The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies1,2,3. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60–0.76, P value = 9.5 × 10−11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees4. Taken together with previous observations on the malaria-protective role of blood group O1,2,3,5, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.
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Genotype and phenotype data underlying this manuscript have been deposited in the European Genome-phenome Archive under accession number EGAS00001001311. Access to individual-level genotype data is available by application to an Independent Data Access Committee: see http://www.malariagen.net/data. For further details of data underlying this manuscript, see http://www.malariagen.net/resource/14.
The Malaria Genomic Epidemiology Network Project is supported by the Wellcome Trust (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundations of the National Institutes of Health (NIH; 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 Medical Research Council (MRC; G0600718; G0600230), the Wellcome Trust Biomedical ethics Enhancement Award (087285) and Strategic Award (096527). D.P.K. receives support from the MRC (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 (075491/Z/04; 090532/Z/09/Z) and the Wellcome Trust Sanger Institute (077012/Z/05/Z and 098051). The Mali MRTC–BMP group is supported by a contract (N01AI85346) and a cooperative agreement (U19AI065683) from the National Institute of Allergy and Infectious Diseases (NIAID) and by a grant (D43TW001589) from the Fogarty International Centre, NIH to University of Maryland and University of Bamako and the Mali-NIAID/NIH International Center for Excellence in Research at the University of Sciences, Techniques, and Technology of Bamako. E.A. received partial funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 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 Fellowships 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 no. 242095–EVIMalaR. The KEMRI-Wellcome Trust Programme is funded through core support from the Wellcome Trust. C.M.N. is supported through a strategic award to the KEMRI-Wellcome Trust Programme by the Wellcome Trust (084538). Tanzania/Kilimanjaro Christian Medical College Joint Malaria Programme, Moshi, Tanzania received funding from MRC grant number G9901439. We acknowledge the work of B. Poudiougou and A. Niangaly for their help in collecting clinical data and biological samples for the Bamako study. We thank L. Jostins and M. Pirinen for advice on statistical analyses.
Extended data figures
This file contains a summary of statistics for 32 autosomal tier 1 loci for logistic regression and linear mixed model tests.
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Journal of Internal Medicine (2019)