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Sci Rep. 2017 Jun 29;7(1):4394. doi: 10.1038/s41598-017-03054-8.

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

Collaborators (235)

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, Craddock N, Crooks L, Curran S, Curtis D, Daly A, Danecek P, Day INM, Day-Williams A, Dominiczak A, Down T, Du Y, Dunham I, Durbin R, Edkins S, Ekong R, Ellis P, Evansa DM, Fitzpatrick DR, Flicek P, Floyd J, Foley AR, Franklin CS, Futema M, Gallagher L, Gaunt TR, Geihs M, Geschwind D, Greenwood CMT, Griffin H, Grozeva D, Guo X, Guo X, Gurling H, Hart D, Holmans P, Howie B, Huang J, Huang L, Hubbard T, Humphries SE, Hurles ME, Hysi P, Iotchkova V, Jackson DK, Jamshidi Y, Joyce C, Karczewski KJ, Kaye J, Keane T, Kemp JP, Kennedy K, Kent A, Khawaja F, van Kogelenberg M, Kolb-Kokocinski A, Lachance G, Langford C, Lawson D, Lee I, Lek M, Li R, Li Y, Liang J, Lin H, Liu R, Lönnqvist J, Lopes LR, Lopes M, MacArthur DG, Mangino M, Marchini J, Maslen J, Mathieson I, McGuffin P, McIntosh AM, McKechanie AG, McQuillin A, Memari Y, Metrustry S, Migone N, Min JL, Mitchison HM, Moayyeri A, Morris A, Morris J, Muntoni F, Northstone K, O'Donovan MC, Onoufriadis A, Oualkacha K, Owen MJ, Palotie A, Panoutsopoulou K, Parker V, Parr JR, Paternoster L, Paunio T, Payne F, Payne SJ, Perry JRB, Pietilainen O, Plagnol V, Pollitt RC, Porteous DJ, Povey S, Quail MA, Quaye L, Raymond FL, Rehnström K, Richards JB, Ridout CK, Ring S, Ritchie GRS, Roberts N, Robinson RL, Savage DB, Scambler P, Schiffels S, Schmidts M, Schoenmakers N, Scott RH, Semple RK, Serra E, Sharp SI, Shaw A, Shihab HA, Shin SY, Skuse D, Small KS, Smee C, Smith BH, Davey Smith G, Soranzo N, Southam L, Spasic-Boskovic O, Spector TD, St Clair D, St Pourcain B, Stalker J, Stevens E, Sun J, Surdulescu G, Suvisaari J, Syrris P, Taylor R, Tian J, Timpson NJ, Tobin MD, Valdes AM, Vandersteen AM, Vijayarangakannan P, Visscher PM, Wain LV, Walter K, Walters JTR, Wang G, Wang J, Wang Y, Ward K, Whyte T, Williams HJ, Williamson KA, Wilson C, Wilson SG, Wong K, Xu C, Yang J, Zhang F, Zhang P, Zheng HF.

Author information

1
Wellcome Trust Sanger Institute, Cambridge, UK.
2
Department of Mathematical and Statistical Sciences, University of Colorado-Denver, Denver, CO, 80204, USA.
3
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
4
The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
5
Center for Pediatric Research, University Children's Hospital Leipzig, Leipzig, Germany.
6
IFB Adiposity Diseases Medical Faculty, University of Leipzig, Leipzig, Germany.
7
Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen and University of Duisburg-Essen, Essen, Germany.
8
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
9
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
10
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
11
Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
12
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
14
Wellcome Trust Sanger Institute, Cambridge, UK. ib1@sanger.ac.uk.
15
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. ib1@sanger.ac.uk.
16
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. isf20@cam.ac.uk.

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.

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