AU - Kang, Guolian
AU - Chianumba, Reuben
AU - Sangeda, Raphael
AU - Mwita, Liberata
AU - Isa, Hezekiah
AU - Agumadu, Uche-Nnebe
AU - Ekong, Rosemary
AU - Faruk, Jamilu A
AU - Jamoh, Bello Y
AU - Adebiyi, Niyi M
AU - Umar, Ismail A
AU - Hassan, Abdulaziz
AU - Grace, Christopher
AU - Goel, Anuj
AU - Inusa, Baba P D
AU - Falchi, Mario
AU - Nkya, Siana
AU - Makani, Julie
AU - Ahmad, Hafsat R
AU - Nnodu, Obiageli
AU - Strouboulis, John
AU - Menzel, Stephan
N1 - Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press.
PY - 2024/5/15
Y1 - 2024/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85192311078&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddae014
DO - 10.1093/hmg/ddae014
M3 - Article
C2 - 38339995
SN - 0964-6906
VL - 33
SP - 919
EP - 929
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
ER -