Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya.

Borrmann, Steffen; Straimer, Judith; Mwai, Leah; Abdi, Abdirahman; Rippert, Anja; Okombo, John; Muriithi, Steven; Sasi, Philip; Kortok, Moses Mosobo; Lowe, Brett; +10 more...Campino, SusanaORCID logo; Assefa, Samuel; Auburn, Sarah; Manske, Magnus; Maslen, Gareth; Peshu, Norbert; Kwiatkowski, Dominic P; Marsh, Kevin; Nzila, Alexis; and Clark, Taane GORCID logo (2013) Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. SCIENTIFIC REPORTS, 3 (1). 3318-. ISSN 2045-2322 DOI: 10.1038/srep03318
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Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.


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