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 Poudiougou Valentina 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 Miguel SanJoaquin 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 for Malaria Genomic Epidemiology Network
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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 HBBABOATP2B4G6PD 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. falciparuminfection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.