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Genome wide association studies define minimal set of loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae

View ORCID ProfileTatum D. Mortimer, Jessica J. Zhang, View ORCID ProfileKevin C. Ma, View ORCID ProfileYonatan H. Grad
doi: https://doi.org/10.1101/2021.08.03.454909
Tatum D. Mortimer
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Jessica J. Zhang
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Kevin C. Ma
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Yonatan H. Grad
1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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ABSTRACT

Background While Neisseria gonorrhoeae poses an urgent public health threat because of increasing antimicrobial resistance, much of the circulating population remains susceptible to historical treatment regimens. Point-of-care diagnostics that report susceptibility could allow for reintroduction of these regimens, but development of such diagnostics has been limited to ciprofloxacin, for which susceptibility can be predicted from a single locus.

Methods We assembled a dataset of 12,045 N. gonorrhoeae genomes with phenotypic resistance data for tetracycline (n = 3,611) and penicillin (n = 6,935). Using conditional genome wide association studies (GWAS), we sought to define genetic variants associated with susceptibility to penicillin and tetracycline. We evaluated the sensitivity and specificity of these variants for predicting susceptibility and non-resistance in our collection of gonococcal genomes.

Findings In our conditional penicillin GWAS, the presence of a genetic variant defined by a non-mosaic penA allele without an insertion at codon 345 was significantly associated with penicillin susceptibility and had the highest negative effect size of significant variants (p = 5.0 x 10-14, β = -2.5). In combination with the absence of blaTEM, this variant predicted penicillin susceptibility with high specificity (99.8%) and moderate sensitivity (36.7%). For tetracycline, the wild type allele at rpsJ codon 57, encoding valine, was significantly associated with tetracycline susceptibility (p = 5.6 x 10-16, β = -1.61) after conditioning on the presence of tetM. The combination of rpsJ codon 57 allele and tetM absence predicted tetracycline susceptibility with high specificity (97.2%) and sensitivity (88.7%).

Interpretation As few as two genetic loci can predict susceptibility to penicillin and tetracycline in N. gonorrhoeae with high specificity. Molecular point-of-care diagnostics targeting these loci have the potential to increase available treatments for gonorrhea.

Funding National Institute of Allergy and Infectious Diseases, the National Science Foundation, and the Smith Family Foundation

Competing Interest Statement

YHG is on the scientific advisory board of Day Zero Diagnostics, has consulted for Quidel and GSK, and has received grant funding from Merck, Pfizer, and GSK.

Footnotes

  • https://github.com/gradlab/pcn_tet_susceptibility_gwas

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 03, 2021.
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Genome wide association studies define minimal set of loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae
Tatum D. Mortimer, Jessica J. Zhang, Kevin C. Ma, Yonatan H. Grad
bioRxiv 2021.08.03.454909; doi: https://doi.org/10.1101/2021.08.03.454909
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Genome wide association studies define minimal set of loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae
Tatum D. Mortimer, Jessica J. Zhang, Kevin C. Ma, Yonatan H. Grad
bioRxiv 2021.08.03.454909; doi: https://doi.org/10.1101/2021.08.03.454909

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