Massachusetts Supranational TB Reference Laboratory; New England Newborn Screening Program; Department of Medicine
Bacteria | Bacterial Infections and Mycoses | Genetic Phenomena | Immunology and Infectious Disease | Microbiology
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.
Genome-wide association studies, Antimicrobial resistance, Bacterial genetics, Tuberculosis
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DOI of Published Version
Nat Commun. 2019 May 13;10(1):2128. doi: 10.1038/s41467-019-10110-6. Link to article on publisher's site
Farhat, Maha R.; Freschi, Luca; Calderon, Roger; Ioerger, Thomas; Snyder, Matthew; Meehan, Conor J.; de Jong, Bouke; Rigouts, Leen; Sloutsky, Alexander; Kaur, Devinder; Sunyaev, Shamil; van Soolingen, Dick; Shendure, Jay; Sacchettini, Jim; and Murray, Megan, "GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions" (2019). Open Access Articles. 3857.
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This work is licensed under a Creative Commons Attribution 4.0 License.