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

by: Ruth J F J Loos, Cecilia M M Lindgren, Shengxu Li, Eleanor Wheeler, Jing Hua H Zhao, Inga Prokopenko, Michael Inouye, Rachel M M Freathy, Antony P P Attwood, Jacques S S Beckmann, Sonja I I Berndt, , Kevin B B Jacobs, Stephen J J Chanock, Richard B B Hayes, Sven Bergmann, Amanda J J Bennett, Sheila A A Bingham, Murielle Bochud, Morris Brown, Stéphane Cauchi, John M M Connell, Cyrus Cooper, George Davey D Smith, Ian Day, Christian Dina, Subhajyoti De, Emmanouil T T Dermitzakis, Alex S F S Doney, Katherine S S Elliott, Paul Elliott, David M M Evans, I Sadaf Farooqi, Philippe Froguel, Jilur Ghori, Christopher J J Groves, Rhian Gwilliam, David Hadley, Alistair S S Hall, Andrew T T Hattersley, Johannes Hebebrand, Iris M M Heid, , Claudia Lamina, Christian Gieger, Thomas Illig, Thomas Meitinger, H-Erich E Wichmann, Blanca Herrera, Anke Hinney, Sarah E E Hunt, Marjo-Riitta R Jarvelin, Toby Johnson, Jennifer D M D Jolley, Fredrik Karpe, Andrew Keniry, Kay-Tee T Khaw, Robert N N Luben, Massimo Mangino, Jonathan Marchini, Wendy L L McArdle, Ralph McGinnis, David Meyre, Patricia B B Munroe, Andrew D D Morris, Andrew R R Ness, Matthew J J Neville, Alexandra C C Nica, Ken K K Ong, Stephen O'Rahilly, Katharine R R Owen, Colin N A N Palmer, Konstantinos Papadakis, Simon Potter, Anneli Pouta, Lu Qi, , Peter Kraft, Susan E E Hankinson, David J J Hunter, Frank B B Hu, Joshua C C Randall, Nigel W W Rayner, Susan M M Ring, Manjinder S S Sandhu, André Scherag, Matthew A A Sims, Kijoung Song, Nicole Soranzo, Elizabeth K K Speliotes, , Helen N N Lyon, Benjamin F F Voight, Martin Ridderstrale, Leif Groop, Holly E E Syddall, Sarah A A Teichmann, Nicholas J J Timpson, Jonathan H H Tobias, Manuela Uda, , Paul Scheet, Serena Sanna, Goncalo R R Abecasis, Giuseppe Albai, Ramaiah Nagaraja, David Schlessinger, Carla I I Ganz Vogel, Chris Wallace, Dawn M M Waterworth, Michael N N Weedon, , Cristen J J Willer, , Anne U U Jackson, Jaakko Tuomilehto, Francis S S Collins, Michael Boehnke, Karen L L Mohlke, Vicki L L Wraight, Xin Yuan, Eleftheria Zeggini, Joel N N Hirschhorn, David P P Strachan, Willem H H Ouwehand, Mark J J Caulfield, Nilesh J J Samani, Timothy M M Frayling, Peter Vollenweider, Gerard Waeber, Vincent Mooser, Panos Deloukas, Mark I I McCarthy, Nicholas J J Wareham, Inês Barroso

Nature genetics (4 May 2008)

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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.

