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GWAS Evaluates Malaria Susceptibility in West Africa

NEW YORK (GenomeWeb News) – In a paper appearing online yesterday in Nature Genetics, an international research team reported on a proof-of-principle genome-wide association study for severe malaria in West African children.

The researchers genotyped nearly 6,000 Gambian children at almost half a million SNPs and did targeted re-sequencing of genomic regions of interest in more than 60 healthy controls. Although they noted that the genetic diversity within African populations complicated their search for strong associations, the team was able to identify a handful of loci that appear to be linked to severe malaria in Gambia, including a previously identified variant in the beta hemoglobin gene HBB.

Malaria can be caused by several Plasmodium parasite species, though P. falciparum infections dominate in sub-Saharan Africa where malaria transmission is the highest. Efforts to eradicate malaria have largely hinged on vaccine and drug development and mosquito control. But, the authors noted, understanding individuals' genetic susceptibility to P. falciparum infection may also offer clues about malaria treatment and prevention.

"Identifying the genetic basis of protective immunity against severe malaria may provide important insights for vaccine development," co-lead author Muminatou Jallow, a researcher at the UK's Medical Research Council Laboratories in Banjul, Gambia, and colleagues wrote.

For the discovery stage of their study, the researchers genotyped 1,060 Gambian children with severe malaria and 1,500 healthy controls using the Affymetrix GeneChip 500K Mapping Array Set. After picking out data during the quality control stage of the study, the researchers were left with data on roughly 400,000 SNPs in 958 cases and 1,382 controls.

The team's initial test for malaria associations turned up more than a dozen SNPs clustered on chromosome 11 near HBB, a gene coding for the beta subunit of hemoglobulin. A previously identified point mutation in the gene leads to an abnormal version of beta hemoglobulin — called hemoglobulin S or HbS — that causes sickle cell anemia but is linked to a slight decrease in malaria risk.

To more fully explore this association, the researchers re-genotyped a SNP in the HBB coding region in their original sample set using the Sequenom iPlex platform and sequenced more than 111,000 bases in the region in 62 of the healthy Gambian controls. In so doing, they found three imputed SNPs with stronger associations than those observed in their initial screen, including the previously identified HbS-causing SNP, which had the strongest association.

When the team compared their results with data from the HapMap project, they found genetic differences between the Gambian and Yoruban populations. Gambian individuals tested tended to show greater genetic diversity than the Yoruban samples from HapMap and had distinct SNP imputation patterns. For instance, the researchers found evidence suggesting HbS may have arisen separately in different African populations.

The researchers also used the Sequenom iPlex to look more closely at parts of the genome that have been previously implicated in malaria resistance, such as loci linked to glucose-6-phosphate deficiency and the ABO blood type, identifying some additional associations.

These analyses also identified potential regions of association on chromosomes 2, 5, and 14, along with signals that may be linked to particular subtypes of malaria. For instance, the researchers noted that signals in the calmodulin-binding transcription activator CAMTA1 and the ryanodine receptor RYR2 appeared to be specific for cerebral malaria.

In a subsequent validation study, the team used the Sequenom iPlex platform to genotype 1,087 severe malaria cases and 2,376 controls, combining that data with principal component analysis-corrected data from the initial GWAS.

Using that approach, they identified tentative associations between severe malaria and several regions, including a locus on chromosome 17 near the cytochrome oxidase gene SCO1 and a locus on chromosome 7 near the dopa decarboxylase gene DDC.

Still, the authors urged caution in interpreting such results, noting that they still need to be replicated in larger studies in different populations.

"Although these findings are of considerable interest, they cannot be regarded as conclusive until they have been replicated at multiple study sites," they wrote, noting that the MalariaGEN consortium is conducting a multi-center study in 11 malaria-endemic populations.

The researchers also stressed the importance of better characterizing genetic variation in African populations and developing genotyping platforms that reflect this variability to improve future GWAS on the continent.

"The major limiting factor, at all stages of GWA analysis in Africa, is the need for population-specific data on genome sequence variation," they concluded. "In the near future, this limiting factor will be overcome by advances in genome sequencing technologies, through initiatives such as the 1000 Genomes Project."

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