Genome-wide association study indicates two novel resistance loci for severe malaria

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Abstract

Malaria causes approximately one million fatalities per year, mostly among African children1. Although highlighted by the strong protective effect of the sickle-cell trait2,3, the full impact of human genetics on resistance to the disease remains largely unexplored4. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful5. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes6, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells7 and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O5,8,9. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.

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Figure 1: Manhattan plots for GWA with severe malaria.
Figure 2: Regional association plots for new loci at 1q32.1 and 16q22.2.

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Acknowledgements

We thank the participating children, their parents and guardians; L. N. Badu, S. Opoku, M. Attan-Ayibo and D. Sambian for technical assistance. Ethical approval was obtained from the Committee for Research, Publications and Ethics of the School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Informed consent was obtained from the parents or guardians of the children and documented by signature, or thumbprint in cases of illiteracy. The study complied with the Ethical Principles for Medical Research Involving Human Subjects as laid out in the Declaration of Helsinki. The study was supported by the National Genome Research Network (NGFN1, NGFN2) of the German Ministry for Education and Research (BMBF). In addition, this study makes use of data generated by MalariaGEN5. A full list of the investigators who contributed to the generation of the data is available from http://www.malariagen.net. The MalariaGEN Project is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates’ Grand Challenges in Global Health Initiative.

Author information

R.D.H., C.T. and A.Z. designed the study. C.T., R.D.H., C.G.M., A.Z. and T.T. drafted the manuscript. D.A., S.A., E.A.A., S.B.N., K.O.K., A.O.Y.A., J.Sy., W.L., J.E. and J.M. recruited cases and controls and acquired materials. C.E., J.Si., B.M. and G.R. performed resequencing and SNP genotyping. T.T., C.T., M.B., M.V., K.S., C.L., A.Z., J.M. and R.D.H. calculated the statistical analysis and/or interpreted data. R.D.H. and A.Z. obtained funding. J.E., T.A., J.M. and A.F. provided administrative, technical or material support. R.D.H., A.Z. and T.A. supervised the study.

Correspondence to Christian Timmann.

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Competing interests

The authors declare no competing financial interests.

Additional information

Genetic variants identified by Sanger-based resequencing at the ATP2B4 and MARVELD3 loci are deposited in dbSNP (see Supplementary Table 5).

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Figures 1-4, Supplementary Tables 1-5 and Supplementary References. (PDF 1013 kb)

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