New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania
Malaria Genomic Epidemiology Network None., Band G., Le QS., Clarke G., Kivinen K., Hubbart C., Jeffreys A., Rowlands K., Leffler E., Jallow M., Conway D., Sisay-Joof F., Sirugo G., d’Alessandro U., Toure O., Thera M., Konate S., Sissoko S., Mangano V., Bougouma E., Sirima S., Amenga-Etego L., Ghansah A., Hodgson A., Wilson M., Enimil A., Ansong D., Evans J., Ademola S., Apinjoh T., Ndila C., Manjurano A., Drakeley C., Reyburn H., Phu NH., Ngoc Quyen NT., Thai CQ., Hien TT., Teo YY., Manning L., Laman M., Michon P., Karunajeewa H., Siba P., Allen S., Allen A., Bahlo M., Davis T., Cornelius V., Shelton J., Spencer CCA., Busby GBJ., Kerasidou A., Drury E., Stalker J., Dilthey A., Mentzer A., McVean G., Bojang K., Doumbo O., Modiano D., Koram K., Agbenyega T., Amodu O., Achidi E., Williams T., Marsh K., Riley E., Molyneux M., Taylor T., Dunstan S., Farrar J., Mueller I., Rockett K., Kwiatkowski D.
Abstract We conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4 . Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria ( h 2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.