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Background  Artemisinin-based combination therapies are the first line of treatment for  Plasmodium falciparum  infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the  kelch13  gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in  kelch13  and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194  P. falciparum  isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014).    Results  We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After  Kelch13 -C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance.    Conclusions  This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the  kelch13  locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.    Electronic supplementary material  The online version of this article (doi:10.1186/s13059-017-1204-4) contains supplementary material, which is available to authorized users.

Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance