407Through rapid genetic adaptation and natural selection, the P. falciparum parasite,
the cause of the most serious form of malaria, is able to develop resistance to antima-
larial drugs, defeating present efforts to control it. GWAS provide a critical hypoth-
esis-generating tool for understanding how this occurs. However, in P. falciparum ,
the limited amount of linkage disequilibrium hinders the power of traditional array-
based GWAS. Feasibility and power improvements gained by using WGS for asso-
ciation studies has been demonstrated (Park et al. 2012 ). The authors analyzed data
from 45 Senegalese parasites and identifi ed genetic changes associated with the
parasites’ in vitro response to 12 different antimalarials. To further increase statisti-
cal power, they adapted a common test for natural selection, XP-EHH (cross-popu-
lation extended haplotype homozygosity), and used it to identify genomic regions
associated with resistance to drugs. Using this sequence-based approach and the
combination of association and selection-based tests, they detected several loci asso-
ciated with drug resistance. These loci included the previously known signals at
pfcrt, dhfr , and pfmdr1 , as well as many genes not previously implicated in drug-
resistance roles, including genes in the ubiquitination pathway. The success of the
analysis presented in this study and demonstrated shortcomings of array-based
approaches support a complete transition to sequence-based GWAS for small, low
linkage-disequilibrium genomes like that of P. falciparum.
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