Genome-wide and fine-resolution association analysis of malaria in West Africa.
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.
Jallow
Muminatou
M
MRC Laboratories, Fajara, Banjul, Gambia.
Teo
Yik Ying
YY
Small
Kerrin S
KS
Rockett
Kirk A
KA
Deloukas
Panos
P
Clark
Taane G
TG
Kivinen
Katja
K
Bojang
Kalifa A
KA
Conway
David J
DJ
Pinder
Margaret
M
Sirugo
Giorgio
G
Sisay-Joof
Fatou
F
Usen
Stanley
S
Auburn
Sarah
S
Bumpstead
Suzannah J
SJ
Campino
Susana
S
Coffey
Alison
A
Dunham
Andrew
A
Fry
Andrew E
AE
Green
Angela
A
Gwilliam
Rhian
R
Hunt
Sarah E
SE
Inouye
Michael
M
Jeffreys
Anna E
AE
Mendy
Alieu
A
Palotie
Aarno
A
Potter
Simon
S
Ragoussis
Jiannis
J
Rogers
Jane
J
Rowlands
Kate
K
Somaskantharajah
Elilan
E
Whittaker
Pamela
P
Widden
Claire
C
Donnelly
Peter
P
Howie
Bryan
B
Marchini
Jonathan
J
Morris
Andrew
A
SanJoaquin
Miguel
M
Achidi
Eric Akum
EA
Agbenyega
Tsiri
T
Allen
Angela
A
Amodu
Olukemi
O
Corran
Patrick
P
Djimde
Abdoulaye
A
Dolo
Amagana
A
Doumbo
Ogobara K
OK
Drakeley
Chris
C
Dunstan
Sarah
S
Evans
Jennifer
J
Farrar
Jeremy
J
Fernando
Deepika
D
Hien
Tran Tinh
TT
Horstmann
Rolf D
RD
Ibrahim
Muntaser
M
Karunaweera
Nadira
N
Kokwaro
Gilbert
G
Koram
Kwadwo A
KA
Lemnge
Martha
M
Makani
Julie
J
Marsh
Kevin
K
Michon
Pascal
P
Modiano
David
D
Molyneux
Malcolm E
ME
Mueller
Ivo
I
Parker
Michael
M
Peshu
Norbert
N
Plowe
Christopher V
CV
Puijalon
Odile
O
Reeder
John
J
Reyburn
Hugh
H
Riley
Eleanor M
EM
Sakuntabhai
Anavaj
A
Singhasivanon
Pratap
P
Sirima
Sodiomon
S
Tall
Adama
A
Taylor
Terrie E
TE
Thera
Mahamadou
M
Troye-Blomberg
Marita
M
Williams
Thomas N
TN
Wilson
Michael
M
Kwiatkowski
Dominic P
DP
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
D006451:Hemoglobin, Sickle