Associations between sickle haemoglobin and the Plasmodium falciparum CLAG and FIKK gene families revealed by meta-analysis of 6,289 African samples

The recent discovery that mutations in the Plasmodium falciparum genome are overrepresented in infections of sickle haemoglobin (HbS)-carriers has highlighted new questions about the underlying biological and evolutionary interaction, yet the full extent of this association is unknown. By meta-analysing host and parasite data from N=6,289 infections, including 831 newly sequenced samples from The Gambia, we implicate several new parasite genome regions in the interaction, including within the CLAG3 nutrient uptake channel and the threonine/serine kinase FIKK3 on chromosome 3. The HbS-associated mutations share unusually strong linkage disequilibrium, and we use a series of analyses to disentangle their complex genetic structure and independent effects. The most prominent signal is observed at a polymorphism shared between two CLAG3 paralogs, estimated to halve the level of protection due to HbS. Alongside previous findings in ACS8 and FIKK4.2, these results now implicate three of the major P. falciparum gene families in host-parasite interactions and open new avenues for functional inquiry.