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A novel locus of resistance to severe malaria in a region of ancient balancing selection

Nature volume 526, pages 253257 (08 October 2015) | Download Citation

Abstract

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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Data deposits

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.

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Acknowledgements

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.

Author information

Author notes

Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

    • Gavin Band
    • , Kirk A. Rockett
    • , Chris C. A. Spencer
    • , Dominic P. Kwiatkowski
    • , Quang Si Le
    • , Geraldine M. Clarke
    • , Ellen M. Leffler
    • , Victoria Cornelius
    • , Sarah Auburn
    • , Christina Hubbart
    • , Anna E. Jeffreys
    • , Kate Rowlands
    • , Alieu Mendy
    • , Rachel Craik
    • , Kathryn Fitzpatrick
    • , Sile Molloy
    • , Lee Hart
    • , Robert Hutton
    • , Angeliki Kerasidou
    •  & Kimberly J. Johnson
  2. The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

    • Kirk A. Rockett
    • , Dominic P. Kwiatkowski
    • , Katja Kivinen
    • , Daniel Mead
    • , Eleanor Drury
    • , Susana G. Campino
    • , Bronwyn MacInnis
    • , Jim Stalker
    •  & Emma Gray
  3. Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia

    • David J. Conway
    • , Kalifa A. Bojang
    • , Muminatou Jallow
    •  & Margaret Pinder
  4. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK

    • David J. Conway
  5. KEMRI-Wellcome Trust Research Programme CGMRC, PO Box 230-80108, Kilifi, Kenya

    • Thomas N. Williams
    • , Kevin Marsh
    • , Alexander Macharia
    • , Carolyne M. Ndila
    • , Charles Newton
    • , Norbert Peshu
    •  & Sophie Uyoga
  6. Faculty of Medicine, Department of Medicine, Imperial College, Exhibition Road, London SW7 2AZ, UK

    • Thomas N. Williams
  7. Blantyre Malaria Project, Queen Elizabeth Central Hospital, College of Medicine, P.O. Box 30096, Chichiri, Blantyre 3, Malawi

    • Terrie Taylor
  8. College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan 48824, USA

    • Terrie Taylor
  9. Malaria Research and Training Centre, Faculty of Medicine University of Bamako, Bamako, Mali

    • Ogobara Doumbo
    • , Mahamadou A. Thera
    • , Ousmane B. Toure
    • , Salimata Konate
    •  & Sibiri Sissoko
  10. University of Rome La Sapienza, Piazzale AldoMoro 5, 00185 Rome, Italy

    • David Modiano
    •  & Valentina D. Mangano
  11. Centre National de Recherche et de Formation sur le Paludisme (CNRFP), 01 BP 2208 Ouagadougou 01, Burkina Faso

    • Sodiomon B. Sirima
    •  & Edith C. Bougouma
  12. Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG 25, Legon, Accra, Ghana

    • Michael D. Wilson
    • , Kwadwo A. Koram
    •  & Anita K. Ghansah
  13. Komfo Anokye Teaching Hospital, PO Box 1934, Kumasi, Ghana

    • Tsiri Agbenyega
    • , Daniel Ansong
    •  & Anthony Enimil
  14. Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

    • Tsiri Agbenyega
    •  & Daniel Ansong
  15. Department of Medical Laboratory Sciences, University of Buea, P.O. Box 63, Buea, South West Region, Cameroon

    • Eric Achidi
  16. Joint Malaria Programme, Kilimanjaro Christian Medical Centre, PO box 2228, Moshi, Tanzania

    • Hugh Reyburn
    • , Chris Drakeley
    •  & Alphaxard Manjurano
  17. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK

    • Hugh Reyburn
    • , Chris Drakeley
    • , Eleanor Riley
    •  & Alphaxard Manjurano
  18. Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, College of Medicine, P.O. Box 30096, Chichiri, Blantyre 3, Malawi

    • Malcolm Molyneux
    • , David Kachala
    •  & Vysaul Nyirongo
  19. Royal Victoria Teaching Hospital, Independence Drive, PO Box 1515, Banjul, The Gambia

    • Muminatou Jallow
  20. Navrongo Health Research Centre, PO Box 114, Navrongo, Ghana

    • Lucas N. Amenga-Etego
    •  & Abraham V. O. Hodgson
  21. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Postfach 30 41 2, D-20324 Hamburg, Germany

    • Jennifer Evans
  22. Kumasi Centre for Collaborative Research, School of Medical Sciences, KNUST, Kumasi, Ghana

    • Jennifer Evans
  23. Department of Biochemistry & Molecular Biology, University of Buea, P.O. Box 63 Buea, South West Region, Cameroon

    • Tobias O. Apinjoh
  24. The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK

    • Angeliki Kerasidou

Consortia

  1. Malaria Genomic Epidemiology Network

    Writing group

    Data analysis

    Project management

    Study site lead investigators

    Clinical data and sample collection

    Sample processing, genotyping, data management and project coordination

Authors

    Contributions

    Details of author contributions are provided in the author list.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Chris C. A. Spencer or Dominic P. Kwiatkowski or Dominic P. Kwiatkowski or Chris C. A. Spencer or Chris C. A. Spencer or Dominic P. Kwiatkowski.

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      Supplementary information

      This file contains Supplementary Notes 1-4 and additional references.

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      Supplementary Table

      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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    https://doi.org/10.1038/nature15390

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