Antimicrobial resistance determinants are associated with Staphylococcus aureus bacteraemia and adaptation to the healthcare environment: a bacterial genome-wide association study

is a major bacterial pathogen in humans, and a dominant cause of severe bloodstream infections. Globally, antimicrobial resistance (AMR) in remains challenging. While human risk factors for infection have been defined, contradictory evidence exists for the role of bacterial genomic variation in disease. To investigate the contribution of bacterial lineage and genomic variation to the development of bloodstream infection, we undertook a genome-wide association study comparing bacteria from 1017 individuals with bacteraemia to 984 adults with asymptomatic nasal carriage. Within 984 carriage isolates, we also compared healthcare-associated (HA) carriage with community-associated (CA) carriage. All major global lineages were represented in both bacteraemia and carriage, with no evidence for different infection rates. However, kmers tagging trimethoprim resistance-conferring mutation F99Y in were significantly associated with bacteraemia-vs-carriage ( 10 -10 ). Pooling variation within genes, bacteraemia-vs-carriage was associated with the presence of (HMP=10 ) as well as the presence of SCCmec (HMP=10 ). Among carriers, no lineages were associated with HA-vs-CA carriage. However, we found a novel signal of HA-vs-CA carriage in the foldase protein , where kmers representing conserved sequence allele were associated with CA carriage ( 10 -10 ), while in , a ciprofloxacin resistance-conferring mutation, L84S, was associated with HA carriage ( 10 ). In an extensive study of bacteraemia and nasal carriage in the UK, we found strong evidence that all lineages are equally capable of causing bloodstream infection, and of being carried in the healthcare environment. Genomic variation in the foldase protein is a novel genomic marker of healthcare origin in but was not associated with bacteraemia. AMR determinants were associated with both bacteraemia and healthcare-associated carriage, suggesting that AMR increases the propensity not only to survive in healthcare environments, but also to cause invasive disease.