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Reappraisal of known malaria resistance loci in a large multicenter study

Nature Genetics volume 46, pages 1197–1204 (2014)Cite this article

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Abstract

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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Figure 1: Forest plots for association with severe malaria and subphenotypes.
Figure 2: Genetic heterogeneity for the severe malaria subtypes cerebral malaria only and severe malarial anemia only within and across African sites for significant loci.

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Acknowledgements

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.

Author information

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Kirk A Rockett, Geraldine M Clarke, Kathryn Fitzpatrick, Christina Hubbart, Anna E Jeffreys, Kate Rowlands, Rachel Craik, Angie Green, Sile Molloy, Kimberly J Johnson, Angeliki Kerasidou, Victoria Cornelius, Lee Hart, Aaron Vanderwal, Miguel SanJoaquin, Gavin Band, Si Quang Le, Matti Pirinen, Chris C A Spencer & Dominic P Kwiatkowski

  2. Wellcome Trust Sanger Institute, Hinxton, UK

    Kirk A Rockett & Dominic P Kwiatkowski

  3. Medical Research Council Centre for Genomics and Global Health, University of Oxford, Oxford, UK

    Kirk A Rockett, Geraldine M Clarke, Chris C A Spencer & Dominic P Kwiatkowski

  4. Medical Research Council Unit, Serrekunda, The Gambia

    Muminatou Jallow, David J Conway, Kalifa A Bojang, Margaret Pinder, Stanley Usen, Fatoumatta Sisay-Joof & Giorgio Sirugo

  5. Royal Victoria Teaching Hospital, Banjul, The Gambia

    Muminatou Jallow

  6. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, UK

    David J Conway

  7. Malaria Research and Training Centre, Faculty of Medicine, University of Bamako, Bamako, Mali

    Ousmane Toure, Mahamadou A Thera, Salimata Konate, Sibiry Sissoko, Amadou Niangaly, Belco Poudiougou & Ogobara Doumbo

  8. Dipartimento di Sanita Publica e Malattie Infettive, University of Rome La Sapienza, Rome, Italy

    Valentina D Mangano & David Modiano

  9. Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso

    Edith C Bougouma & Sodiomon B Sirima

  10. Navrongo Health Research Centre, Navrongo, Ghana

    Lucas N Amenga-Etego

  11. Noguchi Memorial Institute for Medical Research, Accra, Ghana

    Anita Ghansah, Kwadwo A Koram & Michael D Wilson

  12. Komfo Anokye Teaching Hospital, Kumasi, Ghana

    Anthony Enimil & Tsiri Agbenyega

  13. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

    Jennifer Evans

  14. Kumasi Centre for Collaborative Research, Kumasi, Ghana

    Jennifer Evans

  15. Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Olukemi Amodu & Subulade Olaniyan

  16. Department of Biochemistry and Molecular Biology, University of Buea, Buea, Cameroon

    Tobias Apinjoh

  17. Department of Medical Laboratory Sciences, University of Buea, Buea, Cameroon

    Regina Mugri, Andre Ndi & Eric Achidi

  18. KEMRI–Wellcome Trust Research Programme, Kilifi, Kenya

    Carolyne M Ndila, Sophie Uyoga, Alexander Macharia, Norbert Peshu, Thomas N Williams & Kevin Marsh

  19. Department of Medicine, Faculty of Medicine, Imperial College, London, UK

    Thomas N Williams

  20. Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania

    Alphaxard Manjurano, Chris Drakeley & Hugh Reyburn

  21. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

    Alphaxard Manjurano, Eleanor Riley, Chris Drakeley & Hugh Reyburn

  22. Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi

    Vysaul Nyirongo

  23. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

    David Kachala, Sarah J Dunstan, Nguyen Hoan Phu, Nguyen Thi Ngoc Quyen, Cao Quang Thai, Tran Tinh Hien & Jeremy Farrar

  24. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford, UK

    Malcolm Molyneux, Sarah J Dunstan & Jeremy Farrar

  25. Nossal Institute of Global Health, University of Melbourne, Melbourne, Victoria, Australia

    Sarah J Dunstan

  26. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    Nguyen Hoan Phu, Cao Quang Thai & Tran Tinh Hien

