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Genome-wide and fine-resolution association analysis of malaria in West Africa

2009; Nature Portfolio; Volume: 41; Issue: 6 Linguagem: Inglês

10.1038/ng.388

1546-1718

Muminatou Jallow, Yik Ying Teo, Kerrin S. Small, Kirk A. Rockett, Panos Deloukas, Taane G. Clark, Katja Kivinen, Kalifa Bojang, David J. Conway, Margaret Pinder, Giorgio Sirugo, Fatou Sisay-Joof, Stanley Usen, Sarah Auburn, Suzannah J. Bumpstead, Susana Campino, Alison J. Coffey, Andrew Dunham, Andrew E. Fry, Angela Green, Rhian Gwilliam, Sarah Hunt, Michael Inouye, Anna E. Jeffreys, Alieu Mendy, Aarno Palotie, Simon Potter, Jiannis Ragoussis, Jane Rogers, Kate Rowlands, Elilan Somaskantharajah, Pamela Whittaker, Claire Widden, Peter Donnelly, Bryan Howie, Jonathan Marchini, Andrew P. Morris, Miguel SanJoaquin, Eric Achidi, Tsiri Agbenyega, Angela Allen, Olukemi K. Amodu, Patrick H. Corran, Abdoulaye Djimdé, Amagana Dolo, Ogobara K. Doumbo, Chris Drakeley, Sarah J. Dunstan, Jennifer Evans, Jeremy Farrar, Deepika Fernando, Tran Tinh Hien, Rolf D. Horstmann, Muntaser E. Ibrahim, Nadira D. Karunaweera, Gilbert Kokwaro, Kwadwo A. Koram, Martha Lemnge, Julie Makani, Kevin Marsh, P Michon, David Modiano, Malcolm E. Molyneux, Ivo Müeller, Michael Parker, Norbert Peshu, Christopher V. Plowe, Odile Puijalon, John C. Reeder, Hugh Reyburn, Eleanor M. Riley, Anavaj Sakuntabhai, Pratap Singhasivanon, Sodiomon B. Sirima, Adama Tall, Terrie E. Taylor, Mahamadou A. Théra, Marita Troye‐Blomberg, Thomas N. Williams, Michael D. Wilson, Dominic Kwiatkowski,

vaccines and immunoinformatics approaches

Dominic Kwiatkowski and colleagues of the MalariaGEN and the WTCCC consortiums report a genome-wide analysis of severe malaria in The Gambia. They provide guidance for design of GWAS in African populations, and demonstrate the usefulness of multipoint imputation based on population-specific sequencing data. 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.