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

Steffen Borrmann; Judith Straimer; Leah Mwai; Abdirahman Abdi; Anja Rippert; John Okombo; Steven Muriithi; Philip Sasi; Moses Mosobo Kortok; Brett Lowe; Susana Campino; Samuel Assefa; Sarah Auburn; Magnus Manske; Gareth Maslen; Norbert Peshu; Dominic P. Kwiatkowski; Kevin Marsh; Alexis Nzila; Taane G. Clark

doi:10.1038/srep03318

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

Steffen Borrmann^*
, Judith Straimer
, Leah Mwai
, Abdirahman Abdi
, Anja Rippert
, John Okombo
, Steven Muriithi
, Philip Sasi
, Moses Mosobo Kortok
, Brett Lowe
, Susana Campino
, Samuel Assefa
, Sarah Auburn
, Magnus Manske
, Gareth Maslen
, Norbert Peshu
, Dominic P. Kwiatkowski
, Kevin Marsh
, Alexis Nzila
, Taane G. Clark

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

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.

Original language	English
Article number	3318
Journal	Scientific Reports
Volume	3
DOIs	https://doi.org/10.1038/srep03318
State	Published - 2013

Bibliographical note

Funding Information:
We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General

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10.1038/srep03318

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Borrmann, S., Straimer, J., Mwai, L., Abdi, A., Rippert, A., Okombo, J., Muriithi, S., Sasi, P., Kortok, M. M., Lowe, B., Campino, S., Assefa, S., Auburn, S., Manske, M., Maslen, G., Peshu, N., Kwiatkowski, D. P., Marsh, K., Nzila, A., & Clark, T. G. (2013). Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. Scientific Reports, 3, Article 3318. https://doi.org/10.1038/srep03318

@article{3faa5738f2b043d3840397e97c7b6c1b,

title = "Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya",

abstract = "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.",

author = "Steffen Borrmann and Judith Straimer and Leah Mwai and Abdirahman Abdi and Anja Rippert and John Okombo and Steven Muriithi and Philip Sasi and Kortok, \{Moses Mosobo\} and Brett Lowe and Susana Campino and Samuel Assefa and Sarah Auburn and Magnus Manske and Gareth Maslen and Norbert Peshu and Kwiatkowski, \{Dominic P.\} and Kevin Marsh and Alexis Nzila and Clark, \{Taane G.\}",

note = "Funding Information: We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.",

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doi = "10.1038/srep03318",

language = "English",

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Borrmann, S, Straimer, J, Mwai, L, Abdi, A, Rippert, A, Okombo, J, Muriithi, S, Sasi, P, Kortok, MM, Lowe, B, Campino, S, Assefa, S, Auburn, S, Manske, M, Maslen, G, Peshu, N, Kwiatkowski, DP, Marsh, K, Nzila, A & Clark, TG 2013, 'Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya', Scientific Reports, vol. 3, 3318. https://doi.org/10.1038/srep03318

TY - JOUR

T1 - Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

AU - Borrmann, Steffen

AU - Straimer, Judith

AU - Mwai, Leah

AU - Abdi, Abdirahman

AU - Rippert, Anja

AU - Okombo, John

AU - Muriithi, Steven

AU - Sasi, Philip

AU - Kortok, Moses Mosobo

AU - Lowe, Brett

AU - Campino, Susana

AU - Assefa, Samuel

AU - Auburn, Sarah

AU - Manske, Magnus

AU - Maslen, Gareth

AU - Peshu, Norbert

AU - Kwiatkowski, Dominic P.

AU - Marsh, Kevin

AU - Nzila, Alexis

AU - Clark, Taane G.

N1 - Funding Information: We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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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U2 - 10.1038/srep03318

DO - 10.1038/srep03318

M3 - Article

C2 - 24270944

AN - SCOPUS:84888882898

SN - 2045-2322

VL - 3

JO - Scientific Reports

JF - Scientific Reports

M1 - 3318

ER -

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

Abstract

Bibliographical note

UN SDGs

ASJC Scopus subject areas

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