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Genome-wide and fine-resolution association analysis of malaria in West Africa

Nature Genetics volume 41, pages 657665 (2009) | Download Citation

Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10−7 to P = 4 × 10−14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

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Acknowledgements

We thank the Gambian children and their parents and guardians who made this study possible; and the doctors, nurses and fieldworkers at the Royal Victoria Hospital, Banjul and other health clinics who assisted with this work. MalariaGEN's primary funding is from the Wellcome Trust (grant number 077383/Z/05/Z) and from the Bill & Melinda Gates Foundation, through the Foundation for the National Institutes of Health (grant number 566) as part of the Grand Challenges in Global Health initiative. The Wellcome Trust (Sanger Institute core funding) and the Medical Research Council (grant number G0600230) provide additional support for genotyping, bioinformatics and analysis. The MalariaGEN Resource Centre is part of the European Union Network of Excellence on the Biology and Pathology of Malaria Parasites.

Author information

Author notes

    • Muminatou Jallow
    • , Yik Ying Teo
    •  & Kerrin S Small

    These authors contributed equally to this work.

Affiliations

  1. MRC Laboratories, Fajara, Banjul, Gambia.

    • Muminatou Jallow
    • , Kalifa A Bojang
    • , David J Conway
    • , Margaret Pinder
    • , Giorgio Sirugo
    • , Fatou Sisay-Joof
    •  & Stanley Usen
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Yik Ying Teo
    • , Kerrin S Small
    • , Kirk A Rockett
    • , Taane G Clark
    • , Sarah Auburn
    • , Susana Campino
    • , Andrew E Fry
    • , Angela Green
    • , Anna E Jeffreys
    • , Alieu Mendy
    • , Jiannis Ragoussis
    • , Kate Rowlands
    • , Peter Donnelly
    • , Jonathan Marchini
    • , Andrew Morris
    • , Miguel SanJoaquin
    •  & Dominic P Kwiatkowski
  3. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Yik Ying Teo
    • , Kerrin S Small
    • , Kirk A Rockett
    • , Panos Deloukas
    • , Taane G Clark
    • , Katja Kivinen
    • , Sarah Auburn
    • , Suzannah J Bumpstead
    • , Susana Campino
    • , Alison Coffey
    • , Andrew Dunham
    • , Rhian Gwilliam
    • , Sarah E Hunt
    • , Michael Inouye
    • , Aarno Palotie
    • , Simon Potter
    • , Jane Rogers
    • , Elilan Somaskantharajah
    • , Pamela Whittaker
    • , Claire Widden
    •  & Dominic P Kwiatkowski
  4. Department of Statistics, Oxford University, Oxford, UK.

    • Peter Donnelly
    • , Bryan Howie
    •  & Jonathan Marchini
  5. Malawi–Liverpool–Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Chichiri, Blantyre, Malawi.

    • Miguel SanJoaquin
    •  & Malcolm E Molyneux
  6. The University of Buea, Buea, South West Province, Cameroon.

    • Eric Akum Achidi
  7. Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.

    • Tsiri Agbenyega
    •  & Jennifer Evans
  8. Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.

    • Angela Allen
    • , Pascal Michon
    • , Ivo Mueller
    •  & John Reeder
  9. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Angela Allen
  10. Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.

    • Olukemi Amodu
  11. National Institute for Biological Standards and Control, Hertfordshire, UK.

    • Patrick Corran
  12. The Malaria Research & Training Centre, University of Bamako, Bamako, Mali.

    • Abdoulaye Djimde
    • , Amagana Dolo
    • , Ogobara K Doumbo
    •  & Mahamadou Thera
  13. London School of Hygiene & Tropical Medicine, London, UK.

    • Chris Drakeley
    • , Hugh Reyburn
    •  & Eleanor M Riley
  14. Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.

    • Chris Drakeley
    • , Hugh Reyburn
    •  & Eleanor M Riley
  15. Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

    • Sarah Dunstan
    • , Jeremy Farrar
    •  & Tran Tinh Hien
  16. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

    • Jennifer Evans
    •  & Rolf D Horstmann
  17. Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.

    • Deepika Fernando
    •  & Nadira Karunaweera
  18. Institute for Endemic Diseases, University of Khartoum, Medical Service Science Campus, Khartoum, Sudan.

    • Muntaser Ibrahim
  19. Kenyan Medical Research Institute (KEMRI)–Wellcome Trust Programme, Kilifi, Kenya.

    • Gilbert Kokwaro
    • , Kevin Marsh
    • , Norbert Peshu
    •  & Thomas N Williams
  20. Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.

    • Kwadwo A Koram
    •  & Michael Wilson
  21. National Institute for Medical Research, Dar es Salaam, Tanzania.

    • Martha Lemnge
  22. Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.

    • Julie Makani
  23. University of Rome 'La Sapienza', Rome, Italy.

    • David Modiano
  24. The Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Headington, Oxford, UK.

    • Michael Parker
  25. Blantyre Malaria Project, Chichiri, Blantyre 3, Malawi.

    • Christopher V Plowe
    •  & Terrie E Taylor
  26. Howard Hughes Medical Institute/University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Christopher V Plowe
  27. Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France.

    • Odile Puijalon
    •  & Anavaj Sakuntabhai
  28. Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand.

    • Pratap Singhasivanon
  29. Centre National de Recherche et Formation sur le Paludisme, Ouagadougou, Burkina Faso.

    • Sodiomon Sirima
  30. lnstitut Pasteur de Dakar, Dakar, Senegal.

    • Adama Tall
  31. Michigan State University, Department of Internal Medicine, College of Osteopathic Medicine, East Lansing, Michigan, USA.

    • Terrie E Taylor
  32. The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

    • Marita Troye-Blomberg

Consortia

  1. Wellcome Trust Case Control Consortium

    A full list of members is provided in the Supplementary Note.

  2. Malaria Genomic Epidemiology Network

    A full list of members is provided in the Supplementary Note.

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Contributions

The clinical study in The Gambia was designed and carried out by M.J., K.A.B., D.J.C., D.P.K., M. Pinder, G.S., F.S.-J. and S.U. Genotyping and sequencing studies were designed and performed by K.A.R., P. Deloukas, S.A., S.J.B., S.C., A.C., A. Dunham, A.E.F., A.G., R.G., S.E.H., M. Inouye, A.E.J., K.K., A. Mendy, A.P., S.P., J. Ragoussis, J. Rogers, K.R., E.S., P.W. and C.W. The analysis group comprised Y.Y.T., K.S.S., T.G.C., P. Donnelly, J. Marchini, A. Morris, M.S. and D.P.K. This study forms part of a multicenter investigation of genetic resistance to malaria led by E.A.A., T.A., S.A., O.A., K.A.B., D.J.C., P.C., P. Deloukas, A. Djimde, A. Dolo, O.K.D., C.D., S.D., J.E., J.F., D.F., T.T.H., R.D.H., M. Ibrahim, N.K., G.K., K.A.K., D.P.K., M.L., J. Makani, K.M., P.M., D.M., M.E.M., I.M., M. Parker, N.P., C.V.P., O.P., J. Ragoussis, J. Rogers, J. Reeder, H.R., E.M.R., A.S., P.S., S.S., G.S., A.T., T.E.T., M.T., M.T.-B., T.N.W. and M.W. The manuscript was written by D.P.K., Y.Y.T. and K.S.S.

Corresponding author

Correspondence to Dominic P Kwiatkowski.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–10, Supplementary Tables 1–4, Supplementary Methods and Supplementary Note

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DOI

https://doi.org/10.1038/ng.388

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