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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 

Original publication




Journal article


Hum Mol Genet

Publication Date





919 - 929


fetal haemoglobin, genome-wide association study, haplotype analysis, heritability, sickle cell disease, Humans, Anemia, Sickle Cell, Fetal Hemoglobin, Nigeria, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Haplotypes, Female, Male, Adult, Repressor Proteins, Carrier Proteins, Alleles, Nuclear Proteins, Genetic Predisposition to Disease, Adolescent, GTP-Binding Proteins