@article{citeulike:2764340, 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.}, address = {[1] MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. [2] Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. [3] These authors contributed equally to this work.}, author = {Loos, Ruth J F J. and Lindgren, Cecilia M M. and Li, Shengxu and Wheeler, Eleanor and Zhao, Jing Hua H. and Prokopenko, Inga and Inouye, Michael and Freathy, Rachel M M. and Attwood, Antony P P. and Beckmann, Jacques S S. and Berndt, Sonja I I. and and Jacobs, Kevin B B. and Chanock, Stephen J J. and Hayes, Richard B B. and Bergmann, Sven and Bennett, Amanda J J. and Bingham, Sheila A A. and Bochud, Murielle and Brown, Morris and Cauchi, St\'{e}phane and Connell, John M M. and Cooper, Cyrus and Smith, George Davey D. and Day, Ian and Dina, Christian and De, Subhajyoti and Dermitzakis, Emmanouil T T. and Doney, Alex S F S. and Elliott, Katherine S S. and Elliott, Paul and Evans, David M M. and Sadaf Farooqi, I and Froguel, Philippe and Ghori, Jilur and Groves, Christopher J J. and Gwilliam, Rhian and Hadley, David and Hall, Alistair S S. and Hattersley, Andrew T T. and Hebebrand, Johannes and Heid, Iris M M. and and Lamina, Claudia and Gieger, Christian and Illig, Thomas and Meitinger, Thomas and Wichmann, H-Erich E. and Herrera, Blanca and Hinney, Anke and Hunt, Sarah E E. and Jarvelin, Marjo-Riitta R. and Johnson, Toby and Jolley, Jennifer D M D. and Karpe, Fredrik and Keniry, Andrew and Khaw, Kay-Tee T. and Luben, Robert N N. and Mangino, Massimo and Marchini, Jonathan and McArdle, Wendy L L. and McGinnis, Ralph and Meyre, David and Munroe, Patricia B B. and Morris, Andrew D D. and Ness, Andrew R R. and Neville, Matthew J J. and Nica, Alexandra C C. and Ong, Ken K K. and O'Rahilly, Stephen and Owen, Katharine R R. and Palmer, Colin N A N. and Papadakis, Konstantinos and Potter, Simon and Pouta, Anneli and Qi, Lu and and Kraft, Peter and Hankinson, Susan E E. and Hunter, David J J. and Hu, Frank B B. and Randall, Joshua C C. and Rayner, Nigel W W. and Ring, Susan M M. and Sandhu, Manjinder S S. and Scherag, Andr\'{e} and Sims, Matthew A A. and Song, Kijoung and Soranzo, Nicole and Speliotes, Elizabeth K K. and and Lyon, Helen N N. and Voight, Benjamin F F. and Ridderstrale, Martin and Groop, Leif and Syddall, Holly E E. and Teichmann, Sarah A A. and Timpson, Nicholas J J. and Tobias, Jonathan H H. and Uda, Manuela and and Scheet, Paul and Sanna, Serena and Abecasis, Goncalo R R. and Albai, Giuseppe and Nagaraja, Ramaiah and Schlessinger, David and Ganz Vogel, Carla I I. and Wallace, Chris and Waterworth, Dawn M M. and Weedon, Michael N N. and and Willer, Cristen J J. and and Jackson, Anne U U. and Tuomilehto, Jaakko and Collins, Francis S S. and Boehnke, Michael and Mohlke, Karen L L. and Wraight, Vicki L L. and Yuan, Xin and Zeggini, Eleftheria and Hirschhorn, Joel N N. and Strachan, David P P. and Ouwehand, Willem H H. and Caulfield, Mark J J. and Samani, Nilesh J J. and Frayling, Timothy M M. and Vollenweider, Peter and Waeber, Gerard and Mooser, Vincent and Deloukas, Panos and McCarthy, Mark I I. and Wareham, Nicholas J J. and Barroso, In\^{e}s }, citeulike-article-id = {2764340}, doi = {10.1038/ng.140}, issn = {1546-1718}, journal = {Nature genetics}, month = {May}, posted-at = {2008-05-07 09:46:27}, priority = {2}, title = {Common variants near MC4R are associated with fat mass, weight and risk of obesity.}, url = {http://dx.doi.org/10.1038/ng.140}, year = {2008} }