  27. Papua New Guinea Institute of Medical Research, Garoka, Papua New Guinea

    Laurens Manning, Moses Laman, Peter Siba, Pascal Michon & Ivo Mueller

  28. School of Medicine and Pharmacology, Fremantle Hospital Unit, University of Western Australia, Fremantle, Western Australia, Australia

    Laurens Manning, Harin Karunajeewa & Timothy M E Davis

  29. College of Medicine, Swansea University, Swansea, UK

    Steve Allen

  30. Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK

    Angela Allen

  31. Faculty of Health Sciences, Divine Word University, Madang, Papua New Guinea

    Pascal Michon

  32. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Ivo Mueller

  33. Barcelona Centre for International Health Research (CRESIB), Barcelona, Spain

    Ivo Mueller

  34. Nuffield Department of Population Health, Ethox Centre, University of Oxford, Oxford, UK

    Angeliki Kerasidou

  35. London School of Hygiene and Tropical Medicine, London, UK

    Nuno Sepúlveda & Taane G Clark

  36. School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

    Tsiri Agbenyega

  37. Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi

    Terrie Taylor

Consortia

Malaria Genomic Epidemiology Network

  • 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

Contributions

All senior authors from each partner site have approved the final manuscript and their site authorship, acknowledgments and full contributors list. Writing group: G.M.C., D.P.K., S.M., K.A.R. and C.C.A.S. Project management: E.A., T. Agbenyega, S.A., A.A., O.A., K.A.B., D.J.C., V.C., T.M.E.D., O.D., C.D., S.J.D., J.F., T.T.H., K.J.J., H.K., A.K., S.K., K.A.K., D.P.K., K.M., P.M., D.M., M.M., I.M., A. Niangaly, N.P., M. Pinder, B.P., H.R., E.R., K.A.R., P.S., S.B.S., G.S., S.S., T.T., M.A.T., T.N.W. and M.D.W. Sample clinical data collection and management: S.A., A.A., L.N.A.-E., O.A., T. Apinjoh, K.A.B., E.C.B., G.M.C., D.J.C., S.J.D., A.E., J.E., K.F., A. Ghansah, L.H., M.J., D.K., H.K., A.K., S.K., M.L., A. Macharia, V.D.M., A. Manjurano, L.M., P.M., S.M., R.M., A. Niangaly, C.M.N., A. Ndi, V.N., S.O., N.P., N.H.P., M. Pinder, B.P., N.T.N.Q., H.R., K.A.R., M.S., G.S., F.S.-J., S.S., T.T., C.Q.T., M.A.T., O.T., S. Usen, S. Uyoga and A.V. Sample processing, genotyping and management: A.A., L.N.A.-E., O.A., T. Apinjoh, E.C.B., R.C., A.E., A. Ghansah, A. Green, L.H., C.H., M.J., A.E.J., D.K., H.K., M.L., A. Macharia, V.D.M., A. Manjurano, L.M., S.M., R.M., A. Niangaly, C.M.N., A. Ndi, V.N., S.O., N.H.P., N.T.N.Q., K.A.R., K.R., F.S.-J., C.Q.T., O.T., S. Uyoga and A.V. Analysis: G.B., T.G.C., G.M.C., D.P.K., S.Q.L., S.M., M. Pirinen, K.A.R., N.S. and C.C.A.S. Full details on contribution are given in the supplementary material.

Corresponding authors

Correspondence to Kirk A Rockett or Dominic P Kwiatkowski.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Map of the locations of the MalariaGEN Partner Study sites involved in this project.

1. UK Resource Centre, Oxford University and Wellcome Trust Sanger Institute. 2. The Gambia, MRC Laboratories, Banjul. 3. Mali, University of Bamako, Bamako. 4. Burkina Faso, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou. 5. Ghana (Navrongo), Navrongo Memorial Institute for Medical Research with Navrongo Health Research Centre. 6. Ghana (Kumasi), Kwame Nkrumah University of Science and Technology. 7. Nigeria, University of Ibadan.8. Cameroon, University of Buea. 9. Kenya, KEMRI–Wellcome Research Programme, Kilifi. 10. Tanzania, Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi. 11. Malawi, Blantyre Malaria Project with Malawi-Liverpool–Wellcome Programme. 12. Vietnam, Oxford University Clinical Research Unit, Ho Chi Minh City. 13. Papua New Guinea, Papua New Guinea Institute for Medical Research, Madang. See also Supplementary Tables 1 and 2.

