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

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, and Xmn1-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/HbS{beta}0), 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 for BCL11A (lead SNP rs6706648, {beta}=- 0.39, P=4.96 x 10-34) and HBS1L-MYB (lead SNP rs61028892, {beta}=0.73, P=1.18 x 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. Genetically dissecting the two major loci, we defined trait-boosting haplotypes containing suspected or so-far unidentified causal variants. At BCL11A, one such haplotype (trait increase P < 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. At HBS1L- MYB, one haplotype (trait increase P < 0.0001) contains the likely functional rs66650371 ({Delta}3-bp), and a second (P < 0.0001) is tagged by the C allele of rs6102889. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. We detected three novel association signals: SLC28A3 on chromosome 9 (rs115555854: {beta}=- 0.73, P=2.52 x 10-8), TICRR on chromosome 15 (rs140496989: {beta}=-0.43, P=3.34 x 10-8), and PIEZO2 on chromosome 18 (rs58817161: {beta}= -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 loci BCL11A and HBS1L-MYB and detected putative new trait-associated regions.