Paralogous mutations in the Plasmodium falciparum surface anion channel associate with reduced protection due to sickle hemoglobin

Genome-wide association studies of pathogens can uncover new aspects of infection biology and inform interventions. Here, we sequence Plasmodium falciparum genomes from 831 infections of Gambian children, identifying an association with disease severity on chromosome 1 which replicates in Kenyan infections. We then incorporate previously published data from the Gambia, Ghana, Mali, and Kenya in a meta-analysis of association between parasite variation and host sickle hemoglobin (HbS; N = 6,289), revealing several associations beyond the four previously implicated Plasmodium falciparum sickle-associated loci. Prominent among these are mutations affecting the C -terminal of CLAG3 , the major parasite nutrient uptake channel, which are shared between two paralogs and estimated to halve the protective effect of HbS. Further loci, including two members of the FIKK kinase family, are also implicated. Our findings indicate the parasite evolutionary response to HbS is more complex than previously understood, opening new functional and epidemiological questions about this important host-parasite interaction.