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

Francesc Coll; Jody Phelan; Grant A. Hill-Cawthorne; Mridul Nair; Kim Mallard; Shahjahan Ali; Abdallah 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; 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

doi:10.1038/s41588-017-0029-0

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

Francesc Coll, Jody Phelan, Grant A. Hill-Cawthorne, Mridul Nair, Kim Mallard, Shahjahan Ali, Abdallah 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

Research output: Contribution to journal › Article › peer-review

235 Scopus citations

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 language	English (US)
Pages (from-to)	307-316
Number of pages	10
Journal	Nature Genetics
Volume	50
Issue number	2
DOIs	https://doi.org/10.1038/s41588-017-0029-0
State	Published - Jan 22 2018

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https://repository.kaust.edu.sa/bitstream/10754/627255/1/Coll_Phelan_et_al_NG_2018_manuscript.pdf

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Coll, F., Phelan, J., Hill-Cawthorne, G. A., Nair, M., Mallard, K., Ali, S., Abdallah, A., Alghamdi, S., Alsomali, M., Ahmed, A. O., Portelli, S., Oppong, Y., Alves, A., Bessa, T. B., Campino, S., Caws, M., Chatterjee, A., Crampin, A. C., Dheda, K., ... 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

@article{5d1a191c060140af81784f1af9e3121b,

title = "Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis",

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.",

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

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: The project was supported by the KAUST faculty baseline research fund (BAS/1/1020-01-01) to A.P. The authors wish to thank members of the KAUST Bioscience Core laboratory who sequenced samples. We thank the Wellcome Trust Sanger Institute core and pathogen sequencing and informatics teams who were involved in the Malawi and Uganda studies. The work was funded in part by the Wellcome Trust (grant numbers WT096249/Z/11/B, WT088559MA, WT081814/Z/06/Z and WT098051) and the Wellcome Trust–Burroughs Wellcome Fund Infectious Diseases Initiative grant (number 063410/ABC/00/Z). F.C. was the recipient of a Bloomsbury College PhD Studentship and was supported by the Wellcome Trust (201344/Z/16/Z); J. Perdig{\~a}o received a Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia (Portugal) postdoctoral fellowship fund (SFRH/BPD/95406/2013). The Calouste Gulbenkian Foundation, the Institute Gulbenkian in Lisbon and the European Society of Clinical Microbiology and Infectious Diseases supported the research of C.P., J. Perdig{\~a}o, I.P. and M.V. J. Phelan is funded by a BBSRC PhD studentship. T.G.C. is funded by the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1 and MC_PC_15103). N.F. is funded by the Medical Research Council UK (grant number MR/K020420/1). T.M. is supported by the Ministry of Health, Labor and Welfare of Japan (H21-Shinkou-Ippan-008 and H24-Shinkou-Ippan-010). We thank N. Mistry (Foundation for Medical Research, Mumbai) for contributing Mtb archived strains and drug sensitivity testing data. We wish to thank G. Moniz at the Laboratorio Central de Sa{\'u}de P{\'u}blica for supporting the collection of samples in Brazil and the South African National Health Laboratory Service for their contribution providing access to clinical Mtb isolates. The MRC eMedLab computing resource was used for bioinformatics and statistical analysis. The authors declare no conflicts of interest. The work has been performed as part of the TB Global Drug Resistance Collaboration (see URLs).",

year = "2018",

month = jan,

day = "22",

doi = "10.1038/s41588-017-0029-0",

language = "English (US)",

volume = "50",

pages = "307--316",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

Coll, F, Phelan, J, Hill-Cawthorne, GA, Nair, M, Mallard, K, Ali, S, Abdallah, A, 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

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

AU - Mallard, Kim

AU - Ali, Shahjahan

AU - Abdallah, Abdallah

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.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: The project was supported by the KAUST faculty baseline research fund (BAS/1/1020-01-01) to A.P. The authors wish to thank members of the KAUST Bioscience Core laboratory who sequenced samples. We thank the Wellcome Trust Sanger Institute core and pathogen sequencing and informatics teams who were involved in the Malawi and Uganda studies. The work was funded in part by the Wellcome Trust (grant numbers WT096249/Z/11/B, WT088559MA, WT081814/Z/06/Z and WT098051) and the Wellcome Trust–Burroughs Wellcome Fund Infectious Diseases Initiative grant (number 063410/ABC/00/Z). F.C. was the recipient of a Bloomsbury College PhD Studentship and was supported by the Wellcome Trust (201344/Z/16/Z); J. Perdigão received a Fundação para a Ciência e a Tecnologia (Portugal) postdoctoral fellowship fund (SFRH/BPD/95406/2013). The Calouste Gulbenkian Foundation, the Institute Gulbenkian in Lisbon and the European Society of Clinical Microbiology and Infectious Diseases supported the research of C.P., J. Perdigão, I.P. and M.V. J. Phelan is funded by a BBSRC PhD studentship. T.G.C. is funded by the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1 and MC_PC_15103). N.F. is funded by the Medical Research Council UK (grant number MR/K020420/1). T.M. is supported by the Ministry of Health, Labor and Welfare of Japan (H21-Shinkou-Ippan-008 and H24-Shinkou-Ippan-010). We thank N. Mistry (Foundation for Medical Research, Mumbai) for contributing Mtb archived strains and drug sensitivity testing data. We wish to thank G. Moniz at the Laboratorio Central de Saúde Pública for supporting the collection of samples in Brazil and the South African National Health Laboratory Service for their contribution providing access to clinical Mtb isolates. The MRC eMedLab computing resource was used for bioinformatics and statistical analysis. The authors declare no conflicts of interest. The work has been performed as part of the TB Global Drug Resistance Collaboration (see URLs).

PY - 2018/1/22

Y1 - 2018/1/22

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.

UR - http://hdl.handle.net/10754/627255

UR - https://www.nature.com/articles/s41588-017-0029-0

UR - http://www.scopus.com/inward/record.url?scp=85040763196&partnerID=8YFLogxK

U2 - 10.1038/s41588-017-0029-0

DO - 10.1038/s41588-017-0029-0

M3 - Article

C2 - 29358649

SN - 1061-4036

VL - 50

SP - 307

EP - 316

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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