Consortial Project 1
Genome-wide association studies of severe malaria
Consortial project 1 is MalariaGEN's flagship study. We are performing large-scale genome-wide association (GWA) studies to identify genetic variants that are associated with resistance or susceptibility to severe malaria. This Consortial Project has study sites in 11 malaria-endemic countries.
Study sites
- Burkina Faso: Centre National de Recherche et de Formation sur le Paludisme
- Cameroon: University of Buea
- Gambia: MRC Laboratories
- Ghana: Noguchi Memorial Institute for Medical Research with Navrongo Health Research Centre
- Ghana: Kwame Nkrumah University of Science and Technology
- Kenya: KEMRI-Wellcome Research Programme
- Malawi: Blantyre Malaria Project with Malawi-Liverpool-Wellcome Programme
- Mali: University of Bamako
- Nigeria: University of Ibadan
- Papua New Guinea: Papua New Guinea Institute for Medical Research
- Tanzania: Joint Malaria Programme, Kilimanjaro Christian Medical Centre
- Vietnam: Oxford University Clinical Research Unit
Scientific rationale
The concept behind Consortial Project 1 is relatively simple, and is known as genome-wide association (GWA) analysis. We are surveying known genetic markers (called SNPs; single nucleotide polymorphisms) throughout the genomes of patients with malaria (cases) and of healthy individuals from the same populations (controls) to look for differences between these groups that correlate with resistance to disease.
However, there is much complexity. Malaria disease severity is a complex phenotype in which multiple genetic and environmental factors are involved, and large sample sizes are needed because the effect of each individual determinant may be modest. In Consortial Project 1 we hope to overcome these challenges with a 'brute force' approach, by genotyping hundreds of thousands of SNPs across the genomes of thousands of individuals. We predict that the scale of the studies in this Consortial Project will be powerful enough to detect the small individual effects of multiple genetic determinants that probably underlie complex malaria phenotypes like resistance to disease.
Consortial Project 1 leverages several important recent advances in the science of GWA analysis, including the work of the International HapMap Project which established the foundation for a comprehensive catalogue of SNPs and other genetic variants in different human populations, and the Wellcome Trust Case Control Consortium which has provided useful insights into the technical, methodological, analytical, and biological aspects of large-scale, multicentre GWA analysis.
Developing the resource
MalariaGEN partners have so far recruited over 10,000 cases of severe malaria, plus a similar number of ethnically matched population controls. For family-based association studies we have also recruited parents of more than 2000 cases of severe malaria. For each of these subjects we have collected a sample of DNA, and from the malaria cases we have collected detailed clinical and epidemiological data to provide an accurate phenotypic classification.
As well as serving our current programme of genetic asociation studies, this unique collection of DNA samples and clinical data provides an invaluable resource for future work by MalariaGEN's partner institutions and the network as a whole.
Generating data
We have recently completed a pilot case-control GWA study of severe malaria in The Gambia, in which 500,000 SNPs were genotyped in 2500 subjects. This study identified approximately 100 regions of the genome that - with varying levels of statistical confidence - showed evidence of association with severe malaria. The next stage is to determine which of these are true associations, which requires a much more detailed examination of each genomic region in a large number of subjects in different populations.
One of the most important aspects of this first study was to develop a reliable methodology for GWA studies in African populations, which present numerous statistical challenges owing to the great genetic diversity of these populations. These GWA data are available to other researchers through the MalariaGEN Data Release Policy, and a paper describing the main scientific findings has been submitted for publication.
We are now expanding both our sample size and SNP coverage, surveying 1 million SNPs across the genome of 4000 Malawian cases and controls. We are also performing family-based association studies in 4500 individuals in The Gambia, Ghana and Malawi. We expect to complete these studies in the first half of 2009 and will then undertake a meta-analysis of all of our GWA data, defining a consolidated set of genomic regions to take forward into large-scale multicentre replication and fine-mapping studies.