Abstract
Recent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here, we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals used as discovery and replication cohorts, respectively) closely followed from birth to 18–24 months of age, with an assessment of a space- and time-dependent environmental risk of exposure. Both the recurrence of mild malaria attacks and the recurrence of malaria infections as a whole (symptomatic and asymptomatic) were considered. Post-GWAS functional analyses were performed using positional, eQTL, and chromatin interaction mapping to identify the genes underlying association signals. Our study highlights a role of PTPRT, a tyrosine phosphatase receptor involved in STAT3 pathway, in the protection against both mild malaria attacks and malaria infections (p = 9.70 × 10−8 and p = 1.78 × 10−7, respectively, in the discovery cohort). Strong statistical support was also found for a role of MYLK4 (meta-analysis, p = 5.29 × 10−8 with malaria attacks), and for several other genes, whose biological functions are relevant in malaria infection. Results shows that GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.
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Data availability statement
The data sets generated and analyzed during the current study are available from the DataSuds repository (https://doi.org/10.23708/EXSQTM). The data set is not publicly available due to patient confidentiality but are available for researchers who meet the criteria for access to confidential data. All other relevant data are available within the manuscript and its Online Resource files.
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Acknowledgements
This research is a collaboration between the CEA/ Jacob/CNRGH and the IRD/UMR216. We wish to thanks the collaborators of the CERPAGE who participated actively in the longitudinal follow-ups. Longitudinal follow-ups were funded by the French National Research Agency (ANR-SEST 2006 040-01 and ANR-PRSP 2010 012-001); the French ministry of Research and Technology (REFS Nu2006-22) and the Institut de Recherche pour le Développement (IRD). We made use of data previously generated in the MiPPAD study (EDCTP-IP.07.31080.002). The genome-wide scan was supported by the Centre National de Recherche en Génomique Humaine (CNRGH). We are grateful to the Genotoul bioinformatics platform Toulouse Midi-Pyrenees (Bioinfo Genotoul) for providing computing and storage resources.
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Milet, J., Boland, A., Luisi, P. et al. First genome-wide association study of non-severe malaria in two birth cohorts in Benin. Hum Genet 138, 1341–1357 (2019). https://doi.org/10.1007/s00439-019-02079-5
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DOI: https://doi.org/10.1007/s00439-019-02079-5