Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

Abstract

Significant selection pressure has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors, including sickle cell trait, have been associated with reduced risk of developing severe malaria, but do not account for all of the observed phenotypic variation. Identification of novel inherited risk factors relies upon high-resolution genome-wide association studies (GWAS). We present findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, we identify protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all P<10−6), as well as near significant effects for Major Histocompatibility Complex (MHC) haplotypes. Complementary analyses, based on detecting extended haplotype homozygosity, identified SYNJ2BP, GCLC and MHC as potential loci under recent positive selection. Through whole genome sequencing of an independent Tanzanian cohort (parent-child trios n = 247), we confirm the allele frequencies of common polymorphisms underlying associations and selection, as well as the presence of multiple structural variants that could be in linkage with these SNPs. Imputation of structural variants in a region encompassing the glycophorin genes on chromosome 4, led to the characterisation of more than 50 rare variants, and individually no strong evidence of associations with severe malaria in our primary dataset (P>0.3). Our approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease.

Adaptive landscape genetics and malaria across divergent island bird populations

“…These enable detection of single nucleotide polymorphisms (SNPs) throughout the genome that show statistical associations with pathogen infection. In addition to identifying associations at known immune loci (Fellay et al, 2007;He et al, 2015;Wong et al, 2010), GWAS approaches may reveal novel candidate genes (Fu et al, 2012;Ravenhall et al, 2018;Thye et al, 2010) for further study of the evolutionary dynamics between host and pathogen.…”

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

“…Further studies with larger sample sizes are needed to understand the unpinning genetic architecture of severe malaria susceptibility/resistance phenotype. were obtained from the general population (15)(16)(17)(18). All the samples were genotyped on Illumina Omni 2.5M array and were provided in VCF format.…”

“…Even though a number of severe malaria GWASs have recently been implemented in malaria endemic areas in Africa and reported a number novel variants (15)(16)(17)(18), little is known about the proportion of h 2 g and its distribution across chromosomes, functional regions and allele frequency spectrum. We hypothesize that malaria susceptibility and resistance is a complex trait that is mainly under polygenic control.…”

First genome-wide association study of non-severe malaria in two birth cohorts in Benin

“…Finally, a strong association signal in CSMD1 gene on chromosome 8 was evidenced in mild 368 malaria attacks analysis. No functional evidence was found by FUMA for this association signal; 369 however, an association signal in CSMD1 was recently found in a GWAS of severe malaria in 370 Tanzania (20); it is a transmembrane protein, assumed to be a tumor suppressor gene (52), and is 371 also associated with phenotypes as diverse as blood pressure (53) and schizophrenia (54) but there 372 is as of yet no clear scenario to explain its potential role in malaria. 373…”

“…Among those, sickle cell trait (haemoglobin S, HbS), haemoglobin C (HbC) at homozygote 87 state, alpha+ thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency have been 88 associated with a protection against parasite invasion and clinical malaria attacks (7).89 Other association studies have focused on chromosomal regions linked with parasite infection levels 90 and mild malaria susceptibility, in particular 5q31-33 and 6p21-23 (8)(9)(10)(11)(12)(13)(14)(15). In this last region, TNF 91 has been the most studied candidate; NCR3, encoding a cell membrane receptor of natural killer, 92 has been also repeatedly associated with mild malaria (10,16).Since 2010, several genome-wide 93 association studies (GWAS) and meta-analysis have been published on severe malaria (17)(18)(19)(20)(21).94 These studies confirmed the involvement of previously known susceptibility genes (HBB and ABO) 95 and revealed new genes (ATP2B4, the cluster of genes GYP/FREM3, among which GYPA and 96 GYPB appear to play a central role (21)).…”