Publication type
Journal Article
Authors
- Audrey E. Hendricks
- Elena G. Bochukova
- Gaëlle Marenne
- Julia M. Keogh
- Neli Atanassova
- Rebecca Bounds
- Eleanor Wheeler
- Vanisha Mistry
- Elana Henning
- Antje Körner
- Dawn Muddyman
- Shane McCarthy
- Anke Hinney
- Johannes Hebebrand
- Robert A. Scott
- Claudia Langenberg
- Nick J. Wareham
- Praveen Surendran
- Joanna M. Howson
- Adam S. Butterworth
- John Danesh
- Børge G. Nordestgaard
- Sune F. Nielsen
- Shoaib Afzal
- Sofia Papadia
- Sofie Ashford
- Sumedha Garg
- Glenn L. Millhauser
- Rafael I. Palomino
- Alexandra Kwasniewska
- Ioanna Tachmazidou
- Stephen O’Rahilly
- Eleftheria Zeggini
- Inês Barroso
- I. Sadaf Farooqi
Publication date
June 15, 2017
Summary:
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.
Published in
Scientific Reports
Volume
Volume: 7:4394
DOI
http://dx.doi.org/10.1038/s41598-017-03054-8
ISSN
20452322
Subjects
Notes
Open Access
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