BackgroundThe 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, andXmn1-HBG2) have been reported, but a considerable hidden heritability remains.AimBuilding on the power of a large and genetically diverse patient pool present in Nigeria, we conducted a genome-wide association study for HbF levels in patients from three regions of the country with a diverse ethnic make-up.MethodsWe analysed genome-wide trait association 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 analysis, haplotype association analysis and included public functional annotation data (fGCTA).ResultsAssociation signals were detected forBCL11A(lead SNP rs6706648, β=- 0.39,P=4.96 x 10-34) andHBS1L-MYB(lead SNP rs61028892, β=0.73,P=1.18 x 10-9), whereas the variant allele forXmn1-HBG2was found to be very rare. Genetically dissecting the two major loci, we defined trait-boosting haplotypes containing suspected or so-far unidentified causal variants. AtBCL11A, one such haplotype (trait increaseP< 0.0001) contains the putative functional variant rs1427407-‘T’ and a second haplotype (P< 0.0001) is tagged by the rs7565301-‘A’ allele, with no obvious candidate causal variant. AtHBS1L- MYB, one haplotype (trait increaseP< 0.0001) contains the likely functional rs66650371 (Δ3-bp), and a second (P< 0.0001) is tagged by the ‘C’ allele of rs6102889. Together, variants atBCL11AandHBS1L-MYBSNPs explained 24.1% of the trait variance.We detected three novel association signals:SLC28A3on chromosome 9 (rs115555854: β=- 0.73,P=2.52 x 10-8),TICRRon chromosome 15 (rs140496989: β=-0.43,P=3.34 x 10-8), andPIEZO2on chromosome 18 (rs58817161: β= −0.63,P= 8.04 x 10-8). These appeared to be restricted to the Nigerian patient cohort and were not confirmed in the replication cohorts.ConclusionsStudying a diverse cohort of Nigerian patients with sickle cell disease, we genetically dissected the known fetal-haemoglobin lociBCL11AandHBS1L-MYBand detected putative new trait-associated regions.
