Genome-wide linkage analysis of malaria infection intensity and mild disease

Christian Timmann, Jennifer A. Evans, Inke R. König, André Kleensang, Franz Rüschendorf, Julia Lenzen, Jürgen Sievertsen, Christian Becker, Yeetey Enuameh, Kingsley Osei Kwakye, Ernest Opoku, Edmund N.L. Browne, Andreas Ziegler, Peter Nürnberg, Rolf D. Horstmann

Research output: Contribution to journalArticlepeer-review

Abstract

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 × 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.

Original languageEnglish (US)
Pages (from-to)393-400
Number of pages8
JournalPLoS genetics
Volume3
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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