Fig. 4: A joint model for natural genetic resistance to malaria.

a Effect sizes for severe malaria subtypes are estimated in a joint model, which includes the five replicating associated variants and two additional variants (rs33930165, which encodes haemoglobin C, and rs8176746, which reflects the A/B blood group) in associated regions. The model was fit across all 11 populations, assuming the effect on each phenotype is fixed across populations, and including a population indicator and five principal components in each population as covariates. Each variant is encoded according to the mode of inheritance of the protective allele inferred from discovery analysis. Red lines indicate the overall effect across severe malaria subtypes, computed as an inverse variance-weighted mean of the per-phenotype estimates. Only cases with positive measured falciparum parasitaemia were included in model fit. b The frequency of the protective allele (for effects inferred as additive) or protective genotype (for non-additive effects) of each variant in each population. Grey circles depict the minimum, mean and maximum observed frequencies across populations. Coloured circles reflect the per-population frequencies. Frequency estimates are computed using control samples only. c Comparison of effect-size estimates against severe malaria for combinations of genotypes (stacked circles) carried by at least 25 study individuals, across the top six variants in a. Black filled and open circles denote the protective and risk dosage at the corresponding variant, respectively; grey circles denote heterozygote genotype for variants with inferred additive effect. Effect-size estimates are computed using the model as in a assuming independent effects (x axis), or jointly allowing each genotype its own effect (y axis). Source data are provided as a Source Data file.