Figure 1, Key Figure. The main polygenic component of malaria resistance is not enriched in African populations.

(A) 89% of the estimated heritability of severe malaria risk is attributed to variants with effects too small to be confidently detected by GWAS. Reproduced from [7]. (B) SNP-heritability of severe malaria risk is distributed across chromosomes proportional to their length. Replotted from [36]. (C) Strongly associated (large-effect) alleles from a GWAS for severe malaria risk occur at higher frequencies in African populations, compared to European populations (red oval). Smaller-effect alleles, which are less confidently associated, are equally likely to be more frequent in European populations (blue oval). Rank_EUR is the conditional rank of the allele in European populations, given African allele count; values greater than/less than 50% indicate that the allele is more common in Europe/Africa. Reproduced from [7]. (D) Alleles from healthy RBCs associated with reduced P. falciparum growth rate in vitro are not enriched for higher frequencies in African populations (blue oval). Polarized F_ST indicates the differentiation in allele frequencies between African and European populations in 1000 Genomes; values greater than/less than 0 indicate that the allele is more common in Europe/Africa. Replotted from [15]. (E) In donors who lack large-effect alleles for malaria resistance, red cell osmotic fragility is negatively related to exome-wide African ancestry. Replotted from [15]. (F) In donors who lack large-effect alleles for malaria resistance, higher red cell osmotic fragility predicts slower P. falciparum growth in vitro. Replotted from [15]. Panels A and C are reproduced with minor modifications under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).