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

Rjf, Loos; et A. L. Willer Cristen, J.; Wl, McArdle; Zhao, Jing Hua; Loos, Ruth J. F.; Lindgren, Cecilia M.; Sx, Li; Li, Shengxu X.; Rj, Loos; Jh, Zhao; Trial, and Ovarian (PLCO) Cancer Screening; Wheeler, Eleanor; Kb, Jacobs; Se, Hunt; Sj, Chanock; Rb, Hayes; Prokopenko, Inga; Sa, Bingham; Ovarian Cancer Screening, Trial; Inouye, Michael; Screening, Trial Ovarian Cancer; Jm, Connell; Ks, Elliott; Kora,; Wellcome Trust Case Control Consor, Nurses' Health Study FUSION Diabetes Genetics Initiative SardiNIA Study Prostate Lung Colorectal Ovarian KORA; Mr, Järvelin; Rm, Freathy; Smith, George Davey; Lamina, Claudia; Im, Heid; He, Wichmann; Rn, Luben; Jacobs, Kevin B.; Illig, Thomas; Meitinger, Thomas; Jd, Jolley; Pb, Munroe; Wichmann, He-Erich; Sadaf Farooqi, I.; Vl, Wraight; Mj, Neville; Js, Beckmann; Value], Kora [No; Kt, Khaw; Jdm, Jolley; