Common variants near MC4R are associated with fat mass, weight and risk of obesity

Ruth J. F. Loos; Cecilia M. Lindgren; Shengxu Li; Eleanor Wheeler; Jing Hua Zhao; Inga Prokopenko; Michael Inouye; Rachel M. Freathy; Antony P. Attwood; Jacques S. Beckmann; Sonja I. Berndt; Sven Bergmann; Amanda J. Bennett; Sheila A. Bingham; Murielle Bochud; Morris Brown; Stephane Cauchi; John M. Connell; Cyrus Cooper; George Davey Smith; Ian Day; Christian Dina; Subhajyoti De; Emmanouil T. Dermitzakis; Alex S. F. Doney; Katherine S. Elliott; Paul Elliott; David M. Evans; I. Sadaf Farooqi; Philippe Froguel; Jilur Ghori; Christopher J. Groves; Rhian Gwilliam; David Hadley; Alistair S. Hall; Andrew T. Hattersley; Johannes Hebebrand; Iris M. Heid; Blanca Herrera; Anke Hinney; Sarah E. Hunt; Marjo-Riitta Jarvelin; Toby Johnson; Jennifer D. M. Jolley; Fredrik Karpe; Andrew Keniry; Kay-Tee Khaw; Robert N. Luben; Massimo Mangino; Jonathan Marchini; Wendy L. McArdle; Ralph McGinnis; David Meyre; Patricia B. Munroe; Andrew D. Morris; Andrew R. Ness; Matthew J. Neville; Alexandra C. Nica; Ken K. Ong; Stephen O'Rahilly; Katharine R. Owen; Colin N. A. Palmer; Konstantinos Papadakis; Simon Potter; Anneli Pouta; Lu Qi; Joshua C. Randall; Nigel W. Rayner; Susan M. Ring; Manjinder S. Sandhu; Andre Scherag; Matthew A. Sims; Kijoung Song; Nicole Soranzo; Elizabeth K. Speliotes; Holly E. Syddall; Sarah A. Teichmann; Nicholas J. Timpson; Jonathan H. Tobias; Manuela Uda; Carla I. Ganz Vogel; Chris Wallace; Dawn M. Waterworth; Michael N. Weedon; Cristen J. Willer; Vicki L. Wraight; Xin Yuan; Eleftheria Zeggini; Joel N. Hirschhorn; David P. Strachan; Willem H. Ouwehand; Mark J. Caulfield; Nilesh J. Samani; Timothy M. Frayling; Peter Vollenweider; Gerard Waeber; Vincent Mooser; Panos Deloukas; Mark I. McCarthy; Nicholas J. Wareham; Diabetes Genetics Initiative

doi:10.1038/ng.140

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Common variants near MC4R are associated with fat mass, weight and risk of obesity

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Common variants near MC4R are associated with fat mass, weight and risk of obesity

Ruth J. F. Loos, Cecilia M. Lindgren, Shengxu Li, Eleanor Wheeler, Jing Hua Zhao, Inga Prokopenko, Michael Inouye, Rachel M. Freathy, Antony P. Attwood, Jacques S. Beckmann, …

