A fourth locus in thePlasmodium falciparumgenome associated with sickle haemoglobin

Abstract Heterozygosity for sickle haemoglobin (HbS) confers protection against severe malaria caused by the parasite Plasmodium falciparum . Recent work suggests that this protective effect can depend on the parasite genotype. Here, we performed a genome-wide association analysis of P. falciparum against human β-globin genotypes in a sample of 1,368 people with mild malaria in northern Ghana. We replicated the previously identified associations with HbS at two parasite loci. However, a newly identified locus within the serine/threonine kinase FIKK4 . 2 , which we term Pfsa4 , was also associated with HbS; this finding replicated in a published sample from Mali. The Pfsa1-4 mutations vary widely in frequencies across Africa, are absent from Asia, and are highly correlated with each-other across multiple populations. We found no strong associations with haemoglobin C. These findings add new complexity to the emerging picture of association between human and co-evolving malaria parasite genomes, suggesting new avenues for functional exploration.