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

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 M Howson, Adam S. ButterworthJohn 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, Michaela Benzeval, Jonathan Burton, Nicholas Buck, Annette Jäckle, Meena Kumari, Heather Laurie, Peter Lynn, Stephen Pudney, Birgitta Rabe, Dieter Wolke, Kim Overvad, Anne Tjønneland, Francoise Clavel-Chapelon, Rudolf Kaaks, Heiner Boeing, Antonia Trichopoulou, Pietro Ferrari, Domenico Palli, Vittorio Krogha, Salvatore Panico, Rosario Tuminoa, Giuseppe Matullo, Jolanda Boer, Yvonne T. Van Der Schouw, Elisabete Weiderpass, J. Ramon Quiros, María José Sánchez, Carmen Navarro, Conchi Moreno-Iribas, Larraitz Arriola, Olle Melander, Patrik Wennberg, Timothy J. Key, Elio Riboli, Saeed Al Turki, Carl A. Anderson, Richard Anney, Dinu Antony, María Soler Artigas, Muhammad Ayub, Senduran Bala, Jeffrey C. Barrett, Phil Beales, Jamie Bentham, Shoumo Bhattacharyaa, Ewan Birney, Douglas Blackwooda, Martin Bobrow, Patrick F. Bolton, Chris Boustred, Gerome Breen, Mattia Calissanoa, Keren Carss, Ruth Charlton, Krishna Chatterjee, Lu Chen, Antonio Ciampia, Sebahattin Cirak, Peter Clapham, Gail Clement, Guy Coates, Massimiliano Coccaa, David A. Collier, Catherine Cosgrove, Tony Coxa, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Petr Danecek, Ian N.M. Day, Aaron Day-Williams, Anna F. Dominiczak, Thomas Down, Yuanping Du, Ian Dunham, Richard Durbin, Sarah Edkins, Rosemary Ekong, Peter Ellis, David M. Evansa, David R. Fitzpatrick, Paul Flicek, James Floyd, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Tom R. Gaunt, Matthias Geihs, Daniel Geschwind, Celia M T Greenwood, Heather Griffin, Detelina Grozeva, Xiaosen Guo, Xueqin Guo, Hugh Gurling, Deborah Hart, Peter A. Holmans, Bryan Howie, Jie Huang, Liren Huang, Tim Hubbard, Steve E. Humphries, Matthew E. Hurles, Pirro G. Hysi, Valentina Iotchkova, David K. Jackson, Yalda Jamshidi, Chris Joyce, Konrad J. Karczewski, Jane Kaye, Thomas Keane, John P. Kemp, Karen Kennedy, Alastair Kent, Farrah Khawaja, Margriet Van Kogelenberg, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Rui Li, Yingrui Li, Jieqin Liang, Hong Lin, Ryan Liu, Jouko Lönnqvist, Luis R. Lopes, Margarida Lopes, Daniel G. MacArthur, Massimo Mangino, Jonathan Marchini, John Maslen, Iain Mathieson, Peter McGuffin, Andrew M. McIntosh, Andrew G. McKechanie, Andrew McQuillin, Yasin Memari, Sarah Metrustry, Nicola Migone, Josine L. Min, Hannah M. Mitchison, Alireza Moayyeri, Andrew P. Morris, James Morris, Francesco Muntoni, Kate Northstone, Michael C. O'Donovan, Alexandros Onoufriadis, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Stewart J. Payne, John R B Perry, Olli Pietilainen, Vincent Plagnol, Rebecca C. Pollitt, David J. Porteous, Sue Povey, Michael A. Quail, Lydia Quaye, F. Lucy Raymond, Karola Rehnström, J. Brent Richards, Cheryl K. Ridout, Susan M. Ring, Graham R.S. Ritchie, Nicola Roberts, Rachel L. Robinson, David B. Savage, Peter Scambler, Stephan Schiffels, Miriam Schmidts, Nadia Schoenmakers, Richard H. Scott, Robert K. Semple, Eva Serra, Sally I. Sharp, Adam Shaw, Hashem A. Shihab, So Youn Shin, David Skuse, Kerrin S. Small, Carol Smee, Blair H. Smith, George Davey Smith, Nicole Soranzo, Lorraine Southam, Olivera Spasic-Boskovic, Timothy D. Spector, David St Clair, Beate St Pourcain, Jim Stalker, Elizabeth Stevens, Jianping Sun, Gabriela L. Surdulescu, Jaana Suvisaari, Petros Syrris, Rohan Taylor, Jing Tian, Nicholas J. Timpson, Martin D. Tobin, Ana M. Valdes, Anthony M. Vandersteen, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, Klaudia Walter, James T R Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Tamieka Whyte, Hywel J. Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, Changjiang Xu, Jian Yang, Hai Feng Zhang, Pingbo Zhang, Hou-Feng Zheng

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Article number4394
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Fingerprint Dive into the research topics of 'Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity'. Together they form a unique fingerprint.

Cite this