Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer
protection against Plasmodium falciparum malaria, but the precise nature of the protective effect
has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects
in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum
infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multicentre case-control study of severe malaria, using the WHO classification of G6PD mutations to
estimate each individual’s level of enzyme activity from their genotype. Aggregated across all
genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of
cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection
based on these findings indicate that an evolutionary trade-off between different clinical outcomes
of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism
seen in human populations.