Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaelle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Koerner, 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, Borge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Ines, Farooqi, I. Sadaf, UK10K Consortium and Visscher, Peter M. (2017) Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity. Scientific Reports, 7 1: 4394.1-4394.14. doi:10.1038/s41598-017-03054-8

Author Hendricks, Audrey E.
Bochukova, Elena G.
Marenne, Gaelle
Keogh, Julia M.
Atanassova, Neli
Bounds, Rebecca
Wheeler, Eleanor
Mistry, Vanisha
Henning, Elana
Koerner, 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, Borge G.
Nielsen, Sune F.
Afzal, Shoaib
Papadia, Sofia
Ashford, Sofie
Garg, Sumedha
Millhauser, Glenn L.
Palomino, Rafael I.
Kwasniewska, Alexandra
Tachmazidou, Ioanna
O'Rahilly, Stephen
Zeggini, Eleftheria
Barroso, Ines
Farooqi, I. Sadaf
UK10K Consortium
Visscher, Peter M.
Title Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2017-12-01
Sub-type Article (original research)
DOI 10.1038/s41598-017-03054-8
Open Access Status DOI
Volume 7
Issue 1
Start page 4394.1
End page 4394.14
Total pages 14
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Keyword Obesity
Q-Index Code CX
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 09 Aug 2017, 11:07:39 EST by Anthony Yeates on behalf of Learning and Research Services (UQ Library)