Genome wide association study of SNP-, gene-, and pathway-based approaches to identify genes influencing susceptibility to Staphylococcus aureus infections

Abstract

Background: We conducted a genome-wide association study (GWAS) to identify specific genetic variants that underlie susceptibility to diseases caused by Staphylococcus aureus in humans.Methods: Cases (n = 309) and controls (n = 2925) were genotyped at 508,921 single nucleotide polymorphisms (SNPs). Cases had at least one laboratory and clinician confirmed disease caused by S. aureus whereas controls did not. R-package (for SNP association), EIGENSOFT (to estimate and adjust for population stratification) and gene- (VEGAS) and pathway-based (DAVID, PANTHER, and Ingenuity Pathway Analysis) analyses were performed.Results: No SNP reached genome-wide significance. Four SNPs exceeded the p < 10−5 threshold including two (rs2455012 and rs7152530) reaching a p-value < 10−7. The nearby genes were PDE4B (rs2455012), TXNRD2 (rs3804047), VRK1 and BCL11B (rs7152530), and PNPLA5 (rs470093). The top two findings from the gene-based analysis were NMRK2 (pgene = 1.20E-05), which codes an integrin binding molecule (focal adhesion), and DAPK3 (pgene = 5.10E-05), a serine/threonine kinase (apoptosis and cytokinesis). The pathway analyses identified epithelial cell responses to mechanical and non-mechanical stress.Conclusion: We identified potential susceptibility genes for S. aureus diseases in this preliminary study but confirmation by other studies is needed. The observed associations could be relevant given the complexity of S. aureus as a pathogen and its ability to exploit multiple biological pathways to cause infections in humans.

Performance of an electronic health record-based phenotype algorithm to identify community associated methicillin-resistant Staphylococcus aureus cases and controls for genetic association studies

“…The lack of GWAS-significant findings in either European or African Americans is disappointing, but not surprising given the limited sample size and anticipated modest effect size of any common genetic variants pre-disposing to CA-MRSA infection [6, 7, 37]. With CA-MRSA cases not defined in a uniform manner (as detailed above) and not screened for in a uniform manner (also detailed above), measurement error in the identification of cases would be expected to bias any association estimates between SNPs and CA-MRSA to the null.…”

“…Additionally, CA-MRSA strains express increased virulence factors leading to increased tissue destruction and more severe infections [4, 5]. A variety of genetic factors are suspected as a risk factor for recurrent CA-MRSA infection [4, 6, 7], with an increased prevalence in younger, healthier populations with no other identifiable risk factors [8]. …”

Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis

“…The resulting VEGAS2 genes from childhood pneumonia analysis with P , 0.01 were included in the network analysis using Metacore (see online supplement) (30)(31)(32).…”

The Foundation of Precision Medicine: Integration of Electronic Health Records with Genomics Through Basic, Clinical, and Translational Research

“…The papers of group 2 (Kullo et al, 2014a;Mitchell et al, 2014;Namjou et al, 2013;Parihar et al, 2014;Ye et al, 2014) describe different applications of the EHR derived phenotypes. The first paper (Namjou et al, 2013) investigated whether the common variants in the genes FTO, MC4R and TMEM18 associated with BMI in adults are also associated in pediatric population in the eMERGE network.…”

“…They replicated 12 of 21 previously identified lipid-associated SNPs demonstrating the validity of using phenotype data available from the EHR and the usefulness of the Metabochip array. The fifth paper (Ye et al, 2014) performed GWAS to identify genetic variants associated with diseases caused by Staphylococcus aureus infection. They used different approaches to identify the genetic susceptibility from single SNP, gene set and pathway.…”