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 Furnham & 31 others Judith 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

Research output: Contribution to journalArticle

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

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Extensively Drug-Resistant Tuberculosis
Mycobacterium tuberculosis
Genome
Mutation
Ethionamide
Aminosalicylic Acid
Cycloserine
Genome-Wide Association Study
Capreomycin
Genes
Pyrazinamide
Routine Diagnostic Tests
Drug Resistance
Odds Ratio
Pharmaceutical Preparations

Keywords

  • Journal Article

Cite this

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
Coll, Francesc ; Phelan, Jody ; Hill-Cawthorne, Grant A ; Nair, Mridul B ; Mallard, Kim ; Ali, Shahjahan ; Abdallah, Abdallah M ; Alghamdi, Saad ; Alsomali, Mona ; Ahmed, Abdallah O ; Portelli, Stephanie ; Oppong, Yaa ; Alves, Adriana ; Bessa, Theolis Barbosa ; Campino, Susana ; Caws, Maxine ; Chatterjee, Anirvan ; Crampin, Amelia C ; Dheda, Keertan ; Furnham, Nicholas ; Glynn, Judith R ; Grandjean, Louis ; Minh Ha, Dang ; Hasan, Rumina ; Hasan, Zahra ; Hibberd, Martin L ; Joloba, Moses ; Jones-López, Edward C ; Matsumoto, Tomoshige ; Miranda, Anabela ; Moore, David J ; Mocillo, Nora ; Panaiotov, Stefan ; Parkhill, Julian ; Penha, Carlos ; Perdigão, João ; Portugal, Isabel ; Rchiad, Zineb ; Robledo, Jaime ; Sheen, Patricia ; Shesha, Nashwa Talaat ; Sirgel, Frik A ; Sola, Christophe ; Oliveira Sousa, Erivelton ; Streicher, Elizabeth M ; Helden, Paul Van ; Viveiros, Miguel ; Warren, Robert M ; McNerney, Ruth ; Pain, Arnab ; Clark, Taane G. / Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. In: Nature Genetics. 2018 ; Vol. 50, No. 2. pp. 307-316.
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Coll, F, Phelan, J, Hill-Cawthorne, GA, Nair, MB, Mallard, K, Ali, S, Abdallah, AM, Alghamdi, S, Alsomali, M, Ahmed, AO, Portelli, S, Oppong, Y, Alves, A, Bessa, TB, Campino, S, Caws, M, Chatterjee, A, Crampin, AC, Dheda, K, Furnham, N, Glynn, JR, Grandjean, L, Minh Ha, D, Hasan, R, Hasan, Z, Hibberd, ML, Joloba, M, Jones-López, EC, Matsumoto, T, Miranda, A, Moore, DJ, Mocillo, N, Panaiotov, S, Parkhill, J, Penha, C, Perdigão, J, Portugal, I, Rchiad, Z, Robledo, J, Sheen, P, Shesha, NT, Sirgel, FA, Sola, C, Oliveira Sousa, E, Streicher, EM, Helden, PV, Viveiros, M, Warren, RM, McNerney, R, Pain, A & Clark, TG 2018, 'Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis', Nature Genetics, vol. 50, no. 2, pp. 307-316. https://doi.org/10.1038/s41588-017-0029-0

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

In: Nature Genetics, Vol. 50, No. 2, 02.2018, p. 307-316.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

AU - Coll, Francesc

AU - Phelan, Jody

AU - Hill-Cawthorne, Grant A

AU - Nair, Mridul B

AU - Mallard, Kim

AU - Ali, Shahjahan

AU - Abdallah, Abdallah M

AU - Alghamdi, Saad

AU - Alsomali, Mona

AU - Ahmed, Abdallah O

AU - Portelli, Stephanie

AU - Oppong, Yaa

AU - Alves, Adriana

AU - Bessa, Theolis Barbosa

AU - Campino, Susana

AU - Caws, Maxine

AU - Chatterjee, Anirvan

AU - Crampin, Amelia C

AU - Dheda, Keertan

AU - Furnham, Nicholas

AU - Glynn, Judith R

AU - Grandjean, Louis

AU - Minh Ha, Dang

AU - Hasan, Rumina

AU - Hasan, Zahra

AU - Hibberd, Martin L

AU - Joloba, Moses

AU - Jones-López, Edward C

AU - Matsumoto, Tomoshige

AU - Miranda, Anabela

AU - Moore, David J

AU - Mocillo, Nora

AU - Panaiotov, Stefan

AU - Parkhill, Julian

AU - Penha, Carlos

AU - Perdigão, João

AU - Portugal, Isabel

AU - Rchiad, Zineb

AU - Robledo, Jaime

AU - Sheen, Patricia

AU - Shesha, Nashwa Talaat

AU - Sirgel, Frik A

AU - Sola, Christophe

AU - Oliveira Sousa, Erivelton

AU - Streicher, Elizabeth M

AU - Helden, Paul Van

AU - Viveiros, Miguel

AU - Warren, Robert M

AU - McNerney, Ruth

AU - Pain, Arnab

AU - Clark, Taane G

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

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DO - 10.1038/s41588-017-0029-0

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JO - Nature Genetics

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Coll F, Phelan J, Hill-Cawthorne GA, Nair MB, Mallard K, Ali S et al. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics. 2018 Feb;50(2):307-316. https://doi.org/10.1038/s41588-017-0029-0