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


RESULTS
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.
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.
Siana Nkya
SN
Mtatiro
Department of Human genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Tarjinder
T
Singh
King's College London, Department of Molecular Haematology, Division of Cancer Studies, London, United Kingdom.
Helen
H
Rooks
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania.
Josephine
J
Mgaya
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania.
Harvest
H
Mariki
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania.
Deogratius
D
Soka
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; National Institute for Medical Research, Tanga Centre, Tanga, Tanzania.
Bruno
B
Mmbando
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania.
Evarist
E
Msaki
Department of Human genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Iris
I
Kolder
King's College London, Department of Molecular Haematology, Division of Cancer Studies, London, United Kingdom; King's College Hospital NHS Foundation Trust, Department of Haematological Medicine, London, United Kingdom.
Swee Lay
SL
Thein
King's College London, Department of Molecular Haematology, Division of Cancer Studies, London, United Kingdom.
Stephan
S
Menzel
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; MRC International Nutrition Group, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Sharon E
SE
Cox
Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Julie
J
Makani
Department of Human genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Jeffrey C
JC
Barrett
D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D019295:Computational Biology; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D013636:Tanzania
D005319:Fetal Hemoglobin