title: Imputation-based meta-analysis of severe malaria in three African populations.
abstract: Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Band
authors.forename: Quang Si
authors.initials: QS
authors.lastname: Le
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.forename: Fatoumatta
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Kalifa
authors.initials: K
authors.lastname: Bojang
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.forename: Vysaul
authors.initials: V
authors.lastname: Nyirongo
authors.forename: David
authors.initials: D
authors.lastname: Kachala
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.forename: Terrie
authors.initials: T
authors.lastname: Taylor
authors.forename: Carolyne
authors.initials: C
authors.lastname: Ndila
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcock
authors.forename: Robert
authors.initials: R
authors.lastname: Andrews
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Emma
authors.initials: E
authors.lastname: Gray
authors.forename: Christina
authors.initials: C
authors.lastname: Hubbart
authors.forename: Anna
authors.initials: A
authors.lastname: Jeffreys
authors.forename: Kate
authors.initials: K
authors.lastname: Rowlands
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schuldt
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Yik Ying
authors.initials: YY
authors.lastname: Teo
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Chris C A
authors.initials: CC
authors.lastname: Spencer
mesh_terms: D000349:Africa; D001499:Bayes Theorem; D044383:Black People / Q000235:genetics*; D002874:Chromosome Mapping; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D006451:Hemoglobin, Sickle