Genome-wide analysis of multi- and extensively drug-resistant $Mycobacterium\ tuberculosis$
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Shahjahan Ali
- Function : Author
Theolis Barbosa Bessa
- Function : Author
Maxine Caws
- Function : Author
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
- Function : Author
Carlos Penha
- Function : Author
João Perdigão
- Function : Author
Nashwa Talaat Shesha
- Function : Author
Frik Sirgel
- Function : Author
Christophe Sola
- Function : Author
Erivelton Oliveira Sousa
- Function : Author
Elizabeth Streicher
- Function : Author
Paul Van Helden
- Function : Author
Robert Warren
- Function : Author
Arnab Pain
- Function : Author
- PersonId : 777756
- ORCID : 0000-0002-1755-2819
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.