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    Molecular prioritization strategies to identify functional genetic variants in the cardiovascular disease-associated expression QTL Vanin-1

    Access Status
    Open access via publisher
    Authors
    Kaskow, B.
    Diepeveen, L.
    Michael Proffitt, J.
    Rea, A.
    Ulgiati, D.
    Blangero, J.
    Moses, Eric
    Abraham, L.
    Date
    2014
    Type
    Journal Article
    
    Metadata
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    Citation
    Kaskow, B. and Diepeveen, L. and Michael Proffitt, J. and Rea, A. and Ulgiati, D. and Blangero, J. and Moses, E. et al. 2014. Molecular prioritization strategies to identify functional genetic variants in the cardiovascular disease-associated expression QTL Vanin-1. European Journal of Human Genetics. 22 (5): pp. 688-695.
    Source Title
    European Journal of Human Genetics
    DOI
    10.1038/ejhg.2013.208
    ISSN
    1018-4813
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/46593
    Collection
    • Curtin Research Publications
    Abstract

    There is now good evidence that non-coding sequence variants are involved in the heritability of many common complex traits. The current 'gold standard' approach for assessing functionality is the in vitro reporter gene assay to assess allelic differences in transcriptional activity, usually followed by electrophoretic mobility shift assays to assess allelic differences in transcription factor binding. Although widely used, these assays have inherent limitations, including the lack of endogenous chromatin context. Here we present a more contemporary approach to assessing functionality of non-coding sequence variation within the Vanin-1 (VNN1) promoter. By combining 'gold standard' assays with in vivo assessments of chromatin accessibility, we greatly increase our confidence in the statistically assigned functional relevance. The standard assays revealed the-137 single nucleotide variant to be functional but the-587 variant to have no functional relevance. However, our in vivo tests show an allelic difference in chromatin accessibility surrounding the-587 variant supporting strong functional potential at both sites. Our approach advances the identification of functional variants by providing strong in vivo biological evidence for function.

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