Abstract:
The human genetic factors that affect resistance to infectious disease are poorly understood.
Here we report a genome-wide association study in 17,000 severe malaria cases and
population controls from 11 countries, informed by sequencing of family trios and by direct
typing of candidate loci in an additional 15,000 samples. We identify five replicable
associations with genome-wide levels of evidence including a newly implicated variant
on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of
severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate
available functional data and discover an erythroid-specific transcription start site underlying
the known association in ATP2B4, but are unable to identify a likely causal mechanism at the
chromosome 6 locus. Previously reported HLA associations do not replicate in these samples.
This large dataset will provide a foundation for further research on the genetic determinants
of malaria resistance in diverse populations.
