title: A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.
abstract: BACKGROUND
  Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.
  
  
  RESULTS
  Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.
  
  
  CONCLUSIONS
  Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Wendler
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: John
authors.initials: J
authors.lastname: Okombo
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Roberto
authors.initials: R
authors.lastname: Amato
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kiara
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Lewa
authors.initials: L
authors.lastname: Pole
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Magnus
authors.initials: M
authors.lastname: Manske
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Dan
authors.initials: D
authors.lastname: Alcock
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Drury
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Mandy
authors.initials: M
authors.lastname: Sanders
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Oyola
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Malangone
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Dushyanth
authors.initials: D
authors.lastname: Jyothi
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Alistair
authors.initials: A
authors.lastname: Miles
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Bronwyn L
authors.initials: BL
authors.lastname: MacInnis
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.affiliation: Department of Biology, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D016054:DNA, Protozoan / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan