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

Medientyp: E-Artikel
Titel: Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
Beteiligte: Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaëlle; Keogh, Julia M.; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Körner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A.; Langenberg, Claudia; Wareham, Nick J.; Surendran, Praveen; Howson, Joanna M.; Butterworth, Adam S.; Danesh, John; Nordestgaard, Børge G; Nielsen, Sune F; Afzal, Shoaib; [...]
Erschienen: Springer Science and Business Media LLC, 2017
Erschienen in: Scientific Reports
Sprache: Englisch
DOI: 10.1038/s41598-017-03054-8
ISSN: 2045-2322
Schlagwörter: Multidisciplinary
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>GNAS</jats:italic>, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in <jats:italic>BBS1</jats:italic>, <jats:italic>BBS9</jats:italic>, <jats:italic>GNAS</jats:italic>, <jats:italic>MKKS</jats:italic>, <jats:italic>CLOCK</jats:italic> and <jats:italic>ANGPTL6</jats:italic>. The p.S284X variant in <jats:italic>ANGPTL6</jats:italic> 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<jats:sup>−3</jats:sup>), 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 <jats:italic>ANGPTL6</jats:italic> 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.</jats:p>
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