Author
Affilliation
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.
Publisher
Nature Publishing Group
Citation
COLL, Francesc et al. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics, v. 50, p. 307-316, 2018.
DOI
10.1038/s41588-017-0029-0
ISSN
1061-4036
Notes
Bessa, Theolis Barbosa; Sousa, Erivelton Oliveira. Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil. 1Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. 2Pathogen Genomics Laboratory, BESE Division,
King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia. 3Sydney Emerging Infections and Biosecurity Institute and School of
Public Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. 4Laboratory Medicine Department, Faculty of Applied
Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia. 5Department of Microbiology, Faculty of Medicine, Umm Al-Qura University, Makkah,
Saudi Arabia. 6Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne,
Melbourne, Victoria, Australia. 7National Mycobacterium Reference Laboratory, Porto, Portugal. 8Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo
Cruz, Salvador, Brazil. 9Liverpool School of Tropical Medicine, Liverpool, UK. 10Pham Ngoc Thach Hospital for TB and Lung Diseases, Ho Chi Minh City,
Vietnam. 11Foundation for Medical Research, Mumbai, India. 12Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical
Medicine, London, UK. 13Karonga Prevention Study, Chilumba, Karonga, Malawi. 14Lung Infection and Immunity Unit, UCT Lung Institute, University of Cape
Town, Groote Schuur Hospital, Cape Town, South Africa. 15Laboratorio de Enfermedades Infecciosas, Laboratorios de Investigación y Desarrollo, Facultad
de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru. 16Department of Pathology and Laboratory Medicine, Aga Khan University,
Karachi, Pakistan. 17Department of Medical Microbiology, Makerere University College of Health Sciences, Kampala, Uganda. 18Section of Infectious
Diseases, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA, USA. 19Osaka Anti-Tuberculosis
Association, Osaka Hospital, Osaka, Japan. 20Reference Laboratory of Tuberculosis Control, Buenos Aires, Argentina. 21National Center of Infectious and
Parasitic Diseases, Sofia, Bulgaria. 22Wellcome Trust Sanger Institute, Hinxton, UK. 23Instituto Gulbenkian de Ciência, Lisbon, Portugal. 24iMed.ULisboa–
Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal. 25Corporación para Investigaciones Biológicas,
Universidad Pontificia Bolivariana, Medellín, Colombia. 26Regional Laboratory Directorate of Health Affairs, Makkah, Saudi Arabia. 27Division 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. 28Institute for Integrative Cell Biology, CEA, CNRS, Université Paris–Saclay,
Orsay, France. 29Laboratorio Central de Saúde Pública Professor Gonçalo Moniz, Salvador, Brazil. 30Unidade de Microbiologia Médica, Instituto de Higiene
e Medicina Tropical, Universidade Nova de Lisboa (UNL), Lisbon, Portugal. 31Global Station for Zoonosis Control, Global Institution for Collaborative
Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan. Francesc Coll and Jody Phelan contributed equally to this work. Ruth McNerney,
Arnab Pain and Taane G. Clark jointly directed this work.
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