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dc.contributor.authorDennis, Megan Y.
dc.contributor.authorParacchini, Silvia
dc.contributor.authorScerri, Thomas S.
dc.contributor.authorProkunina-Olsson, Ludmila
dc.contributor.authorKnight, Julian C.
dc.contributor.authorWade-Martins, Richard
dc.contributor.authorCoggill, Penny
dc.contributor.authorBeck, Stephan
dc.contributor.authorGreen, Eric D.
dc.contributor.authorMonaco, Anthony P.
dc.date.accessioned2013-12-03T09:31:07Z
dc.date.available2013-12-03T09:31:07Z
dc.date.issued2009-03
dc.identifier.citationDennis , M Y , Paracchini , S , Scerri , T S , Prokunina-Olsson , L , Knight , J C , Wade-Martins , R , Coggill , P , Beck , S , Green , E D & Monaco , A P 2009 , ' A common variant associated with dyslexia reduces expression of the KIAA0319 gene ' , PLoS Genetics , vol. 5 , no. 3 , e1000436 . https://doi.org/10.1371/journal.pgen.1000436en
dc.identifier.issn1553-7390
dc.identifier.otherPURE: 15870739
dc.identifier.otherPURE UUID: c807d006-b679-41d6-a1fe-aaa275a30a50
dc.identifier.otherWOS: 000266320100042
dc.identifier.otherScopus: 63449106260
dc.identifier.otherORCID: /0000-0001-9934-8602/work/60428106
dc.identifier.urihttp://hdl.handle.net/10023/4238
dc.descriptionThis work was supported by the Wellcome Trust (MYD, SP, TSS, JCK, RWM, PC, SB, and APM), the Intramural Research Programs of the National Human Genome Research Institute (MYD and EDG) and National Cancer Institute (MPO), and the NIH/Ox-Cam Graduate Partnership Program (MYD).en
dc.description.abstractNumerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.
dc.format.extent10
dc.language.isoeng
dc.relation.ispartofPLoS Geneticsen
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.en
dc.subjectReading-disabilityen
dc.subjectDevelopmental Dyslexiaen
dc.subjectTranscription Factoren
dc.subjectNeuronal Migrationen
dc.subjectHuman Genomeen
dc.subjectFunctional Elementsen
dc.subjectSusceptibility Geneen
dc.subjectNuclear-Matrixen
dc.subjectDna-Sequencesen
dc.subjectLarge-Sampleen
dc.subjectQH426 Geneticsen
dc.subject.lccQH426en
dc.titleA common variant associated with dyslexia reduces expression of the KIAA0319 geneen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1000436
dc.description.statusPeer revieweden


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