title: Genome-wide and fine-resolution association analysis of malaria in West Africa.
abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
authors.affiliation: MRC Laboratories, Fajara, Banjul, Gambia.
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.forename: Yik Ying
authors.initials: YY
authors.lastname: Teo
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.forename: Kalifa A
authors.initials: KA
authors.lastname: Bojang
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Fatou
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Stanley
authors.initials: S
authors.lastname: Usen
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Suzannah J
authors.initials: SJ
authors.lastname: Bumpstead
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Alison
authors.initials: A
authors.lastname: Coffey
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunham
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Fry
authors.forename: Angela
authors.initials: A
authors.lastname: Green
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hunt
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
authors.forename: Anna E
authors.initials: AE
authors.lastname: Jeffreys
authors.forename: Alieu
authors.initials: A
authors.lastname: Mendy
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Simon
authors.initials: S
authors.lastname: Potter
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: Kate
authors.initials: K
authors.lastname: Rowlands
authors.forename: Elilan
authors.initials: E
authors.lastname: Somaskantharajah
authors.forename: Pamela
authors.initials: P
authors.lastname: Whittaker
authors.forename: Claire
authors.initials: C
authors.lastname: Widden
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Bryan
authors.initials: B
authors.lastname: Howie
authors.forename: Jonathan
authors.initials: J
authors.lastname: Marchini
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.forename: Miguel
authors.initials: M
authors.lastname: SanJoaquin
authors.forename: Eric Akum
authors.initials: EA
authors.lastname: Achidi
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Angela
authors.initials: A
authors.lastname: Allen
authors.forename: Olukemi
authors.initials: O
authors.lastname: Amodu
authors.forename: Patrick
authors.initials: P
authors.lastname: Corran
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimde
authors.forename: Amagana
authors.initials: A
authors.lastname: Dolo
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
authors.forename: Sarah
authors.initials: S
authors.lastname: Dunstan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Evans
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.forename: Deepika
authors.initials: D
authors.lastname: Fernando
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.forename: Muntaser
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Nadira
authors.initials: N
authors.lastname: Karunaweera
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kokwaro
authors.forename: Kwadwo A
authors.initials: KA
authors.lastname: Koram
authors.forename: Martha
authors.initials: M
authors.lastname: Lemnge
authors.forename: Julie
authors.initials: J
authors.lastname: Makani
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Pascal
authors.initials: P
authors.lastname: Michon
authors.forename: David
authors.initials: D
authors.lastname: Modiano
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Michael
authors.initials: M
authors.lastname: Parker
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.forename: Odile
authors.initials: O
authors.lastname: Puijalon
authors.forename: John
authors.initials: J
authors.lastname: Reeder
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Sodiomon
authors.initials: S
authors.lastname: Sirima
authors.forename: Adama
authors.initials: A
authors.lastname: Tall
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Thera
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D002874:Chromosome Mapping; D005006:Ethnicity / Q000235:genetics; D005714:Gambia; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D012720:Severity of Illness Index
chemical_list: D006451:Hemoglobin, Sickle