RIS record

TY - JOUR ID - citeulike:2764340 L3 - citeulike-article-id:2764340 TI - Common variants near MC4R are associated with fat mass, weight and risk of obesity. JF - Nature genetics AD - [1] MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. [2] Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. [3] These authors contributed equally to this work. SN - 1546-1718 N2 - 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. AU - Loos, Ruth J F AU - Lindgren, Cecilia M AU - Li, Shengxu AU - Wheeler, Eleanor AU - Zhao, Jing Hua AU - Prokopenko, Inga AU - Inouye, Michael AU - Freathy, Rachel M AU - Attwood, Antony P AU - Beckmann, Jacques S AU - Berndt, Sonja I AU - Jacobs, Kevin B AU - Chanock, Stephen J AU - Hayes, Richard B AU - Bergmann, Sven AU - Bennett, Amanda J AU - Bingham, Sheila A AU - Bochud, Murielle AU - Brown, Morris AU - Cauchi, Stéphane AU - Connell, John M AU - Cooper, Cyrus AU - Smith, George Davey AU - Day, Ian AU - Dina, Christian AU - De, Subhajyoti AU - Dermitzakis, Emmanouil T AU - Doney, Alex S F AU - Elliott, Katherine S AU - Elliott, Paul AU - Evans, David M AU - Sadaf Farooqi, I AU - Froguel, Philippe AU - Ghori, Jilur AU - Groves, Christopher J AU - Gwilliam, Rhian AU - Hadley, David AU - Hall, Alistair S AU - Hattersley, Andrew T AU - Hebebrand, Johannes AU - Heid, Iris M AU - Lamina, Claudia AU - Gieger, Christian AU - Illig, Thomas AU - Meitinger, Thomas AU - Wichmann, H-Erich AU - Herrera, Blanca AU - Hinney, Anke AU - Hunt, Sarah E AU - Jarvelin, Marjo-Riitta AU - Johnson, Toby AU - Jolley, Jennifer D M AU - Karpe, Fredrik AU - Keniry, Andrew AU - Khaw, Kay-Tee AU - Luben, Robert N AU - Mangino, Massimo AU - Marchini, Jonathan AU - McArdle, Wendy L AU - McGinnis, Ralph AU - Meyre, David AU - Munroe, Patricia B AU - Morris, Andrew D AU - Ness, Andrew R AU - Neville, Matthew J AU - Nica, Alexandra C AU - Ong, Ken K AU - O'Rahilly, Stephen AU - Owen, Katharine R AU - Palmer, Colin N A AU - Papadakis, Konstantinos AU - Potter, Simon AU - Pouta, Anneli AU - Qi, Lu AU - Kraft, Peter AU - Hankinson, Susan E AU - Hunter, David J AU - Hu, Frank B AU - Randall, Joshua C AU - Rayner, Nigel W AU - Ring, Susan M AU - Sandhu, Manjinder S AU - Scherag, André AU - Sims, Matthew A AU - Song, Kijoung AU - Soranzo, Nicole AU - Speliotes, Elizabeth K AU - Lyon, Helen N AU - Voight, Benjamin F AU - Ridderstrale, Martin AU - Groop, Leif AU - Syddall, Holly E AU - Teichmann, Sarah A AU - Timpson, Nicholas J AU - Tobias, Jonathan H AU - Uda, Manuela AU - Scheet, Paul AU - Sanna, Serena AU - Abecasis, Goncalo R AU - Albai, Giuseppe AU - Nagaraja, Ramaiah AU - Schlessinger, David AU - Ganz Vogel, Carla I AU - Wallace, Chris AU - Waterworth, Dawn M AU - Weedon, Michael N AU - Willer, Cristen J AU - Jackson, Anne U AU - Tuomilehto, Jaakko AU - Collins, Francis S AU - Boehnke, Michael AU - Mohlke, Karen L AU - Wraight, Vicki L AU - Yuan, Xin AU - Zeggini, Eleftheria AU - Hirschhorn, Joel N AU - Strachan, David P AU - Ouwehand, Willem H AU - Caulfield, Mark J AU - Samani, Nilesh J AU - Frayling, Timothy M AU - Vollenweider, Peter AU - Waeber, Gerard AU - Mooser, Vincent AU - Deloukas, Panos AU - McCarthy, Mark I AU - Wareham, Nicholas J AU - Barroso, Inês PY - 2008/05/04/ UR - http://dx.doi.org/10.1038/ng.140 ER -

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