Supplementary Figure 2 Chromosomal map of the genes included in Supplementary Tables 5–7.

All genes are referenced to GRCh37, dbSNP137 and Ensembl build 73.

Supplementary Figure 3 Distribution of P values from multiple-association analyses at 55 SNPs having a prior association with severe malaria.

–log10 P values from combined analyses across the 12 contributing Consortial Project 1 study sites for severe malaria and the subtypes cerebral malaria and severe malarial anemia under additive, recessive, dominant and heterozygote advantage models. Results are shown for all individuals combined for (a) 0 < –log10 (P) ≤ 10 and (b) 10 < –log10 (P) < 250; results are shown in two panels for optimal viewing. The vertical dashed line indicates a P-value threshold of 1 × 10–3.

Supplementary Figure 4 Forest plots for interaction between ATP2B4 and HbC for association with severe malaria.

Odds ratios and 95% confidence intervals are shown for the interaction between ATP2B4 (rs10900585) and HbC (rs33930165) for association with severe malaria in all individuals combined across West African sites (Burkina Faso, The Gambia, Ghana, Mali, Cameroon and Nigeria). Results are adjusted for sex and ancestry. The baseline genotype is GG/GG, representing double ancestral homozygotes. OR = 1, indicating no effect, is highlighted by the gray horizontal dashed line.

Supplementary Figure 5 Genetic heterogeneity of the severe malaria subtypes cerebral malaria and severe malarial anemia within and across African populations for all loci.

Bar plots show the posterior probability on each of nine models of association where effects on the two subtypes are fixed, independent or correlated within a population combined with being fixed, independent or correlated across all the populations, as indicated by the different colors; the remainder of the posterior probability is on the null model where there is no effect on any of the subtypes. Before seeing the data, the null model is assumed to have 80% probability; the remaining 20% is divided equally among the other models. Approximate Bayes factors (ABFs), calculated as the ratio of the marginal likelihoods of a given model and the null model, are used to compare the evidence between models. (See the Online Methods for details and the specification of priors.) The dashed line at posterior probability = 20% indicates where the combined posterior probability of the non-null models is greater than their combined prior probability.

Supplementary Figure 6 Performance of sample collection across the set of 65 core SNPs (not including ATP2B4) successfully genotyped for all samples.

Samples have been ranked in order of pass rate from high to low (x axis) and plotted against their pass rate (y axis). A total of 33,138 samples were assayed, with 32,349 samples achieving a pass rate of ≥90% (98% of the sample received).

Supplementary Figure 7 Hardy-Weinberg equilibrium analysis of genotype data by SNP and country/ancestry.

A P value for Hardy-Weinberg equilibrium was calculated for each SNP and country/ancestry, discarding ancestry groups where the chromosome with the minor allele count fell below five (Forensic Sci. Int. 149, 279–286, 2005). X-chromosome SNPs used female genotypes only. At each SNP, the Hardy-Weinberg equilibrium P values calculated for each country/ancestry were transformed to unsigned log values and ranked from high to low. Each line corresponds to a single SNP and shows the transformed P values plotted as a function of their rank. The vertical dashed line at rank 5 represents the threshold for the number of ancestry groups failing the Hardy-Weinberg equilibrium test at a significance level of 1 × 10–4, a conservative threshold to allow for multiple tests (represented by the dashed horizontal line). Lines crossing into the top right of the area defined by the two dashed lines therefore represent SNPs that failed more than five tests and therefore were removed from further analysis. Using these cutoffs, the TNF c.-376G>A (rs1800750) SNP, indicated by the red line, was removed from further analysis owing to an excess of heterozygotes.

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Supplementary Figures 1–7, Supplementary Tables 1–25 and Supplementary Note. (PDF 6228 kb)

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Malaria Genomic Epidemiology Network. Reappraisal of known malaria resistance loci in a large multicenter study. Nat Genet 46, 1197–1204 (2014). https://doi.org/10.1038/ng.3107

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