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

Loos, Ruth J. F.; Lindgren, Cecilia M.; Li, Shengxu; Wheeler, Eleanor; Zhao, Jing Hua; Prokopenko, Inga; Inouye, Michael; Freathy, Rachel M.; Attwood, Antony P. and Beckmann, Jacques S., et al. (2008) In Nature Genetics 40(6). p.768-775
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... (More)
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. (Less)
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Nature Genetics
volume
40
issue
6
pages
768 - 775
publisher
Nature Publishing Group
external identifiers
  • wos:000256212000019
  • scopus:44349142294
ISSN
1546-1718
DOI
10.1038/ng.140
language
English
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yes
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e5825bc5-a319-4b99-9dc2-d028af4cf8e1 (old id 1201605)
date added to LUP
2008-09-15 11:41:53
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2017-11-19 03:42:26
@article{e5825bc5-a319-4b99-9dc2-d028af4cf8e1,
  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.},
  author       = {Loos, Ruth J. F. and Lindgren, Cecilia M. and Li, Shengxu and Wheeler, Eleanor and Zhao, Jing Hua and Prokopenko, Inga and Inouye, Michael and Freathy, Rachel M. and Attwood, Antony P. and Beckmann, Jacques S. and Berndt, Sonja I. and Bergmann, Sven and Bennett, Amanda J. and Bingham, Sheila A. and Bochud, Murielle and Brown, Morris and Cauchi, Stephane and Connell, John M. and Cooper, Cyrus and Smith, George Davey and Day, Ian and Dina, Christian and De, Subhajyoti and Dermitzakis, Emmanouil T. and Doney, Alex S. F. and Elliott, Katherine S. and Elliott, Paul and Evans, David M. and Farooqi, I. Sadaf and Froguel, Philippe and Ghori, Jilur and Groves, Christopher J. and Gwilliam, Rhian and Hadley, David and Hall, Alistair S. and Hattersley, Andrew T. and Hebebrand, Johannes and Heid, Iris M. and Herrera, Blanca and Hinney, Anke and Hunt, Sarah E. and Jarvelin, Marjo-Riitta and Johnson, Toby and Jolley, Jennifer D. M. and Karpe, Fredrik and Keniry, Andrew and Khaw, Kay-Tee and Luben, Robert N. and Mangino, Massimo and Marchini, Jonathan and McArdle, Wendy L. and McGinnis, Ralph and Meyre, David and Munroe, Patricia B. and Morris, Andrew D. and Ness, Andrew R. and Neville, Matthew J. and Nica, Alexandra C. and Ong, Ken K. and O'Rahilly, Stephen and Owen, Katharine R. and Palmer, Colin N. A. and Papadakis, Konstantinos and Potter, Simon and Pouta, Anneli and Qi, Lu and Randall, Joshua C. and Rayner, Nigel W. and Ring, Susan M. and Sandhu, Manjinder S. and Scherag, Andre and Sims, Matthew A. and Song, Kijoung and Soranzo, Nicole and Speliotes, Elizabeth K. and Syddall, Holly E. and Teichmann, Sarah A. and Timpson, Nicholas J. and Tobias, Jonathan H. and Uda, Manuela and Vogel, Carla I. Ganz and Wallace, Chris and Waterworth, Dawn M. and Weedon, Michael N. and Willer, Cristen J. and Wraight, Vicki L. and Yuan, Xin and Zeggini, Eleftheria and Hirschhorn, Joel N. and Strachan, David P. and Ouwehand, Willem H. and Caulfield, Mark J. and Samani, Nilesh J. and Frayling, Timothy M. and Vollenweider, Peter and Waeber, Gerard and Mooser, Vincent and Deloukas, Panos and McCarthy, Mark I. and Wareham, Nicholas J. and Barroso, Ines and Cancer Screening Trial:, The Prostate, Lung, Colorectal, and Ovarian (PLCO) and Ridderstråle, Martin and Groop, Leif and al, et},
  issn         = {1546-1718},
  language     = {eng},
  number       = {6},
  pages        = {768--775},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Common variants near MC4R are associated with fat mass, weight and risk of obesity},
  url          = {http://dx.doi.org/10.1038/ng.140},
  volume       = {40},
  year         = {2008},
}