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

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posted on 2018-04-10, 08:22 authored by 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. Howson, Adam S. Butterworth, John 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, Understanding Society Scientific Group, EPIC-CVD Consortium, UK10K Consortium
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.


This work was supported by the Wellcome Trust (ISF, IB) (098497/Z/12/Z; WT098051), Medical Research Council (ISF, SOR) (MRC_MC_UU_12012/5), NIHR Cambridge Biomedical Research Centre (ISF, IB, SOR), Bernard Wolfe Health Neuroscience Endowment (ISF), European Research Council (ISF) and NIH grant DK064265 (GLM), the European Community’s Seventh Framework Programme (FP7/2007–2013) project Beta-JUDO n°279153 (ISF, AK). This study comprises one arm of the UK10K Consortium (WT091310). The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website AH and JH were funded by the German Ministry for Education and Research (National Genome Research Net-Plus 01GS0820), the German Research Foundation (DFG; HI865/2-1), the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreements n°245009 and n°262055. We thank participants and staff of the Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study, and the Copenhagen General Population Study for their important contributions (CCHS, CGPS, CIHDS). CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were supported by grants awarded to the University of Cambridge from the EU Framework Programme 7 (HEALTH-F2-2012-279233), the UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), the European Research Council (268834), the UK National Institute for Health Research Cambridge Biomedical Research Centre, Merck and Pfizer. We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidem



Scientific Reports, 2017, 7 (1)

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