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dc.contributor.authorFarhat, M.R.
dc.contributor.authorFreschi, L.
dc.contributor.authorCalderon, R.
dc.contributor.authorIoerger, T.
dc.contributor.authorSnyder, M.
dc.contributor.authorMeehan, Conor J.
dc.contributor.authorde Jong, B.C.
dc.contributor.authorRigouts, L.
dc.contributor.authorSloutsky, A.
dc.contributor.authorKaur, D.
dc.contributor.authorSunyaev, S.
dc.contributor.authorvan Soolingen, D.
dc.contributor.authorShendure, J.
dc.contributor.authorSacchettini, J.
dc.contributor.authorMurray, M.
dc.date.accessioned2019-09-16T21:28:44Z
dc.date.accessioned2019-09-30T15:19:45Z
dc.date.available2019-09-16T21:28:44Z
dc.date.available2019-09-30T15:19:45Z
dc.date.issued2019-05-13
dc.identifier.citationFarhat MR, Freschi L, Calderon R et al (2019) GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions. Nature Communications. 10(1): article 2128.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17274
dc.descriptionYesen_US
dc.description.abstractDrug 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.en_US
dc.description.sponsorshipBiomedical research grant from the American Lung Association (PI MF, RG-270912-N), a K01 award from the BD2K initiative (PI MF, ES026835), and an NIAID U19 CETR grant (P.I. M.M., AI109755), the Belgian Science Policy (Belspo) (L.R., C.J.M.).en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1038/s41467-019-10110-6en_US
dc.rights(c) 2019 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)en_US
dc.subjectAntimicrobial resistanceen_US
dc.subjectBacterial geneticsen_US
dc.subjectGenome-wide association studiesen_US
dc.subjectTuberculosisen_US
dc.titleGWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regionsen_US
dc.status.refereedYesen_US
dc.date.Accepted2019-04-18
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.date.updated2019-09-16T20:28:46Z
refterms.dateFOA2019-09-30T15:20:11Z


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