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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

Principal components plot (PC2 v PC1) with bases formed using genotypes of individuals of African descent included in Hapmap3 study.ASW: African ancestry in Southwest USA, LWK: Luhya in Webuhe, Kenya, MKK: Maasai in Kinyawa, Kenya, TZ: Tanzanian study population, YRI: Yoruba in Ibadan, Nigeria.
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pone-0111464-g002: Principal components plot (PC2 v PC1) with bases formed using genotypes of individuals of African descent included in Hapmap3 study.ASW: African ancestry in Southwest USA, LWK: Luhya in Webuhe, Kenya, MKK: Maasai in Kinyawa, Kenya, TZ: Tanzanian study population, YRI: Yoruba in Ibadan, Nigeria.

Mentions: Standard technical QC was performed using PLINK to remove potential sources of technical and genetic bias [18]. A total of 85 samples either found with abnormal heterozygosity (defined as 3 standard deviation from the mean), gender mismatch, and those with more than 3% of missing data were excluded from the study. Following identity-by-descent analysis, we removed duplicate samples and identified individuals in first, second, and third-degree relationships. Principal components analysis (PCA) was performed using EIGENSTRAT with 1000 Genomes Phase 1 populations as reference groups [19]. We observed population substructure and admixture within the cohort (Figure 2), and identified 262 individuals showing clear separation from the core population. Following sample removal, rare and low quality variants (more than 3% data missing,<10−6 Hardy-Weinberg chi-square P-values, and <1% MAF) were excluded, resulting in a typed dataset of 1,827,523 variants in 1,742 individuals.


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)

Principal components plot (PC2 v PC1) with bases formed using genotypes of individuals of African descent included in Hapmap3 study.ASW: African ancestry in Southwest USA, LWK: Luhya in Webuhe, Kenya, MKK: Maasai in Kinyawa, Kenya, TZ: Tanzanian study population, YRI: Yoruba in Ibadan, Nigeria.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111464-g002: Principal components plot (PC2 v PC1) with bases formed using genotypes of individuals of African descent included in Hapmap3 study.ASW: African ancestry in Southwest USA, LWK: Luhya in Webuhe, Kenya, MKK: Maasai in Kinyawa, Kenya, TZ: Tanzanian study population, YRI: Yoruba in Ibadan, Nigeria.
Mentions: Standard technical QC was performed using PLINK to remove potential sources of technical and genetic bias [18]. A total of 85 samples either found with abnormal heterozygosity (defined as 3 standard deviation from the mean), gender mismatch, and those with more than 3% of missing data were excluded from the study. Following identity-by-descent analysis, we removed duplicate samples and identified individuals in first, second, and third-degree relationships. Principal components analysis (PCA) was performed using EIGENSTRAT with 1000 Genomes Phase 1 populations as reference groups [19]. We observed population substructure and admixture within the cohort (Figure 2), and identified 262 individuals showing clear separation from the core population. Following sample removal, rare and low quality variants (more than 3% data missing,<10−6 Hardy-Weinberg chi-square P-values, and <1% MAF) were excluded, resulting in a typed dataset of 1,827,523 variants in 1,742 individuals.

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