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 po...
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | BMC Medical Genomics |
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| Online Access: | http://link.springer.com/article/10.1186/s12920-019-0564-x |
| _version_ | 1818414088045199360 |
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| author | Delesa Damena Awany Denis Lemu Golassa Emile R. Chimusa |
| author_facet | Delesa Damena Awany Denis Lemu Golassa Emile R. Chimusa |
| author_sort | Delesa Damena |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T11:13:32Z |
| format | Article |
| id | doaj.art-b2486a50c5be466db66b5bccadcbcad9 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-14T11:13:32Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-b2486a50c5be466db66b5bccadcbcad92022-12-21T23:04:10ZengBMCBMC Medical Genomics1755-87942019-08-0112111410.1186/s12920-019-0564-xGenome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospectsDelesa Damena0Awany Denis1Lemu Golassa2Emile R. Chimusa3Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape TownDivision of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape TownAklilu Lema Institute of Pathobiology, Addis Ababa UniversityDivision of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape TownAbstract 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.http://link.springer.com/article/10.1186/s12920-019-0564-xGenome-wide association studyP. falciparum malariaSusceptibilityResistanceHeritabilityPathways |
| spellingShingle | Delesa Damena Awany Denis Lemu Golassa Emile R. Chimusa Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects BMC Medical Genomics Genome-wide association study P. falciparum malaria Susceptibility Resistance Heritability Pathways |
| title | Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects |
| title_full | Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects |
| title_fullStr | Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects |
| title_full_unstemmed | Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects |
| title_short | Genome-wide association studies of severe P. falciparum malaria susceptibility: progress, pitfalls and prospects |
| title_sort | genome wide association studies of severe p falciparum malaria susceptibility progress pitfalls and prospects |
| topic | Genome-wide association study P. falciparum malaria Susceptibility Resistance Heritability Pathways |
| url | http://link.springer.com/article/10.1186/s12920-019-0564-x |
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