Genome-wide linkage analysis of malaria infection intensity and mild disease.
Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha(+) thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5-11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 x 10(-5), locus-specific heritability of 37.7%; 95% confidence interval, 15.7%-59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria.
Timmann
Christian
C
Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. timmann@bni-hamburg.de
Evans
Jennifer A
JA
König
Inke R
IR
Kleensang
André
A
Rüschendorf
Franz
F
Lenzen
Julia
J
Sievertsen
Jürgen
J
Becker
Christian
C
Enuameh
Yeetey
Y
Kwakye
Kingsley Osei
KO
Opoku
Ernest
E
Browne
Edmund N L
EN
Ziegler
Andreas
A
Nürnberg
Peter
P
Horstmann
Rolf D
RD
D044383:Black People; D002648:Child; D002879:Chromosomes, Human, Pair 10; D015331:Cohort Studies; D019353:Endemic Diseases; D008040:Genetic Linkage; D005819:Genetic Markers; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D008126:Lod Score; D008288:Malaria / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology; D020411:Oligonucleotide Array Sequence Analysis; D018512:Parasitemia; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012424:Rural Population; D012720:Severity of Illness Index; D035781:Siblings
D005819:Genetic Markers