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; Ines Barroso; 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

Journal article

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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

PMCID: PMC2669167

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 - without role: Ruth J. F. Loos - Massachusetts Rehabilitation Commission
Cecilia M. Lindgren - University of Oxford
Shengxu Li - Massachusetts Rehabilitation Commission
Eleanor Wheeler - Wellcome Sanger Institute
Jing Hua Zhao - Massachusetts Rehabilitation Commission
Inga Prokopenko - University of Oxford
Michael Inouye - Wellcome Sanger Institute
Rachel M. Freathy - Supreme Council Of Health
Antony P. Attwood - Wellcome Sanger Institute
Jacques S. Beckmann - University of Lausanne
Sonja I. Berndt - NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA
Sven Bergmann - University of Lausanne
Amanda J. Bennett - University of Oxford
Sheila A. Bingham - Massachusetts Rehabilitation Commission
Murielle Bochud - College Station Medical Center
Morris Brown - University of Cambridge
Stephane Cauchi - Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France
John M. Connell - University of Glasgow
Cyrus Cooper - University of Southampton
George Davey Smith - University of Bristol
Ian Day - University of Southampton
Christian Dina - Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France
Subhajyoti De - Massachusetts Rehabilitation Commission
Emmanouil T. Dermitzakis - Wellcome Sanger Institute
Alex S. F. Doney - University of Dundee
Katherine S. Elliott - University of Oxford
Paul Elliott - University of London
David M. Evans - University of Oxford
I. Sadaf Farooqi - Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England
Philippe Froguel - Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France
Jilur Ghori - Wellcome Sanger Institute
Christopher J. Groves - University of Oxford
Rhian Gwilliam - Wellcome Sanger Institute
David Hadley - University of London
Alistair S. Hall - University of Leeds
Andrew T. Hattersley - Supreme Council Of Health
Johannes Hebebrand - University of Duisburg-Essen
Iris M. Heid - GSF, Inst Epidemiol, D-85764 Neuherberg, Germany
Blanca Herrera - University of Oxford
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 - University of Cambridge
Fredrik Karpe - University of Oxford
Andrew Keniry - Wellcome Sanger Institute
Kay-Tee Khaw - University of Cambridge
Robert N. Luben - University of Cambridge
Massimo Mangino - University of Leicester
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 - Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England
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 - 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 - University of Oxford
Nigel W. Rayner - University of Oxford
Susan M. Ring - University of Bristol
Manjinder S. Sandhu - Massachusetts Rehabilitation Commission
Andre Scherag - University of Duisburg-Essen
Matthew A. Sims - Massachusetts Rehabilitation Commission
Kijoung Song - College Station Medical Center
Nicole Soranzo - Wellcome Sanger Institute
Elizabeth K. Speliotes - Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA
Holly E. Syddall - University of Southampton
Sarah A. Teichmann - Massachusetts Rehabilitation Commission
Nicholas J. Timpson - University of Oxford
Jonathan H. Tobias - University of Bristol
Manuela Uda - CNR, Ist Neurogenet & Neurofarmacol, I-09100 Cagliari, Italy
Carla I. Ganz Vogel - University of Duisburg-Essen
Chris Wallace - William Harvey Research Institute
Dawn M. Waterworth - College Station Medical Center
Michael N. Weedon - Supreme Council Of Health
Cristen J. Willer - Biostat
Vicki L. Wraight - Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England
Xin Yuan - College Station Medical Center
Eleftheria Zeggini - University of Oxford
Joel N. Hirschhorn - Broad Institute
David P. Strachan - University of London
Willem H. Ouwehand - University of Cambridge
Mark J. Caulfield - William Harvey Research Institute
Nilesh J. Samani - University of Leicester
Timothy M. Frayling - Supreme Council Of Health
Peter Vollenweider - College Station Medical Center
Gerard Waeber - College Station Medical Center
Vincent Mooser - College Station Medical Center
Panos Deloukas - Wellcome Sanger Institute
Mark I. McCarthy - University of Oxford
Nicholas J. Wareham - Massachusetts Rehabilitation Commission
Ines Barroso - Wellcome Sanger Institute
Diabetes Genetics Initiative
Publication Details: Nature genetics, Vol.40(6), pp.768-775
Publisher: Springer Nature
Number of pages: 8
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 ZIAHG000024 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) F32 DK079466; K23 DK080145-01; R01 DK072193; F32 DK079466-01; P30 DK040561; K23 DK080145; P30 DK040561-13 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
Identifiers: 9934691608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article