Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and isassociated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci wouldspecifically address the benefits of HbF increases in patients. Here, we have applied statisticalmethods using the most representative variants:rs1427407andrs6545816inBCL11A,rs66650371(3-bp deletion) andrs9376090inHMIP-2A,rs9494142andrs9494145inHMIP-2B,andrs7482144(Xmn1-HBG2in theb-globin locus) to createg(HbF), a genetic quantitativevariable for HbF in SCD. Only patients aged$5 years with complete genotype and HbFdata were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbSb0thalassemia formed the“discovery”cohort. Multiple linear regression modeling rational-ized the 7 variants down to 4 markers (rs6545816,rs1427407,rs66650371, andrs7482144)eachindependentlycontributing HbF-boosting alleles, together accounting for 21.8% of HbFvariability (r2) in the HbSS or HbSb0patients. The model was replicated with consistentr2in 2 different cohorts: 27.5% in HbSC patients (N5186) and 23% in 994 Tanzanian HbSSpatients.g(HbF), our 4-variant model, provides a robust approach to account for the geneticcomponent of HbF in SCD and is of potential utility in sickle genetic and clinical studiesMedical Research Council,United Kingdom G0001249 and ID62593 (S.L.T.) and a grantfrom Shire Pharmaceuticals (S.M. and S.L.T.). This work isalso supported by the University College London HospitalsBiomedical Research Centre, and by awards establishing theFarr Institute of Health Informatics Research at UCL Partners, fromthe Medical Research Council, Arthritis Research UK, BritishHeart Foundation, Cancer Research UK, Chief ScientistOffice, Economic and Social Research Council, Engineering andPhysical Sciences Research Council, National Institute for HealthResearch, National Institute for Social Care and Health Research,and Wellcome Trust grant MR/K006584/1 (S. Newhouse).