Reappraisal of known malaria resistance loci in a large multicenter study

Kirk A. Rockett, Geraldine M. Clarke, Kathryn Fitzpatrick, Christina Hubbart, Anna E. Jeffreys, Kate Rowlands, Rachel Craik, Muminatou Jallow, David J. Conway, Kalifa A. Bojang, Margaret Pinder, Stanley Usen, Fatoumatta Sisay-Joof, Giorgio Sirugo, Ousmane Toure, Mahamadou A. Thera, Salimata Konate, Sibiry Sissoko, Amadou Niangaly, Belco PoudiougouValentina D. Mangano, Edith C. Bougouma, Sodiomon B. Sirima, David Modiano, Lucas N. Amenga-Etego, Anita Ghansah, Kwadwo A. Koram, Michael D. Wilson, Anthony Enimil, Jennifer Evans, Olukemi Amodu, Subulade Olaniyan, Tobias Apinjoh, Regina Mugri, Andre Ndi, Carolyne M. Ndila, Sophie Uyoga, Alexander Macharia, Norbert Peshu, Thomas N. Williams, Alphaxard Manjurano, Eleanor Riley, Chris Drakeley, Hugh Reyburn, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Sarah J. Dunstan, Nguyen Hoan Phu, Nguyen Thi Ngoc Quyen, Cao Quang Thai, Tran Tinh Hien, Laurens Manning, Moses Laman, Peter Siba, Harin Karunajeewa, Steve Allen, Angela Allen, Timothy M.E. Davis, Pascal Michon, Ivo Mueller, Angie Green, Sile Molloy, Kimberly J. Johnson, Angeliki Kerasidou, Victoria Cornelius, Lee Hart, Aaron Vanderwal, Miguelsan Joaquin, Gavin Band, Si Quang Le, Matti Pirinen, Nuno Sepúlveda, Chris C.A. Spencer, Taane G. Clark, Tsiri Agbenyega, Eric Achidi, Ogobara Doumbo, Jeremy Farrar, Kevin Marsh, Terrie Taylor, Dominic P. Kwiatkowski

Research output: Contribution to journalArticlepeer-review

174 Citations (Scopus)

Abstract

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10 '4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Original languageEnglish
Pages (from-to)1197-1204
Number of pages8
JournalNature Genetics
Volume46
Issue number11
DOIs
Publication statusPublished - 5 Nov 2014
Externally publishedYes

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