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dc.contributor.authorColl, Francesc
dc.contributor.authorPhelan, Jody
dc.contributor.authorHill-Cawthorne, Grant A.
dc.contributor.authorNair, Mridul
dc.contributor.authorMallard, Kim
dc.contributor.authorAli, Shahjahan
dc.contributor.authorAbdallah, Abdallah
dc.contributor.authorAlghamdi, Saad
dc.contributor.authorAlsomali, Mona
dc.contributor.authorAhmed, Abdallah O.
dc.contributor.authorPortelli, Stephanie
dc.contributor.authorOppong, Yaa
dc.contributor.authorAlves, Adriana
dc.contributor.authorBessa, Theolis Barbosa
dc.contributor.authorCampino, Susana
dc.contributor.authorCaws, Maxine
dc.contributor.authorChatterjee, Anirvan
dc.contributor.authorCrampin, Amelia C.
dc.contributor.authorDheda, Keertan
dc.contributor.authorFurnham, Nicholas
dc.contributor.authorGlynn, Judith R.
dc.contributor.authorGrandjean, Louis
dc.contributor.authorMinh Ha, Dang
dc.contributor.authorHasan, Rumina
dc.contributor.authorHasan, Zahra
dc.contributor.authorHibberd, Martin L.
dc.contributor.authorJoloba, Moses
dc.contributor.authorJones-López, Edward C.
dc.contributor.authorMatsumoto, Tomoshige
dc.contributor.authorMiranda, Anabela
dc.contributor.authorMoore, David J.
dc.contributor.authorMocillo, Nora
dc.contributor.authorPanaiotov, Stefan
dc.contributor.authorParkhill, Julian
dc.contributor.authorPenha, Carlos
dc.contributor.authorPerdigão, João
dc.contributor.authorPortugal, Isabel
dc.contributor.authorRchiad, ‍Zineb
dc.contributor.authorRobledo, Jaime
dc.contributor.authorSheen, Patricia
dc.contributor.authorShesha, Nashwa Talaat
dc.contributor.authorSirgel, Frik A.
dc.contributor.authorSola, Christophe
dc.contributor.authorOliveira Sousa, Erivelton
dc.contributor.authorStreicher, Elizabeth M.
dc.contributor.authorHelden, Paul Van
dc.contributor.authorViveiros, Miguel
dc.contributor.authorWarren, Robert M.
dc.contributor.authorMcNerney, Ruth
dc.contributor.authorPain, Arnab
dc.contributor.authorClark, Taane G.
dc.date.accessioned2018-03-11T06:54:12Z
dc.date.available2018-03-11T06:54:12Z
dc.date.issued2018-01-22
dc.identifier.citationColl F, Phelan J, Hill-Cawthorne GA, Nair MB, Mallard K, et al. (2018) Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics 50: 307–316. Available: http://dx.doi.org/10.1038/s41588-017-0029-0.
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.pmid29358649
dc.identifier.doi10.1038/s41588-017-0029-0
dc.identifier.urihttp://hdl.handle.net/10754/627255
dc.description.abstractTo 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.
dc.description.sponsorshipThe 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).
dc.publisherSpringer Nature
dc.relation.urlhttps://www.nature.com/articles/s41588-017-0029-0
dc.titleGenome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Core Lab
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.contributor.departmentNGS, qPCR and Single Cell Genomics
dc.contributor.departmentPathogen Genomics Laboratory
dc.identifier.journalNature Genetics
dc.contributor.institutionFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, , United Kingdom
dc.contributor.institutionSydney Emerging Infections and Biosecurity Institute and School of Public Health, Sydney Medical School, University of Sydney, Sydney, NSW, , , Australia
dc.contributor.institutionLaboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, , Saudi Arabia
dc.contributor.institutionDepartment of Microbiology, Faculty of Medicine, Umm Al-Qura University, Makkah, , Saudi Arabia
dc.contributor.institutionDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, , , Australia
dc.contributor.institutionNational Mycobacterium Reference Laboratory, Porto, , Portugal
dc.contributor.institutionCentro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, , Brazil
dc.contributor.institutionPham Ngoc Thach Hospital for TB and Lung Diseases, Ho Chi Minh City, , Viet Nam
dc.contributor.institutionLiverpool School of Tropical Medicine, Liverpool, , United Kingdom
dc.contributor.institutionFoundation for Medical Research, Mumbai, , India
dc.contributor.institutionKaronga Prevention Study, Chilumba, Karonga, , Malawi
dc.contributor.institutionFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, , United Kingdom
dc.contributor.institutionLung Infection and Immunity Unit, UCT Lung Institute, University of Cape Town, Groote Schuur Hospital, Cape Town, , , South Africa
dc.contributor.institutionLaboratorio de Enfermedades Infecciosas, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, , Peru
dc.contributor.institutionDepartment of Pathology and Laboratory Medicine, Aga Khan University, Karachi, , Pakistan
dc.contributor.institutionDepartment of Medical Microbiology, Makerere University College of Health Sciences, Kampala, , Uganda
dc.contributor.institutionSection of Infectious Diseases, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA, , United States
dc.contributor.institutionOsaka Anti-Tuberculosis Association, Osaka Hospital, Osaka, , Japan
dc.contributor.institutionReference Laboratory of Tuberculosis Control, Buenos Aires, , Argentina
dc.contributor.institutionNational Center of Infectious and Parasitic Diseases, Sofia, , Bulgaria
dc.contributor.institutionWellcome Trust Sanger Institute, Hinxton, , United Kingdom
dc.contributor.institutionInstituto Gulbenkian de Ciência, Lisbon, , Portugal
dc.contributor.institutioniMed.ULisboa–Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, , , Portugal
dc.contributor.institutionCorporación para Investigaciones Biológicas, Universidad Pontificia Bolivariana, Medellín, , , Colombia
dc.contributor.institutionRegional Laboratory Directorate of Health Affairs, Makkah, , Saudi Arabia
dc.contributor.institutionDivision of Molecular Biology and Human Genetics, SAMRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, , South Africa
dc.contributor.institutionInstitute for Integrative Cell Biology, CEA, CNRS, Université Paris–Saclay, Orsay, , , France
dc.contributor.institutionLaboratorio Central de Saúde Pública Professor Gonçalo Moniz, Salvador, , Brazil
dc.contributor.institutionUnidade de Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (UNL), Lisbon, , , Portugal
dc.contributor.institutionGlobal Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, , Japan
kaust.personHill-Cawthorne, Grant A.
kaust.personNair, Mridul
kaust.personAli, Shahjahan
kaust.personAbdallah, Abdallah
kaust.personAlsomali, Mona Ismael Ibrahim
kaust.personRchiad, ‍Zineb
kaust.personPain, Arnab
kaust.grant.numberBAS/1/1020-01-01
refterms.dateFOA2020-06-29T13:45:06Z
dc.date.published-online2018-01-22
dc.date.published-print2018-02


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