Genome-wide association study of susceptibility to pneumococcal carriage amongst children

Abstract

BackgroundPneumococcal disease is a leading cause of paediatric pneumonia and meningitis. Pneumococcal colonisation is the fundamental step to pneumococcal disease causation. We aimed to identify genetic loci associated with pneumococcal colonisation amongst children. MethodsWe conducted a genome-wide association study on 2111 Nepalese children, comprising 1346 cases carrying pneumococcus and 765 controls. We tested 8.1 million imputed variants using logistic regression and ten principal components as covariates. Fine mapping and functional evidence were used to identify suspected causal variants and related genes of interest. FindingsA cluster of 22 variants of genome-wide significance (p<5x10-8) were identified on chromosome 12q21.31, eight of which were within PPFIA2. Fine mapping of this region identified 5 variants within 0.1 Mb of the 5 region of PPFIA2 all of which are significant eQTLs for PPFIA2. We further describe three loci (10q23.31, 12q23.1, and 20p11.21) which had variants with highly suggestive associations (p<5x10-7)with pneumococcal carriage. InterpretationOur study demonstrate human susceptibility to pneumococcal carriage to be polygenic with genetic variations which regulate PPFIA2 expression playing a key role in the ability for pneumococcus to colonise children. Targeting these genetic factors and the associated pathways are a means for preventing pneumococcal disease. FundingThis study was supported by funding from Gavi - the vaccine alliance, the European Unions Horizon 2020 research and innovation program under grant agreement number 668303 (PERFORM), and a Robert Austrian Research Award. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPneumococcus, through the causation of pneumonia and invasive disease, is a common infectious cause of death in children. Pneumococcal colonisation is the seminal step to disease development. Yet, there are limited data on how human genetics influence pneumococcal carriage. Added value of this studyThe study examined the genetic association of pneumococcal carriage in 1346 healthy children and 765 controls with four genetic regions of interest prioritised. Fine mapping and functional analyses of these regions support PPFIA2, HRT7, NTN4, and FOXA2 as genes of interest for susceptibility to pneumococcal colonisation. Implications of all the available evidenceOur study shows a link between multiple genes and pneumococcal colonisation. Improved understanding of the action of these genes in the respiratory tract may inform novel approaches to disease prevention.