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

Francesc Coll, Jody Phelan, Grant A Hill-Cawthorne, Mridul B Nair, Kim Mallard, Shahjahan Ali, Abdallah M Abdallah, Saad Alghamdi, Mona Alsomali, Abdallah O Ahmed, Stephanie Portelli, Yaa Oppong, Adriana Alves, Theolis Barbosa Bessa, Susana Campino, Maxine Caws, Anirvan Chatterjee, Amelia C Crampin, Keertan Dheda, Nicholas FurnhamJudith R Glynn, Louis Grandjean, Dang Minh Ha, Rumina Hasan, Zahra Hasan, Martin L Hibberd, Moses Joloba, Edward C Jones-López, Tomoshige Matsumoto, Anabela Miranda, David J Moore, Nora Mocillo, Stefan Panaiotov, Julian Parkhill, Carlos Penha, João Perdigão, Isabel Portugal, Zineb Rchiad, Jaime Robledo, Patricia Sheen, Nashwa Talaat Shesha, Frik A Sirgel, Christophe Sola, Erivelton Oliveira Sousa, Elizabeth M Streicher, Paul Van Helden, Miguel Viveiros, Robert M Warren, Ruth McNerney, Arnab Pain, Taane G Clark

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78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)307-316
Number of pages10
JournalNature Genetics
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 2018

Keywords

  • Journal Article

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    Coll, F., Phelan, J., Hill-Cawthorne, G. A., Nair, M. B., Mallard, K., Ali, S., ... Clark, T. G. (2018). Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics, 50(2), 307-316. https://doi.org/10.1038/s41588-017-0029-0