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

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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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Figure 1: Principal components analysis of population structure within The Gambia.
Figure 2: Principal components analysis of population structure for the Gambian study sample in relation to HapMap reference panels.
Figure 3: Quantile-quantile plots of association test statistic.
Figure 4: Genome-wide signals of association with severe malaria.
Figure 5: Association signal at the HBB locus.
Figure 6: Extent of LD surrounding HbS.

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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

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.

Correspondence to Dominic P Kwiatkowski.

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

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

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Supplementary Figures 1–10, Supplementary Tables 1–4, Supplementary Methods and Supplementary Note (PDF 1193 kb)

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