GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions.
Antitubercular Agents
/ pharmacology
DNA Mutational Analysis
Drug Resistance, Multiple, Bacterial
/ genetics
Genetic Loci
/ genetics
Genome, Bacterial
/ genetics
Genome-Wide Association Study
Humans
Microbial Sensitivity Tests
Mutation
Mycobacterium tuberculosis
/ drug effects
Promoter Regions, Genetic
/ genetics
Sputum
/ microbiology
Tuberculosis, Multidrug-Resistant
/ drug therapy
Whole Genome Sequencing
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
16
10
2018
accepted:
18
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
14
6
2019
Statut:
epublish
Résumé
Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.
Identifiants
pubmed: 31086182
doi: 10.1038/s41467-019-10110-6
pii: 10.1038/s41467-019-10110-6
pmc: PMC6513847
doi:
Substances chimiques
Antitubercular Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2128Subventions
Organisme : NIEHS NIH HHS
ID : K01 ES026835
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI109755
Pays : United States
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