GWAS-Informed Molecular Analysis of Susceptibility Loci for Severe Malaria in Children from the North Central Geopolitical Zone

Genome-wide association studies (GWAS) have identified several susceptibility loci influencing the risk of severe malaria, including HbS, ABO blood group, and immune regulatory gene variants. Validation and functional analysis of these loci in Nigerian pediatric populations provides context-specific evidence to support malaria genetic epidemiology research. This study performed GWAS-informed molecular analysis of severe malaria susceptibility loci in children hospitalized with severe malaria across Kogi, Kwara, and Niger States in the North Central geopolitical zone. Blood samples were collected from 250 children with severe malaria (cerebral malaria, severe anemia, respiratory distress) and 250 matched healthy controls from the same communities. Genotyping was performed using the H3Africa SNP array on the Illumina iScan platform, providing coverage of over 2.5 million SNPs. Association analysis was conducted using PLINK v1.9, with population structure controlled by principal component analysis. Secondary analysis examined independent SNPs at GWAS-confirmed loci including HBB, CD36, CR1, and IL12B. Significant associations were confirmed for the HbS protective effect (OR: 0.24, p=4.2x10-12) and ABO blood group O (OR: 0.61, p=1.8x10-5). A novel suggestive association was identified at a CD36 missense variant (rs3211938) not previously reported in West African malaria GWAS datasets. These data extend severe malaria genetic susceptibility mapping into an underrepresented Nigerian pediatric population. Keywords: GWAS, severe malaria, susceptibility loci, H3Africa array, North Central Nigeria.