Esoh, Kevin K., Apinjoh, Tobias O., Amambua-Ngwa, Alfred, Nyanjom, Steven G., Chimusa, Emile Rugamika, Amenga-Etego, Lucas, Wonkam, Ambroise and Achidi, Eric A. (2023) Genome-wide association study identifies novel candidate malaria resistance genes in Cameroon. Human Molecular Genetics. ddad026. ISSN 0964-6906 (In Press)
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Abstract
Recent data suggest that only a small fraction of severe malaria heritability is explained by the totality of genetic markers discovered so far. The extensive genetic diversity within African populations means that significant associations are likely to be found in Africa. In their series of multi-site genome-wide association studies (GWAS) across sub-Saharan Africa, the Malaria Genomic Epidemiology Network (MalariaGEN) observed specific limitations and encouraged country-specific analyses. Here, we present findings of a GWAS of Cameroonian participants that contributed to MalariaGEN projects (n = 1103). We identified protective associations at polymorphisms within the enhancer region of CHST15 (FDR < 0.02) that are specific to populations of African ancestry, and that tag strong eQTLs of CHST15 in hepatic cells. In-silico functional analysis revealed a signature of epigenetic regulation of CHST15 that is preserved in populations in historically malaria endemic regions, with haplotype analysis revealing a haplotype that is specific to these populations. Association analysis by ethnolinguistic group identified protective associations within SOD2 (FDR < 0.04), a gene previously shown to be significantly induced in pre-asymptomatic malaria patients from Cameroon. Haplotype analysis revealed substantial heterogeneity within the beta-like globin (HBB) gene cluster among the major ethnic groups in Cameroon confirming differential malaria pressure and underscoring age-old fine-scale genetic structure within the country. Our findings revealed novel insights in the evolutionary genetics of populations living in Cameroon under malaria pressure with new significant protective loci (CHST15 and SOD2) and emphasized the significant attenuation of genetic association signals by fine-scale genetic structure.
| Item Type: | Article |
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| Additional Information: | Funding information: This research was funded by MIMPAC and MIM/TDR grant [A11034 to E.A.A.], and NIH, National Heart Lung and Blood Institute grant [5U24HL135600-04 to A.W]. The views expressed in this publication are those of the author(s). The authors acknowledge the Centre for High Performance Computing (CHPC), South Africa, for providing computational resources to this research project. Computations were also performed using facilities provided by the University of Cape Town’s ICTS High Performance Computing team: hpc.uct.ac.za. |
| Subjects: | C400 Genetics C700 Molecular Biology, Biophysics and Biochemistry |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Depositing User: | Elena Carlaw |
| Date Deposited: | 17 Feb 2023 09:00 |
| Last Modified: | 17 Feb 2023 09:00 |
| URI: | https://nrl.northumbria.ac.uk/id/eprint/51423 |
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