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

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, Lung Colorectal Prostate, Trial Ovarian Cancer Screening, Kevin B. Jacobs, Stephen J. Chanock, Richard B. Hayes, Sven Bergmann, Amanda J. Bennett, Sheila A. Bingham, Murielle BochudMorris 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, Kora [No Value], Claudia Lamina, Christian Gieger, Thomas Illig, Thomas Meitinger, H. Erich Wichmann, 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, Andy 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, Study Nurses' Health, Joshua C. Randall, Nigel W. Rayner, Susan M. Ring, Manjinder S. Sandhu, Andre Scherag, Matthew A. Sims, Kijoung Song, Nicole Soranzo, Elizabeth K. Speliotes, Initiative Diabetes Genetics, Holly E. Syddall, Sarah A. Teichmann, Nicholas J. Timpson, Jonathan H. Tobias, Manuela Uda, N. I. A. Study Sardi, Carla I. Ganz Vogel, Chris Wallace, Dawn M. Waterworth, Michael N. Weedon, Consortium Wellcome Trust Case Control, et al. Willer Cristen J.

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Abstract

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.
Translated title of the contributionCommon variants near MC4R are associated with fat mass, weight and risk of obesity
Original languageEnglish
Pages (from-to)768-775
Number of pages8
JournalNature Genetics
Volume40
Issue number6
DOIs
Publication statusPublished - May 2008

Bibliographical note

M1 - 6

Loos RJ Lindgren CM Li S Wheeler E Zhao JH Prokopenko I Inouye M Freathy RM Attwood AP Beckmann JS Berndt SI Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Jacobs KB Chanock SJ Hayes RB Bergmann S Bennett AJ Bingham SA Bochud M Brown M Cauchi S Connell JM Cooper C Smith GD Day I Dina C De S Dermitzakis ET Doney AS Elliott KS Elliott P Evans DM Sadaf Farooqi I Froguel P Ghori J Groves CJ Gwilliam R Hadley D Hall AS Hattersley AT Hebebrand J Heid IM KORA Lamina C Gieger C Illig T Meitinger T Wichmann HE Herrera B Hinney A Hunt SE Jarvelin MR Johnson T Jolley JD Karpe F Keniry A Khaw KT Luben RN Mangino M Marchini J McArdle WL McGinnis R Meyre D Munroe PB Morris AD Ness AR Neville MJ Nica AC Ong KK O'Rahilly S Owen KR Palmer CN Papadakis K Potter S Pouta A Qi L Nurses' Health Study Randall JC Rayner NW Ring SM Sandhu MS Scherag A Sims MA Song K Soranzo N Speliotes EK Diabetes Genetics Initiative Syddall HE Teichmann SA Timpson NJ Tobias JH Uda M SardiNIA Study Vogel CI Wallace C Waterworth DM Weedon MN Wellcome Trust Case Control Consortium Willer CJ FUSION Wraight Yuan X Zeggini E Hirschhorn JN Strachan DP Ouwehand WH Caulfield MJ Samani NJ Frayling TM Vollenweider P Waeber G Mooser V Deloukas P McCarthy MI Wareham NJ Barroso I Kraft P Hankinson SE Hunter DJ Hu FB Lyon HN Voight BF Ridderstrale M Groop L Scheet P Sanna S Abecasis GR Albai G Nagaraja R Schlessinger D Jackson AU Tuomilehto J Collins FS Boehnke M Mohlke KL (PLCO) Burton PR Clayton DG Cardon LR Craddock N Duncanson A Kwiatkowski DP Todd JA Donnelly P Barrett JC Davison D Easton D Leung HT Marchini JL Morris AP Spencer CC Tobin MD Boorman JP Cant B Everson U Hussey JM Knight AS Koch K Meech E Nutland S Prowse CV Stevens HE Taylor NC Walters GR Walker NM Watkins NA Winzer T Jones RW Pembrey M Breen G St Clair D Caesar S Gordon-Smith K Jones L Fraser C Green EK Grozeva D Hamshere ML Holmans PA Jones IR Kirov G Moskvina V Nikolov I O'Donovan MC Owen MJ Collier DA Elkin A Farmer A Williamson R McGuffin P Young AH Ferrier IN Ball SG Balmforth AJ Barrett JH Bishop DT Iles MM Maqbool A Yuldasheva N Braund PS Dixon RJ Stevens S Thompson JR Bredin F Tremelling M Parkes M Drummond H Lees CW Nimmo ER Satsangi J Fisher SA Forbes A Lewis CM Onnie CM Prescott NJ Sanderson J Mathew CG Barbour J Mohiuddin MK Todhunter CE Mansfield JC Ahmad T Cummings FR Jewell DP Webster J Brown MJ Lathrop GM Connell J Dominiczak A Marcano CA Burke B Dobson R Gungadoo J Lee KL Newhouse SJ Onipinla A Xue M Caulfield M Farrall M Barton A Bruce IN Donovan H Eyre S Gilbert PD Hider SL Hinks AM John SL Potter C Silman AJ Symmons DP Thomson W Worthington J Dunger DB Widmer B Lango H Perry JR Shields BM Hitman GA Walker M Newport M Sirugo G Lyons E Vannberg F Hill AV Bradbury LA Farrar C Pointon JJ Wordsworth P Brown MA Franklyn JA Heward JM Simmonds MJ Gough SC Seal S Stratton MR Rahman N Ban M Goris A Sawcer SJ Compston A Conway D Jallow M Rockett KA Bumpstead SJ Chaney A Downes K Ghori MJ King E Ravindrarajah R Whittaker P Widden C Withers D Cardin NJ Ferreira T Pereira-Gale J Hallgrimsdottir IB Howie BN Su Z Teo YY Vukcevic D Bentley D 068545 (United Kingdom Wellcome Trust) 076113 (United Kingdom Wellcome Trust) 077016 (United Kingdom Wellcome Trust) 079557 (United Kingdom Wellcome Trust) 084713 (United Kingdom Wellcome Trust) F32 DK079466-01 (United States NIDDK NIH HHS) G0000934(68341) (United Kingdom Medical Research Council) G0601261(80227) (United Kingdom Medical Research Council) G9521010(63660) (United Kingdom Medical Research Council) K23 DK080145-01 (United States NIDDK NIH HHS) P30 DK040561-13 (United States NIDDK NIH HHS) R01 DK072193-01 (United States NIDDK NIH HHS) R01 DK072193-02 (United States NIDDK NIH HHS) R01 DK072193-03 (United States NIDDK NIH HHS) (United Kingdom British Heart Foundation) (United Kingdom Cancer Research UK) (United Kingdom Medical Research Council) (United Kingdom Wellcome Trust)

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