Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

Abstract

Background Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Severe malaria is associated with high morbidity and mortality and results from complications such as cerebral malaria, severe anaemia or respiratory distress. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to a heritable phenomenon called "benign ethnic neutropenia" (BEN). Neutrophils defend against bacterial infections but have been shown to be detrimental in pre-clinical malaria models, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. We tested this hypothesis by performing a genome-wide association study (GWAS) of circulating neutrophil count and a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria in individuals of predominantly African ancestry. Results We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank (N=5,976). We identified previously unknown loci regulating neutrophil count in a non-European population. This was followed by a two-sample bi-directional MR analysis between neutrophil count and severe malaria (MalariaGEN, N=17,056). We identified 73 loci (r2=0.1) associated with neutrophil count, including the well-known rs2814778 variant responsible for BEN. The greatest evidence for an effect was found between neutrophil count and severe anaemia, although the confidence intervals crossed the null. MR analyses failed to suggest evidence for an effect of the combined severe malaria syndromes or individual subtypes (severe malaria anaemia, cerebral malaria, other severe malaria) on neutrophil count. Conclusion Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malarial anemia.