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

Abstract

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.

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Acknowledgements

We thank all the individuals who participated in this study, and T. Nguyen and M. Beaudoin for DNA genotyping support. We thank S. Raychaudhuri for critical reading of the manuscript, G. Boucher for statistical advice and the CARe Sickle Cell Disease working group for providing the Cooperative Study of Sickle Cell Disease (CSSCD) principal components. This work was funded by the Fondation de l'Institut de Cardiologie de Montréal (to G.L.) and was supported by an Innovations in Clinical Research Award grant from the Doris Duke Charitable Foundation (to G.L. and J.N.H.). Resequencing services were provided by the University of Washington, Department of Genome Sciences, under US Federal Government contract number N01-HV-48194 from the National Heart, Lung, and Blood Institute.

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Authors and Affiliations

Authors

Contributions

V.G.S., S.H.O., J.N.H. and G.L. conceived and designed the experiment. G.G., C.D.P. and G.L. performed the experiments. G.G., C.D.P. and G.L. analyzed the data. G.G., C.D.P., V.G.S., S.H.O., J.N.H. and G.L. contributed reagents, materials and/or analysis tools. G.G. and G.L. wrote the paper with contributions from all authors.

Corresponding author

Correspondence to Guillaume Lettre.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–10 and Supplementary Figures 1 and 2 (PDF 579 kb)

Supplementary Table 2

DNA sequence variants identified at the BCL11A, HBS1L-MYB and A-globin loci by DNA re-sequencing in the HapMap Northern European (CEU) and West African (YRI) founders, and in 70 sickle cell anemia (SCA) patients from the Cooperative Study of Sickle Cell Disease (CSSCD) (XLS 255 kb)

Supplementary Table 3

Association results with HbF levels for all 95 common SNPs (minor allele frequency A1%) genotyped in 1,032 African-American sickle cell anemia (SCA) patients from the Cooperative Study of Sickle Cell Disease (CSSCD) (XLS 35 kb)

Supplementary Table 6

Association results to fetal hemoglobin (HbF) levels for imputed SNPs (XLS 103 kb)

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Galarneau, G., Palmer, C., Sankaran, V. et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 42, 1049–1051 (2010). https://doi.org/10.1038/ng.707

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