Genome-wide association study of global Plasmodium vivax populations provides insights into the evolution of drug resistance

Abstract Increasing reports of chloroquine resistance (CQR) in Plasmodium vivax endemic regions has led to several countries, including Indonesia, to adopt dihydroarteminsin-piperaquine instead. Evidence for the major candidate, pvmdr1, as a putative determinant for CQR is conflicting. Using a genome-wide approach, we perform genomic analysis of 1,534 P. vivax isolates across 29 endemic countries, detailing population structure, patterns of relatedness, selection, and resistance profiling, providing insight into putative drivers of CQR. Differential selection metrics applied between isolates from low-grade and high-grade CQR regions revealed sweeps in a locus proximal to pvmdr1 and in transcriptional regulation genes. Our investigation of the temporal dynamics of selective sweeps in 106 isolates from Indonesian Papua, the epicentre of CQR, revealed pvmrp1 as an emerging candidate for piperaquine resistance. Overall, our work provides novel markers for resistance surveillance in candidate loci, supported by evidence of regions under recent directional selection in this continually evolving parasite.