Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
Authors: Hendricks Audrey E. , Bochukova Elena G. , Marenne Gaëlle , Keogh Julia M. , Atanassova Neli , Bounds Rebecca , Wheeler Eleanor , Mistry Vanisha , Henning Elana , Körner Antje , Muddyman Dawn , McCarthy Shane , Hinney Anke , Hebebrand Johannes , Scott Robert A. , Langenberg Claudia , Wareham Nick J. , Surendran Praveen , Howson Joanna M. , Butterworth Adam S. , Danesh John , Nordestgaard Børge G , Nielsen Sune F , Afzal Shoaib , Papadia Sofia , Ashford Sofie , Garg Sumedha , Millhauser Glenn L. , Palomino Rafael I. , Kwasniewska Alexandra , Tachmazidou Ioanna , O’Rahilly Stephen , Zeggini Eleftheria , Barroso Inês , Farooqi I. Sadaf ,   Understanding Society Scientific Group, Benzeval Michaela , Burton Jonathan , Buck Nicholas , Jäckle Annette , Kumari Meena , Laurie Heather , Lynn Peter , Pudney Stephen , Rabe Birgitta , Wolke Dieter ,   EPIC-CVD Consortium, Overvad Kim , Tjønneland Anne , Clavel-Chapelon Francoise , Kaaks Rudolf , Boeing Heiner , Trichopoulou Antonia , Ferrari Pietro , Palli Domenico , Krogha Vittorio , Panico Salvatore , Tuminoa Rosario , Matullo Giuseppe , Boer Jolanda , van. der. Schouw Yvonne , Weiderpass Elisabete , Quiros J. Ramon , Sánchez María-José , Navarro Carmen , Moreno-Iribas Conchi , Arriola Larraitz , Melander Olle , Wennberg Patrik , Key Timothy J. , Riboli Elio ,   UK10K Consortium, Turki Saeed Al , Anderson Carl A. , Anney Richard , Antony Dinu , Soler Artigas María , Ayub Muhammad , Bala Senduran , Barrett Jeffrey C. , Beales Phil , Bentham Jamie , Bhattacharyaa Shoumo , Birney Ewan , Blackwooda Douglas , Bobrow Martin , Bolton Patrick F. , Boustred Chris , Breen Gerome , Calissanoa Mattia , Carss Keren , Charlton Ruth , Chatterjee Krishna , Chen Lu , Ciampia Antonio , Cirak Sebahattin , Clapham Peter , Clement Gail , Coates Guy , Coccaa Massimiliano , Collier David A. , Cosgrove Catherine , Coxa Tony , Craddock Nick , Crooks Lucy , Curran Sarah , Curtis David , Daly Allan , Danecek Petr , Day Ian N. M. , Day-Williams Aaron , Dominiczak Anna , Down Thomas , Du Yuanping , Dunham Ian , Durbin Richard , Edkins Sarah , Ekong Rosemary , Ellis Peter , Evansa David M. , Fitzpatrick David R. , Flicek Paul , Floyd James , Foley A. Reghan , Franklin Christopher S. , Futema Marta , Gallagher Louise , Gaunt Tom R. , Geihs Matthias , Geschwind Daniel , Greenwood Celia M. T. , Griffin Heather , Grozeva Detelina , Guo Xiaosen , Guo Xueqin , Gurling Hugh , Hart Deborah , Holmans Peter , Howie Bryan , Huang Jie , Huang Liren , Hubbard Tim , Humphries Steve E. , Hurles Matthew E. , Hysi Pirro , Iotchkova Valentina , Jackson David K. , Jamshidi Yalda , Joyce Chris , Karczewski Konrad J. , Kaye Jane , Keane Thomas , Kemp John P. , Kennedy Karen , Kent Alastair , Khawaja Farrah , van Kogelenberg Margriet , Kolb-Kokocinski Anja , Lachance Genevieve , Langford Cordelia , Lawson Daniel , Lee Irene , Lek Monkol , Li Rui , Li Yingrui , Liang Jieqin , Lin Hong , Liu Ryan , Lönnqvist Jouko , Lopes Luis R. , Lopes Margarida , MacArthur Daniel G. , Mangino Massimo , Marchini Jonathan , Maslen John , Mathieson Iain , McGuffin Peter , McIntosh Andrew M. , McKechanie Andrew G. , McQuillin Andrew , Memari Yasin , Metrustry Sarah , Migone Nicola , Min Josine L. , Mitchison Hannah M. , Moayyeri Alireza , Morris Andrew , Morris James , Muntoni Francesco , Northstone Kate , O’Donovan Michael C. , Onoufriadis Alexandros , Oualkacha Karim , Owen Michael J. , Palotie Aarno , Panoutsopoulou Kalliope , Parker Victoria , Parr Jeremy R. , Paternoster Lavinia , Paunio Tiina , Payne Felicity , Payne Stewart J. , Perry John R. B. , Pietilainen Olli , Plagnol Vincent , Pollitt Rebecca C. , Porteous David J. , Povey Sue , Quail Michael A. , Quaye Lydia , Raymond F. Lucy , Rehnström Karola , Richards J. Brent , Ridout Cheryl K. , Ring Susan , Ritchie Graham R. S. , Roberts Nicola , Robinson Rachel L. , Savage David B. , Scambler Peter , Schiffels Stephan , Schmidts Miriam , Schoenmakers Nadia , Scott Richard H. , Semple Robert K. , Serra Eva , Sharp Sally I. , Shaw Adam , Shihab Hashem A. , Shin So-Youn , Skuse David , Small Kerrin S. , Smee Carol , Smith Blair H. , Davey Smith George , Soranzo Nicole , Southam Lorraine , Spasic-Boskovic Olivera , Spector Timothy D. , St Clair David , St Pourcain Beate , Stalker Jim , Stevens Elizabeth , Sun Jianping , Surdulescu Gabriela , Suvisaari Jaana , Syrris Petros , Taylor Rohan , Tian Jing , Timpson Nicholas J. , Tobin Martin D. , Valdes Ana M. , Vandersteen Anthony M. , Vijayarangakannan Parthiban , Visscher Peter M. , Wain Louise V. , Walter Klaudia , Walters James T. R. , Wang Guangbiao , Wang Jun , Wang Yu , Ward Kirsten , Whyte Tamieka , Williams Hywel J. , Williamson Kathleen A. , Wilson Crispian , Wilson Scott G. , Wong Kim , Xu ChangJiang , Yang Jian , Zhang Feng , Zhang Pingbo , Zheng Hou-Feng 
Published: June 2017

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.