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Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, Mmbando B, Msaki E, Kolder I, Thein SL, Menzel S, Cox SE, Makani J, Barrett JC - PLoS ONE (2014)

Bottom Line: We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports.This is the largest GWAS study in SCA in Africa.We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

View Article: PubMed Central - PubMed

Affiliation: Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; Department of Biological Sciences, Dar es Salaam University College of Education, Dar-es-salaam, Tanzania.

ABSTRACT

Background: Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered.

Methods and findings: We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6). These associations could not be replicated in a SCA population in the UK.

Conclusions: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

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Related in: MedlinePlus

Summary of the genome-wide association results of normalized HbF within Tanzanian individuals with SCA.Q–Q plot of the observed versus the expected P-values from a linear mixed model for the entire set of 15,153,765 SNPs.
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pone-0111464-g003: Summary of the genome-wide association results of normalized HbF within Tanzanian individuals with SCA.Q–Q plot of the observed versus the expected P-values from a linear mixed model for the entire set of 15,153,765 SNPs.

Mentions: We performed a genome wide association study for HbF in a discovery cohort of 1,213 patients (52.6% females) with SCA and a replication cohort of 321 patients (54.8% females) of African Caribbean descent or West African descent. Details on age, sex and HbF levels are presented in Table 1. The genomic control (λGC) for the analysed SNPs was 1.0156 and a Q–Q plot of the observed versus expected P-values is shown in Figure 3. The absence of an early departure of the observed P-values suggests that our data are not affected by problems with genotyping, imputation, and uncontrolled sample relatedness or population stratification. The distribution of association P-values (Manhattan plot) for HbF level is shown in Figure 4.


Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, Mmbando B, Msaki E, Kolder I, Thein SL, Menzel S, Cox SE, Makani J, Barrett JC - PLoS ONE (2014)

Summary of the genome-wide association results of normalized HbF within Tanzanian individuals with SCA.Q–Q plot of the observed versus the expected P-values from a linear mixed model for the entire set of 15,153,765 SNPs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221031&req=5

pone-0111464-g003: Summary of the genome-wide association results of normalized HbF within Tanzanian individuals with SCA.Q–Q plot of the observed versus the expected P-values from a linear mixed model for the entire set of 15,153,765 SNPs.
Mentions: We performed a genome wide association study for HbF in a discovery cohort of 1,213 patients (52.6% females) with SCA and a replication cohort of 321 patients (54.8% females) of African Caribbean descent or West African descent. Details on age, sex and HbF levels are presented in Table 1. The genomic control (λGC) for the analysed SNPs was 1.0156 and a Q–Q plot of the observed versus expected P-values is shown in Figure 3. The absence of an early departure of the observed P-values suggests that our data are not affected by problems with genotyping, imputation, and uncontrolled sample relatedness or population stratification. The distribution of association P-values (Manhattan plot) for HbF level is shown in Figure 4.

Bottom Line: We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports.This is the largest GWAS study in SCA in Africa.We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

View Article: PubMed Central - PubMed

Affiliation: Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; Department of Biological Sciences, Dar es Salaam University College of Education, Dar-es-salaam, Tanzania.

ABSTRACT

Background: Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered.

Methods and findings: We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ0) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6). These associations could not be replicated in a SCA population in the UK.

Conclusions: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

Show MeSH
Related in: MedlinePlus