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dc.contributor.authorPullabhatla, Ven_US
dc.contributor.authorRoberts, ALen_US
dc.contributor.authorLewis, MJen_US
dc.contributor.authorMauro, Den_US
dc.contributor.authorMorris, DLen_US
dc.contributor.authorOdhams, CAen_US
dc.contributor.authorTombleson, Pen_US
dc.contributor.authorLiljedahl, Uen_US
dc.contributor.authorVyse, Sen_US
dc.contributor.authorSimpson, MAen_US
dc.contributor.authorSauer, Sen_US
dc.contributor.authorde Rinaldis, Een_US
dc.contributor.authorSyvänen, A-Cen_US
dc.contributor.authorVyse, TJen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2019-02-27T10:01:45Z
dc.date.issued2018-02-01en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29177435en_US
dc.identifier4644524en_US
dc.identifier.citationHum Mol Genet, 2018, 27 (3), pp. 421 - 429en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3102
dc.identifier.eissn1460-2083en_US
dc.identifier.doi10.1093/hmg/ddx407en_US
dc.description.abstractThe omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.en_US
dc.format.extent421 - 429en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAdulten_US
dc.subjectAutoantibodiesen_US
dc.subjectChromatography, Gelen_US
dc.subjectDNA (Cytosine-5-)-Methyltransferasesen_US
dc.subjectExomeen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectGenome-Wide Association Studyen_US
dc.subjectGenotypeen_US
dc.subjectHEK293 Cellsen_US
dc.subjectHumansen_US
dc.subjectLupus Erythematosus, Systemicen_US
dc.subjectMutationen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectProtein Kinase C-deltaen_US
dc.subjectYoung Adulten_US
dc.titleDe novo mutations implicate novel genes in systemic lupus erythematosus.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-11-14en_US
rioxxterms.versionofrecord10.1093/hmg/ddx407en_US
rioxxterms.licenseref.startdate2018-02-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfHum Mol Geneten_US
pubs.issue3en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Protein Networks
pubs.publication-statusPublisheden_US
pubs.volume27en_US
pubs.embargo.termsNot knownen_US
icr.researchteamProtein Networksen_US
dc.contributor.icrauthorVyse, Simonen_US


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