The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association inATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in diverse populations.

Ebb and flow of parasite populations: The population genetics of the malaria parasite Plasmodium falciparum across Africa is poorly understood but important to know for grasping the risks and dynamics of the spread of drug resistance. Harnessing the power of genomics, Amambua-Ngwa et al. of the Plasmodium Diversity Network Africa found substantial population structure within Africa that is consistent with human and vector population divergence (see the Perspective by Sibley). Specific signatures of selection by antimalarial drugs were detected, along with indications of the effect of colonization and slavery. Furthermore, whole-genome sequencing showed that there is extensive gene flow among the different regions and that Ethiopia has a distinctive population of P. falciparum , which may be indicative of coexistence with another malaria parasite, P. vivax. Science , this issue p. 813 ; see also p. 752

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired in the past decade on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low gravidity, and low gestational age. The effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant mortality. P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated. Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections, respectively. Compared to microscopy, RDTs have a lower sensitivity. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28-47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria, a combination of quinine + clyndamycin is recommended in all trimesters, while artesunate+ clindamycin or any other ACT known to be effective in the region are recommended in the second and third trimesters. For severe malaria, quinine (parenteral) is recommended in the first trimester while artesunate (parenteral) is recommended in the second and third trimesters.

As indicators of burden of malaria have substantially decreased in The Gambia, reaching a pre-elimination status may be attainable. Achieving this goal requires in-depth understanding of the current burden of Plasmodium falciparum infection. A nationwide cross-sectional survey was conducted in 2012 to determine the prevalence of P. falciparum infection, and to describe its heterogeneity and associated risk factors. Finger-prick blood samples were collected for microscopy, species-specific PCR and haemoglobin measurement. A total of 9,094 participants were included and median age was 11.9 years (IQR 5, 28). Overall prevalence of P. falciparum was 16.01 % with marked heterogeneity between sites (4.32–36.75 %) and within villages in each site (1.63–49.13 %). Across all sites, 51.17 % (745/1,456) of infections were asymptomatic and 35.61 % (448/1,258) were sub-microscopic. The odds of P. falciparum infection were higher in older children; 5–15 years (OR = 1.90; 95 % CI 1.60–2.26), adults (OR = 1.48; 95 % CI 1.24–1.78) and participants with moderate anaemia (OR = 1.62; 95 % CI 1.32–1.99). The current malaria control interventions are not sufficient to interrupt transmission in The Gambia as malaria prevalence is still relatively high in the eastern part of the country. New interventions aiming at interrupting transmission are needed and should be urgently evaluated.