Jun 27, 2014

Increased power from bacterial genome-wide association conditional on known effects identifies Neisseria gonorrhoeae macrolide resistance mutations in the 50S ribosomal protein L4

BioRxiv : the Preprint Server for Biology
Christopher John MungallYonatan H Grad

Abstract

The emergence of resistance to azithromycin complicates treatment of N. gonorrhoeae , the etiologic agent of gonorrhea. Population genomic analyses of clinical isolates have demonstrated that some azithromycin resistance remains unexplained after accounting for the contributions of known resistance mutations in the 23S rRNA and the MtrCDE efflux pump. Bacterial genome-wide association studies (GWAS) offer a promising approach for identifying novel resistance genes but must adequately address the challenge of controlling for genetic confounders while maintaining power to detect variants with lower effect sizes. Compared to a standard univariate GWAS, conducting GWAS conditioned on known resistance mutations with high effect sizes substantially reduced the number of variants that reached genome-wide significance and identified a G70D mutation in the 50S ribosomal protein L4 (encoded by the gene rplD ) as significantly associated with increased azithromycin minimum inhibitory concentrations (β = 1.03, 95% CI [0.76, 1.30]). The role and prevalence of these rplD mutations in conferring macrolide resistance in N. gonorrhoeae had been unclear. Here, we experimentally confirmed our GWAS results, identified other resistance-associated m...Continue Reading

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Mentioned in this Paper

Genome
Mathematical Formula
Genomics
Core
Gene Ontology
Validation
Decision for Surgery
EQQ _ Embedded Query Language Query

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