Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation

We used resequencing and genotyping in African Americans with sickle cell anemia (SCA) to characterize associations with fetal hemoglobin (HbF) levels at the BCL11A, HBS1L-MYB and β-globin loci. Fine-mapping of HbF association signals at these loci confirmed seven SNPs with independent effects and increased the explained heritable variation in HbF levels from 38.6% to 49.5%. We also identified rare missense variants that causally implicate MYB in HbF production.

[1]  Stephen W. Hartley,et al.  Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. , 2010, Blood.

[2]  T. Spector,et al.  Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults , 2007, Proceedings of the National Academy of Sciences.

[3]  Simon Heath,et al.  A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15 , 2007, Nature Genetics.

[4]  J. Hirschhorn,et al.  Supporting Online Material Materials and Methods Figs. S1 to S10 Tables S1 to S7 References Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-specific Repressor Bcl11a , 2022 .

[5]  J. Hirschhorn,et al.  DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease , 2008, Proceedings of the National Academy of Sciences.

[6]  Yusuke Nakamura,et al.  A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E , 2009, Human Genetics.

[7]  D. Labie,et al.  Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Todd,et al.  Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes , 2009, Science.

[9]  David B. Goldstein,et al.  Rare Variants Create Synthetic Genome-Wide Associations , 2010, PLoS biology.

[10]  Gonçalo R. Abecasis,et al.  Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia , 2008, Proceedings of the National Academy of Sciences.

[11]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[12]  G. Abecasis,et al.  Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians , 2006, PLoS genetics.

[13]  Serena Sanna,et al.  Amelioration of Sardinian beta0 thalassemia by genetic modifiers. , 2009, Blood.

[14]  Stuart H. Orkin,et al.  Developmental and species-divergent globin switching are driven by BCL11A , 2009, Nature.