Immunogenetics of Susceptibility and Resistance to Severe Malaria: Genome-Wide Association Study in Three Nigerian Geopolitical Zones

The genetic basis of differential susceptibility to severe Plasmodium falciparum malaria involves complex polygenic and population-specific variation that genome-wide association studies in African populations are uniquely positioned to elucidate. This research conducts the first Nigeria-specific genome-wide association study of severe malaria susceptibility across ethnically diverse populations in the South South, North West, and North Central geopolitical zones. Participants will include 600 children with bacteriologically or clinically confirmed severe malaria phenotypes including cerebral malaria, severe anaemia, and respiratory distress, and 600 age-matched mild malaria controls. Genome-wide genotyping will be performed on the H3Africa SNP array, followed by imputation to the African Genome Resources reference panel. GWAS analysis will apply logistic regression with ancestry principal components as covariates. Trans-ethnic meta-analysis will increase power and identify shared versus population-specific loci. Candidate gene regions will be interrogated for functional annotation, eQTL colocalization, and pathway enrichment. HbS protective allele heterozygosity, G6PD, and complement receptor 1 polymorphisms will serve as validation benchmarks. Original contributions include a comprehensive Nigerian-specific GWAS landscape for severe malaria, novel susceptibility loci discovery, and a population stratification resource for future Nigerian genomics studies. Findings will directly inform risk stratification tools and provide biological rationale for novel therapeutic targets in the highest-burden malaria population globally. Keywords: GWAS, severe malaria, immunogenetics, H3Africa, susceptibility loci