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Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects.

ABSTRACT: BACKGROUND:P. falciparum malaria has been recognized as one of the prominent evolutionary selective forces of human genome that led to the emergence of multiple host protective alleles. A comprehensive understanding of the genetic bases of severe malaria susceptibility and resistance can potentially pave ways to the development of new therapeutics and vaccines. Genome-wide association studies (GWASs) have recently been implemented in malaria endemic areas and identified a number of novel association genetic variants. However, there are several open questions around heritability, epistatic interactions, genetic correlations and associated molecular pathways among others. Here, we assess the progress and pitfalls of severe malaria susceptibility GWASs and discuss the biology of the novel variants. RESULTS:We obtained all severe malaria susceptibility GWASs published thus far and accessed GWAS dataset of Gambian populations from European Phenome Genome Archive (EGA) through the MalariaGen consortium standard data access protocols. We noticed that, while some of the well-known variants including HbS and ABO blood group were replicated across endemic populations, only few novel variants were convincingly identified and their biological functions remain to be understood. We estimated SNP-heritability of severe malaria at 20.1% in Gambian populations and showed how advanced statistical genetic analytic methods can potentially be implemented in malaria susceptibility studies to provide useful functional insights. CONCLUSIONS:The ultimate goal of malaria susceptibility study is to discover a novel causal biological pathway that provide protections against severe malaria; a fundamental step towards translational medicine such as development of vaccine and new therapeutics. Beyond singe locus analysis, the future direction of malaria susceptibility requires a paradigm shift from single -omics to multi-stage and multi-dimensional integrative functional studies that combines multiple data types from the human host, the parasite, the mosquitoes and the environment. The current biotechnological and statistical advances may eventually lead to the feasibility of systems biology studies and revolutionize malaria research.

SUBMITTER: Damena D

PROVIDER: S-EPMC6693204 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects.

Damena Delesa D Denis Awany A Golassa Lemu L Chimusa Emile R ER

BMC medical genomics 20190814 1

<h4>Background</h4>P. falciparum malaria has been recognized as one of the prominent evolutionary selective forces of human genome that led to the emergence of multiple host protective alleles. A comprehensive understanding of the genetic bases of severe malaria susceptibility and resistance can potentially pave ways to the development of new therapeutics and vaccines. Genome-wide association studies (GWASs) have recently been implemented in malaria endemic areas and identified a number of novel ...[more]

PMID: 31409341

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Project description:BACKGROUND:The ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite P. vivax remain little characterized. RESULTS:We examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of P. vivax in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of P. vivax. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the pvmdr-1 locus, putatively associated with drug resistance. CONCLUSION:These findings support the feasibility of genome-wide association studies in carefully selected populations of P. vivax, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.

Dataset Information

Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects.

Publications

Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects.

Similar Datasets

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