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Multicenter Study
. 2010 Mar 4;115(9):1815-22.
doi: 10.1182/blood-2009-08-239517. Epub 2009 Dec 16.

Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster

Nadia Solovieff  1 , Jacqueline N Milton, Stephen W Hartley, Richard Sherva, Paola Sebastiani, Daniel A Dworkis, Elizabeth S Klings, Lindsay A Farrer, Melanie E Garrett, Allison Ashley-Koch, Marilyn J Telen, Supan Fucharoen, Shau Yin Ha, Chi-Kong Li, David H K Chui, Clinton T Baldwin, Martin H Steinberg
Affiliations
Multicenter Study

Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster

Nadia Solovieff et al. Blood. .

Abstract

In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or beta thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E-08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E-21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in gamma-globin gene expression.

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Figures

Figure 1
Figure 1
Manhattan plot summarizing the GWAS results for CSSCD using the additive model. The large spike on chromosome 2 corresponds to a region containing BCL11A, and the moderate spike on chromosome 11 corresponds to a region containing olfactory genes OR51B5 and OR51B6.
Figure 2
Figure 2
QQ plot of CSSCD GWAS for the additive model. The QQ plot shows minimal to no inflation in the test statistics with a genomic control value of 1.003.
Figure 3
Figure 3
LD plots for regions on chromosome 11 and 2 showing an enrichment of significant associations. LD plot was generated with the program Haploview 4.1 using the data for CSSCD subjects. Each diamond represents the value of D′, with the standard LD color scheme: white, D′ < 1 and LOD < 2; blue, D′ = 1 and LOD < 2; shades of pink/red, D′ < 1 and LOD ≥ 2; bright red, D′ = 1 and LOD ≥ 2. The top panel displays the −log10 P value for each SNP in the additive model for CSSCD. (A) BCL11A on chromosome 2. (B) Region on chromosome 11 containing OR51B5 and OR51B6.
Figure 4
Figure 4
The human HBB locus and upstream olfactory receptor genes, chromosome 11 from 5 150 000 to 5 500 000 base pairs. Regions of interest (solid) were identified as associated with HbF levels in Sardinians, and regions of interest (striped) were identified in the current GWAS. rs500684 and rs2071348 were significantly associated with HbF in CSSCD (P = 4.7E−08, P = 2.5E−05). rs139161 and rs968856 (brackets) were reported among the top SNPs in Sardinians but were not significantly associated with HbF in the CSSCD or replication sets. Note that base pair locations are reported along the forward direction in kilobases, whereas the HBB locus is transcribed in the reverse direction. CTCF binding predictions were generated by screening for high-interest potential matches from a BLAST search (http://blast.ncbi.nlm.nih.gov) using one of 2 published CTCF consensus sequences: either 5′-GTGGCCACCAGGGGGCGCCG-3′ or 5′-CCGCTAGGGGGCAGCA-3′.
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References

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