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dc.contributor.authorAgrawal, Neha
dc.contributor.authorLawler, Katherine
dc.contributor.authorDavidson, Catherine
dc.contributor.authorKeogh, Julia M
dc.contributor.authorLegg, Robert
dc.contributor.authorINTERVAL
dc.contributor.authorBarroso, Ines
dc.contributor.authorFarooqi, Ismaa
dc.contributor.authorBrand, Andrea
dc.date.accessioned2022-01-07T16:47:39Z
dc.date.available2022-01-07T16:47:39Z
dc.date.issued2021-11
dc.identifier.issn1544-9173
dc.identifier.otherPMC8575313
dc.identifier.other34748544
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332338
dc.descriptionFunder: NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust
dc.descriptionFunder: NHS National Institute for Health Research Clinical Research Network
dc.descriptionFunder: Royal Society Darwin Trust Research Professorship
dc.descriptionFunder: NIHR Senior Investigator Award
dc.descriptionFunder: Health Data Research UK
dc.descriptionFunder: Higher Education Funding Council for England Catalyst
dc.descriptionFunder: NIHR Cambridge Biomedical Research Centre
dc.descriptionFunder: Bernard Wolfe Health Neuroscience Endowment
dc.descriptionFunder: The Botnar Fondation
dc.description.abstractThe discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1545-7885
dc.sourcenlmid: 101183755
dc.subjectAnimals
dc.subjectHumans
dc.subjectDrosophila melanogaster
dc.subjectObesity
dc.subjectDrosophila Proteins
dc.subjectCase-Control Studies
dc.subjectPedigree
dc.subjectAge of Onset
dc.subjectSignal Transduction
dc.subjectHomozygote
dc.subjectMutation
dc.subjectFemale
dc.subjectMale
dc.subjectGenetic Testing
dc.subjectGenetic Association Studies
dc.titlePredicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
dc.typeArticle
dc.date.updated2022-01-07T16:47:38Z
prism.issueIdentifier11
prism.publicationNamePLoS Biol
prism.volume19
dc.identifier.doi10.17863/CAM.79784
dcterms.dateAccepted2021-09-29
rioxxterms.versionofrecord10.1371/journal.pbio.3001255
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidAgrawal, Neha [0000-0002-3916-5844]
dc.contributor.orcidDavidson, Catherine [0000-0002-4784-1398]
dc.contributor.orcidLegg, Robert [0000-0002-7237-4744]
dc.contributor.orcidBarroso, Ines [0000-0001-5800-4520]
dc.contributor.orcidFarooqi, Ismaa [0000-0001-7609-3504]
dc.contributor.orcidBrand, Andrea [0000-0002-2089-6954]
dc.identifier.eissn1545-7885
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idMedical Research Council (MR/L003120/1)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idWellcome Trust (103792/Z/14/Z)
pubs.funder-project-idWellcome Trust (207462/Z/17/Z)
pubs.funder-project-idWellcome Trust (208363/Z/17/Z)
pubs.funder-project-idBritish Heart Foundation (RG/18/13/33946)
cam.issuedOnline2021-11-08


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International