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

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HENDRICKS, AE, BOCHUKOVA, EG, MARENNE, G, KEOGH, JM, ATANASSOVA, N, BOUNDS, R, WHEELER, E, MISTRY, V, HENNING, E, KÖRNER, A, MUDDYMAN, D, MCCARTHY, S, HINNEY, A, HEBEBRAND, J, SCOTT, RA, LANGENBERG, C, WAREHAM, NJ, SURENDRAN, P, HOWSON, JM, BUTTERWORTH, AS, DANESH, J, NORDESTGAARD, BG, NIELSEN, SF, AFZAL, S, PAPADIA, S, ASHFORD, S, GARG, S, MILLHAUSER, GL, PALOMINO, RI, KWASNIEWSKA, A, TACHMAZIDOU, I, O'RAHILLY, S, ZEGGINI, E, BARROSO, I, FAROOQI, IS, BENZEVAL, M, BURTON, J, BUCK, N, JÄCKLE, A, KUMARI, M, LAURIE, H, LYNN, P, PUDNEY, S, RABE, B, WOLKE, D, OVERVAD, K, TJØNNELAND, A, CLAVEL-CHAPELON, F, KAAKS, R, BOEING, H, TRICHOPOULOU, A, FERRARI, P, PALLI, D, KROGHA, V, PANICO, S, TUMINOA, R, MATULLO, G, BOER, J, VAN DER SCHOUW, Y, WEIDERPASS, E, QUIROS, JR, SÁNCHEZ, MJ, NAVARRO, C, MORENO-IRIBAS, C, ARRIOLA, L, MELANDER, O, WENNBERG, P, KEY, TJ, RIBOLI, E, TURKI, SA, ANDERSON, CA, ANNEY, R, ANTONY, D, SOLER ARTIGAS, M, AYUB, M, BALA, S, BARRETT, JC, BEALES, P, BENTHAM, J, BHATTACHARYAA, S, BIRNEY, E, BLACKWOODA, D, BOBROW, M, BOLTON, PF, BOUSTRED, C, BREEN, G, CALISSANOA, M, CARSS, K, CHARLTON, R, CHATTERJEE, K, CHEN, L, CIAMPIA, A, CIRAK, S, CLAPHAM, P, CLEMENT, G, COATES, G, COCCAA, M, COLLIER, DA, COSGROVE, C, COXA, T and CROOKS, Lucy (2017). Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. Scientific Reports, 7 (1), p. 4394. [Article]

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Abstract

© 2017 The Author(s). 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.

More Information

Open Access URL:

https://www.nature.com/articles/s41598-017-03054-8

Open Access Version:

Published version

Additional Information:

Authored by the UK10K Consortium. For the full list of authors please see the published version: https://www.nature.com/articles/s41598-017-03054-8

Uncontrolled Keywords:

Animals; Case-Control Studies; Chromogranins; Female; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Mice; Models, Molecular; Mutation; Obesity, Morbid; Odds Ratio; Pediatric Obesity; Pedigree; Protein Conformation; Rodentia; Understanding Society Scientific Group; EPIC-CVD Consortium; UK10K Consortium; Animals; Humans; Rodentia; Mice; Obesity, Morbid; Genetic Predisposition to Disease; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Odds Ratio; Case-Control Studies; Pedigree; Protein Conformation; Mutation; Models, Molecular; Female; Male; Genetic Variation; Genetic Association Studies; Pediatric Obesity

Page Range:

p. 4394

Event Location:

England

Identifiers

Identification Number:

10.1038/s41598-017-03054-8

ORCID for Lucy Crooks: