Muminatou JallowYik Ying TeoKerrin S. SmallKirk A. RockettPanos DeloukasTaane G. ClarkKatja KivinenKalifa A. BojangDavid J. ConwayMargaret PinderGiorgio SirugoFatou Sisay-JoofStanley UsenSarah AuburnSuzannah J. BumpsteadSusana CampinoAlison CoffeyAndrew DunhamAndrew E. FryAngela GreenRhian GwilliamSarah E. HuntMichael InouyeAnna E. JeffreysAlieu MendyAarno PalotieSimon PotterJiannis RagoussisJane RogersKate RowlandsElilan SomaskantharajahPamela WhittakerClaire WiddenPeter DonnellyBryan HowieJonathan MarchiniAndrew MorrisMiguel SanjoaquinEric Akum AchidiTsiri AgbenyegaAngela AllenOlukemi AmoduPatrick CorranAbdoulaye DjimdeAmagana DoloOgobara K. DoumboChris DrakeleySarah DunstanJennifer EvansJeremy FarrarDeepika FernandoTran Tinh HienRolf D. HorstmannMuntaser IbrahimNadira KarunaweeraGilbert KokwaroKwadwo A. KoramMartha LemngeJulie MakaniKevin MarshPascal MichonDavid ModianoMalcolm E. MolyneuxIvo MuellerMichael ParkerNorbert PeshuChristopher V. PloweOdile PuijalonJohn ReederHugh ReyburnEleanor M. RileyAnavaj SakuntabhaiPratap SinghasivanonSodiomon SirimaAdama TallTerrie E. TaylorMahamadou TheraMarita Troye-BlombergThomas N. WilliamsMichael WilsonDominic P. KwiatkowskiMedical Research Council Laboratories GambiaWellcome Trust Centre for Human GeneticsWellcome Trust Sanger InstituteUniversity of OxfordUniversity of Malawi College of MedicineUniversity of BueaKwame Nkrumah University of Science and TechnologyPapua New Guinea Institute of Medical ResearchWeatherall Institute of Molecular MedicineUniversity of IbadanNational Institute for Biological Standards and ControlUniversity of BamakoLondon School of Hygiene & Tropical MedicineKilimanjaro Christian Medical CentreUCLBernhard Nocht Institut fur Tropenmedizin HamburgUniversity of Colombo Faculty of MedicineKhartoum UniversityWellcome Trust Research Laboratories NairobiUniversity of GhanaNational Institute for Medical Research TangaMuhimbili University of Health and Allied SciencesUniversita degli Studi di Roma La SapienzaBlantyre Malaria ProjectUniversity of Maryland, BaltimoreInstitut Pasteur, ParisMahidol UniversityCentre National de Recherche et de Formation sur le PaludismeLnstitut Pasteur de DakarMichigan State UniversityDepartment of Molecular Biosciences, The Wenner-Gren Institute2018-09-132018-09-132009-06-01Nature Genetics. Vol.41, No.6 (2009), 657-66515461718106140362-s2.0-67349278465https://repository.li.mahidol.ac.th/handle/20.500.14594/27218We 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/ng.388