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    Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity.

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    Author
    Hendricks, AE; Bochukova, EG; Marenne, G; Keogh, JM; Atanassova, N; Bounds, R; Wheeler, E; Mistry, V; Henning, E; Körner, A; ...
    Date
    2017-06-29
    Source Title
    Scientific Reports
    Publisher
    Springer Science and Business Media LLC
    University of Melbourne Author/s
    Kaye, Jane
    Affiliation
    Melbourne Law School
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Hendricks, A. E., Bochukova, E. G., Marenne, G., Keogh, J. M., Atanassova, N., Bounds, R., Wheeler, E., Mistry, V., Henning, E., Körner, A., Muddyman, D., McCarthy, S., Hinney, A., Hebebrand, J., Scott, R. A., Langenberg, C., Wareham, N. J., Surendran, P., Howson, J. M. ,... UK10K Consortium (2017). Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity.. Sci Rep, 7 (1), pp.4394-. https://doi.org/10.1038/s41598-017-03054-8.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257101
    DOI
    10.1038/s41598-017-03054-8
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491520
    Abstract
    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

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