TY - JOUR
T1 - Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity
AU - Hendricks, Audrey E.
AU - Bochukova, Elena G.
AU - Marenne, Gaëlle
AU - Keogh, Julia M
AU - Atanassova, Neli
AU - Bounds, Rebecca
AU - Wheeler, Eleanor
AU - Mistry, Vanisha
AU - Henning, Elana
AU - Understanding Society Scientific Group
AU - Körner, Antje
AU - Muddyman, Dawn
AU - McCarthy, Shane
AU - Hinney, Anke
AU - Hebebrand, Johannes
AU - Scott, Robert A
AU - Langenberg, Claudia
AU - Wareham, Nick J
AU - Surendran, Praveen
AU - Howson, Joanna Mm
AU - Butterworth, Adam S
AU - Danesh, John
AU - EPIC-CVD Consortium
AU - Nordestgaard, Børge
AU - Nielsen, Sune Fallgaard
AU - Afzal, Shoaib
AU - Papadia, Sofia
AU - Ashford, Sofie
AU - Garg, Sumedha
AU - Millhauser, Glenn L.
AU - Palomino, Rafael I.
AU - Kwasniewska, Alexandra
AU - Tachmazidou, Ioanna
AU - O'Rahilly, Stephen
AU - Zeggini, Eleftheria
AU - UK10K Consortium
AU - Barroso, Inês
AU - Farooqi, I Sadaf
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-017-03054-8
DO - 10.1038/s41598-017-03054-8
M3 - Journal article
C2 - 28663568
AN - SCOPUS:85021671193
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 4394
ER -