Genome-wide association study identifies novel candidate malaria resistance genes in Cameroon
Loading...
Date
2023
Journal Title
Journal ISSN
Volume Title
Publisher
Human Molecular Genetics
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 [Benjamin–Hochberg false discovery rate (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 amongst 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.
Description
Research Article
Keywords
malaria, genetic, sub-Saharan Africa, Malaria Genomic Epidemiology Network (MalariaGEN)