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.
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The MalariaGEN Project is supported by the Wellcome Trust (WT077383/Z/05/Z) and the Bill and Melinda Gates Foundation through The Foundation for the National Institutes of Health (FNIH, USA) (566) as part of the Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (090770/Z/09/Z). This research was supported by the UK Medical Research Council (G0600718 and G0600230) and by the Wellcome Trust Biomedical Ethics Enhancement Award (087285) and Strategic Award (096527). D.P.K. receives support from the UK Medical Research Council (G19/9). C.C.A.S. was supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z) and the Wellcome Trust Sanger Institute (098051/Z/05/Z). The Malaria Research and Training Center–Bandiagara Malaria Project (MRTC-BMP) in Mali group is supported by an Interagency Committee on Disability Research (ICDR) grant from the National Institute of Allergy and Infectious Diseases/US National Institutes of Health (NIAID/NIH) to the University of Maryland and the University of Bamako (USTTB) and by the Mali-NIAID/NIH International Centers for Excellence in Research (ICER) at USTTB. Contributions from Nigeria to CP1 were supported financially by a grant within the BioMalPar European Network of Excellence (LSHP-CT-2004-503578). E.A. received partial funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095-EVIMalaR and the Central African Network for Tuberculosis, HIV/AIDS and Malaria (CANTAM) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP). T.N.W. is funded by Senior Fellowship awards from the Wellcome Trust (076934/Z/05/Z and 091758/Z/10/Z) and through the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095-EVIMalaR. The Kenya Medical Research Institute (KEMRI)–Wellcome Trust Programme is funded through core support from the Wellcome Trust. This paper is published with the permission of the director of KEMRI. C.M.N. is supported through a strategic award to the KEMRI–Wellcome Trust Programme from the Wellcome Trust (084538). The Joint Malaria Programme, Kilimanjaro Christian Medical Centre in Tanzania received funding from a UK MRC grant (G9901439). We would like to thank all the Vietnamese individuals who agreed to provide samples for this study. We acknowledge the work of the clinical staff from the Hospital of Tropical Diseases, HCMC and Phuoc Long and Dong Xoai District Hospitals in Binh Phuoc province, Vietnam, who initially diagnosed and studied the individuals with severe malaria. We would like to thank N.T. Hieu and his staff from Hung Vuong Obstetric Hospital for the collection of the cord blood controls. The clinical component of this study was funded through the Wellcome Trust Major Overseas Program in Vietnam (089276/Z/09/Z). L.M. was supported through Basser (Royal Australasian College of Physicians) and National Health and Medical Research Council (NHMRC) scholarships. M.L. was supported through a Fogarty Foundation Scholarship. T.M.E.D. was supported through an NHMRC practitioner fellowship.
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Supplementary Figures 1–7, Supplementary Tables 1–25 and Supplementary Note.
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Nature Reviews Genetics (2019)