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Journal Articles Nature Genetics Year : 2018

Genome-wide analysis of multi- and extensively drug-resistant $Mycobacterium\ tuberculosis$

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Shahjahan Ali
  • Function : Author
Theolis Barbosa Bessa
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Maxine Caws
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Anirvan Chatterjee
  • Function : Author
Amelia Crampin
  • Function : Author
Keertan Dheda
  • Function : Author
Judith Glynn
  • Function : Author
Dang Minh Ha
  • Function : Author
Rumina Hasan
  • Function : Author
Zahra Hasan
  • Function : Author
Edward Jones-López
  • Function : Author
Anabela Miranda
  • Function : Author
Nora Mocillo
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Carlos Penha
  • Function : Author
João Perdigão
  • Function : Author
Jaime Robledo
  • Function : Author
  • PersonId : 957696
Nashwa Talaat Shesha
  • Function : Author
Frik Sirgel
  • Function : Author
Christophe Sola
  • Function : Author
Erivelton Oliveira Sousa
  • Function : Author
Elizabeth Streicher
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Paul Van Helden
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Robert Warren
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Abstract

To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 $Mycobacterium\ tuberculosis$ clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps ($drrA$ and $Rv2688c$) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

Dates and versions

cea-01882216 , version 1 (26-09-2018)

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Cite

Francesc Coll, Jody Phelan, Grant Hill-Cawthorne, Mridul Nair, Kim Mallard, et al.. Genome-wide analysis of multi- and extensively drug-resistant $Mycobacterium\ tuberculosis$. Nature Genetics, 2018, 50, pp.307 - 316. ⟨10.1038/s41588-017-0029-0⟩. ⟨cea-01882216⟩

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