Genome-wide heritability analysis of severe malaria susceptibility and resistance reveals evidence of polygenic inheritance

ABSTRACT Objective Estimating SNP-heritability ( h 2 g ) of severe malaria/resistance and its distribution across the genome might shed new light in to the underlying biology. Method We investigated h 2 g of severe malaria susceptibility and resistance from genome-wide association study (GWAS) dataset (sample size =11, 657). We partitioned the h 2 g in to chromosomes, allele frequencies and annotations. We further examined none-cell type specific and cell type specific enrichments from GWAS-summary statistics. Results We estimated the h 2 g of severe malaria at 0.21 (se=0.05, p=2.7×10 −5 ), 0.20 (se =0.05, p=7.5×10 −5 ) and 0.17 (se =0.05, p= 7.2×10 −4 ) in Gambian, Kenyan and Malawi populations, respectively. The h 2 g attributed to the GWAS significant SNPs and the well-known sickle cell ( HbS ) variant was approximately 0.07 and 0.03, respectively. We prepared African population reference panel and obtained comparable h 2 g estimate (0.21 (se = 0.02, p< 1×10 −5 )) from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h 2 g in protein coding genic SNPs while summary statistics analysis suggests pattern of enrichment in multiple categories. Conclusion We report for the first time that the heritability of malaria susceptibility and resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Overall, our results suggest that malaria susceptibility and resistance is a polygenic trait. Further studies with larger sample sizes are needed to better understand the underpinning genetics of resistance and susceptibility to severe malaria.