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dc.contributor.authorAsimit, Jenniferen
dc.contributor.authorRainbow, Daniel Ben
dc.contributor.authorFortune, Maryen
dc.contributor.authorGrinberg, Nastasiyaen
dc.contributor.authorWicker, Linda Sen
dc.contributor.authorWallace, Chrisen
dc.date.accessioned2019-07-17T23:30:13Z
dc.date.available2019-07-17T23:30:13Z
dc.date.issued2019-07-19en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/294722
dc.description.abstractThousands of genetic variants are associated with human disease risk, but linkage disequilibrium (LD) hinders fine-mapping the causal variants. Both lack of power, and joint tagging of two or more distinct causal variants by a single non-causal SNP, lead to inaccuracies in fine-mapping, with stochastic search more robust than stepwise. We develop a computationally efficient multinomial fine-mapping (MFM) approach that borrows information between diseases in a Bayesian framework. We show that MFM has greater accuracy than single disease analysis when shared causal variants exist, and negligible loss of precision otherwise. MFM analysis of six immune mediated diseases reveals causal variants undetected in individual disease analysis, including in IL2RA where we confirm functional effects of multiple causal variants using allele-specific expression in sorted CD4+ T cells from genotype-selected individuals. MFM has the potential to increase fine-mapping resolution in related diseases enabling the identification of associated cellular and molecular phenotypes.
dc.description.sponsorshipThis work was supported by the MRC (MC UU 00002/4, MR/R021368/1), the Wellcome Trust (096388, 099772, 107212, 107881), the JDRF (9-2011-253 and 5-SRA-2015-130-A-N), the National Institute for Health Research Cambridge Biomedical Research Centre (BRC), and Dementia Platforms UK.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAll rights reserved
dc.rightsAttribution 4.0 International
dc.rights.uri
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCD4-Positive T-Lymphocytesen
dc.subjectHumansen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectBayes Theoremen
dc.subjectChromosome Mappingen
dc.subjectAutoimmunityen
dc.subjectGene Expression Regulationen
dc.subjectGenotypeen
dc.subjectLinkage Disequilibriumen
dc.subjectPhenotypeen
dc.subjectPolymorphism, Single Nucleotideen
dc.subjectAllelesen
dc.subjectModels, Geneticen
dc.subjectInterleukin-2 Receptor alpha Subuniten
dc.subjectGenome-Wide Association Studyen
dc.subjectGenetic Association Studiesen
dc.subjectCTLA-4 Antigenen
dc.titleStochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameNature communicationsen
prism.startingPage3216
prism.volume10en
dc.identifier.doi10.17863/CAM.41825
dcterms.dateAccepted2019-07-02en
rioxxterms.versionofrecord10.1038/s41467-019-11271-0en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-07-19en
dc.contributor.orcidAsimit, Jennifer [0000-0002-4857-2249]
dc.contributor.orcidRainbow, Daniel B [0000-0003-4931-3289]
dc.contributor.orcidFortune, Mary [0000-0002-6006-4343]
dc.contributor.orcidGrinberg, Nastasya [0000-0002-2727-5130]
dc.contributor.orcidWicker, Linda S [0000-0001-7771-0324]
dc.contributor.orcidWallace, Catriona [0000-0001-9755-1703]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (107881/Z/15/Z)
pubs.funder-project-idMRC (1185)
pubs.funder-project-idMRC (MR/R021368/1)
pubs.funder-project-idWELLCOME TRUST (107212/Z/15/Z)
pubs.funder-project-idJuvenile Diabetes Research Foundation Ltd (JDRF) (5-SRA-2015-130-A-N)
pubs.funder-project-idWellcome Trust (099772/Z/12/Z)
pubs.funder-project-idWellcome Trust (096388/Z/11/Z)
pubs.funder-project-idNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
pubs.funder-project-idMedical Research Council (MC_UU_00002/4)
cam.orpheus.successThu Jan 30 10:41:52 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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