Reappraisal of known malaria resistance loci in a large multicenter study

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.

Figure 1. Forest plots for association with severe malaria and sub phenotypes

Odds ratios and 95% confidence intervals (CI) are shown for Sickle-cell trait (rs334, heterozygote model), Blood group O (rs8176719, recessive model), ATP2B4 (rs10900585, dominant model), G6PD deficiency (rs1050828, additive model) and (e) CD40LG (rs3092945, recessive model) for association with cerebral malaria (lines with red dots) and severe malarial anaemia (lines with blue dots) in all individuals combined. Results are adjusted for gender, ethnicity and (with the exception of rs334) for sickle cell trait. Results are not presented when the sample size is too small (fewer than 5 cases or controls with relevant genotype) or for locations where the derived allele is absent. Further details are available in Supplementary Tables 11–19. The OR=1 for no effect is highlighted by the vertical dashed line.

Figure 2. Genetic heterogeneity of severe malaria subtypes cerebral malaria only and severe malarial anaemia only within and across African sites for significant loci

Bar plots show the distribution of probability between each of nine models of association where the effects on each phenotype are fixed, independent or correlated within a site combined with being fixed independent or correlated across all sites (see legend). Models are a priori assumed to be equally likely (See Online Methods and Supplementary Note for details). Results are shown for SNPs rs334 (HbS, heterozygote model) in HBB, rs8176719 homozygotes (Blood Group O) in ABO, rs10900585 in ATP2B4, G6PD+202 (rs1050828) in G6PD and rs3092945 in CD40LG.