An Exome Wide Genotyping Study using SNP-, Gene-, and Pathway-Based Approaches to Identify Genes Influencing Susceptibility to Staphylococcus aureus Infections
Matthew P. Schield1, Zhan (Harold) Ye2, Steven J. Schrodi1, Sanjay K. Shukla1
1Center for Human Genetics, 2Biomedical Informatics Research Center
Research area: Genetics
Background: S. aureus is a leading cause of invasive bacterial infections, and is a major source of mortality and morbidity around the world. Approximately 30-50% of the general population is colonized by this bacterium, however, only a small percentage will acquire a medically-attended infection. In this genomic association study, we tested variants across the exome within a cohort of 4572 individuals in Marshfield Clinic’s Personalized Medicine Research Project to identify inherited factors that could lead to susceptibility of S. aureus infections.
Methods: A case-control design was used in the study. Cases (n = 821) were individuals with microbiology laboratory confirmed S. aureus infections, and controls (n = 3751) were individuals with no history of S. aureus infections in their Electronic Medical Record at Marshfield Clinic. Cases and controls were genotyped at 370,031 single nucleotide polymorphisms (SNPs). SNP-, gene- and pathway-based analyses were done using PLINK, VEGAS2, and PANTHER, respectively.
Results: There were no SNPs that reached genome wide significance (p < 5x10-8), however, many SNPs exceeded suggestive significance of p < 10-5. Of these SNPs, 16 are biologically significant in S. aureus infections. From the gene-based analyses, 20 candidate genes were identified that are associated with S. aureus infection. Pathway analysis identified T-cell signaling, cytokine signaling, and evasion of host defenses enriched from the top 50 genes ranked by p-values.
Conclusions: Many candidate SNPs, genes, and pathways were identified that could predispose individuals to S. aureus infections. The findings support earlier conclusions that S. aureus is a complex pathogen. Replication and functional studies are needed for the SNPs and genes identified in this study to find their role in the many infection pathways used by Staphylococcus aureus.