Nature genetics, Vol.40(6), pp.768-775

01/06/2008

DOI: https://doi.org/10.1038/ng.140

PMID: 18454148

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

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Title: Common variants near MC4R are associated with fat mass, weight and risk of obesity
Creators: Ruth J. F. Loos - MRC Epidemiology Unit
Cecilia M. Lindgren - Wellcome Centre for Human Genetics
Shengxu Li - MRC Epidemiology Unit
Eleanor Wheeler - Wellcome Sanger Institute
Jing Hua Zhao - Addenbrooke's Hospital
Inga Prokopenko - Wellcome Centre for Human Genetics
Michael Inouye - Wellcome Sanger Institute
Rachel M. Freathy - Peninsula College of Medicine and Dentistry
Antony P. Attwood - Wellcome Sanger Institute
Jacques S. Beckmann - University of Lausanne
Sonja I. Berndt - National Cancer Institute
Sven Bergmann - University of Lausanne
Amanda J. Bennett - University of Oxford
Sheila A. Bingham - Wellcome Trust
Murielle Bochud - University Hospital of Lausanne
Morris Brown - University of Cambridge
Stephane Cauchi - Centre National de la Recherche Scientifique
John M. Connell - University of Glasgow
Cyrus Cooper - University of Southampton
George Davey Smith - University of Bristol
Ian Day - University of Southampton
Christian Dina - Institut Pasteur de Lille
Subhajyoti De - MRC Laboratory of Molecular Biology
Emmanouil T. Dermitzakis - Wellcome Sanger Institute
Alex S. F. Doney - Ninewells Hospital
Katherine S. Elliott - University of Oxford
Paul Elliott - Imperial College London
David M. Evans - Wellcome Centre for Human Genetics
I. Sadaf Farooqi - Addenbrooke's Hospital
Philippe Froguel - Institut Pasteur de Lille
Jilur Ghori - Wellcome Sanger Institute
Christopher J. Groves - Oxford Centre for Diabetes, Endocrinology and Metabolism
Rhian Gwilliam - Wellcome Sanger Institute
David Hadley - St George's, University of London
Alistair S. Hall - University of Leeds
Andrew T. Hattersley - Peninsula College of Medicine and Dentistry
Johannes Hebebrand - University of Duisburg-Essen
Iris M. Heid - GSF, Inst Epidemiol, D-85764 Neuherberg, Germany
Blanca Herrera - Oxford Centre for Diabetes, Endocrinology and Metabolism
Anke Hinney - University of Duisburg-Essen
Sarah E. Hunt - Wellcome Sanger Institute
Marjo-Riitta Jarvelin - University of London
Toby Johnson - University of Lausanne
Jennifer D. M. Jolley - NHS Blood and Transplant
Fredrik Karpe - University of Oxford
Andrew Keniry - Wellcome Sanger Institute
Kay-Tee Khaw - University of Cambridge
Robert N. Luben - University of Cambridge
Massimo Mangino - Glenfield Hospital
Jonathan Marchini - University of Oxford
Wendy L. McArdle - University of Bristol
Ralph McGinnis - Wellcome Sanger Institute
David Meyre - Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France
Patricia B. Munroe - William Harvey Research Institute
Andrew D. Morris - University of Dundee
Andrew R. Ness - University of Bristol
Matthew J. Neville - University of Oxford
Alexandra C. Nica - Wellcome Sanger Institute
Ken K. Ong - Addenbrooke's Hospital
Stephen O'Rahilly - Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England
Katharine R. Owen - University of Oxford
Colin N. A. Palmer - University of Dundee
Konstantinos Papadakis - St George's, University of London
Simon Potter - Wellcome Sanger Institute
Anneli Pouta - Natl Publ Hlth Inst, Dept Child & Adolescent Hlth, Oulu 90221, Finland
Lu Qi - Harvard University
Joshua C. Randall - Oxford Centre for Diabetes, Endocrinology and Metabolism
Nigel W. Rayner - Oxford Centre for Diabetes, Endocrinology and Metabolism
Susan M. Ring - University of Bristol
Manjinder S. Sandhu - University of Cambridge
Andre Scherag - University of Duisburg-Essen
Matthew A. Sims - Addenbrooke's Hospital
Kijoung Song - College Station Medical Center
Nicole Soranzo - Wellcome Sanger Institute
Elizabeth K. Speliotes - Massachusetts General Hospital
Holly E. Syddall - University of Southampton
Sarah A. Teichmann - MRC Laboratory of Molecular Biology
Nicholas J. Timpson - University of Bristol
Jonathan H. Tobias - University of Bristol
Manuela Uda - Institute of Genetic and Biomedical Research
Carla I. Ganz Vogel - University of Duisburg-Essen
Chris Wallace - William Harvey Research Institute
Dawn M. Waterworth - College Station Medical Center
Michael N. Weedon - Peninsula College of Medicine and Dentistry
Cristen J. Willer - University of Michigan–Ann Arbor
Vicki L. Wraight - University of Cambridge
Xin Yuan - College Station Medical Center
Eleftheria Zeggini - Wellcome Centre for Human Genetics
Joel N. Hirschhorn - Broad Institute
David P. Strachan - St George's, University of London
Willem H. Ouwehand - University of Cambridge
Mark J. Caulfield - William Harvey Research Institute
Nilesh J. Samani - Glenfield Hospital
Timothy M. Frayling - Peninsula College of Medicine and Dentistry
Peter Vollenweider - University Hospital of Lausanne
Gerard Waeber - University Hospital of Lausanne
Vincent Mooser - College Station Medical Center
Panos Deloukas - Wellcome Sanger Institute
Mark I. McCarthy - Oxford Centre for Diabetes, Endocrinology and Metabolism
Nicholas J. Wareham - Addenbrooke's Hospital
Diabetes Genetics Initiative
Publication Details: Nature genetics, Vol.40(6), pp.768-775
Publisher: Springer Nature
Number of pages: 8
Date published: 01/06/2008
Grant note: Cancer Research UK G9824984 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) U1475000001 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission DHCS/07/07/008 / National Institute for Health Research; National Institute for Health Research (NIHR) British Heart Foundation ZIAAG000675 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) DHCS/07/07/008 / Department of Health; European Commission P30DK040561 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) MC_QA137934; G0701863; U.1475.00.002.00001.01 (85824); MC_U106188470; G0601261; G9521010; G0600331; G0000934; MC_U105161047; MC_U105630924; MC_UP_A620_1014; MC_U106179472; G0401527; G0000934(68341); G9824984; G9828345; MC_U147585824; G9521010(63660); G0600705; G0400874 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission 090532; 079557; 077016; 084713; 068545; 076113 / Wellcome Trust; European Commission
Identifiers: 99928902802346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

Common variants near MC4R are associated with fat mass, weight and risk of obesity

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