Genome-Wide Association Studies of Drug-Resistance Determinants.
Population genetic strategies that leverage association, selection, and linkage have identified drug-resistant loci. However, challenges and limitations persist in identifying drug-resistance loci in malaria. In this review we discuss the genetic basis of drug resistance and the use of genome-wide association studies, complemented by selection and linkage studies, to identify and understand mechanisms of drug resistance and response. We also discuss the implications of nongenetic mechanisms of drug resistance recently reported in the literature, and present models of the interplay between nongenetic and genetic processes that contribute to the emergence of drug resistance. Throughout, we examine artemisinin resistance as an example to emphasize challenges in identifying phenotypes suitable for population genetic studies as well as complications due to multiple-factor drug resistance.
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Disease, Boston, MA, USA; The Broad Institute of MIT and Harvard, Infectious Disease Initiative, Cambridge, MA, USA; Simmons College, School of Nursing and Health Science, Boston, MA, USA. Electronic address: svolkman@hsph.harvard.edu.
Sarah K
SK
Volkman
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Disease, Boston, MA, USA; Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Jonathan
J
Herman
Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Disease, Boston, MA, USA; The Broad Institute of MIT and Harvard, Infectious Disease Initiative, Cambridge, MA, USA.
Amanda K
AK
Lukens
The Broad Institute of MIT and Harvard, Infectious Disease Initiative, Cambridge, MA, USA; Harvard University, Organismic and Evolutionary Biology, Cambridge, MA, USA.
Daniel L
DL
Hartl
D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*
D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin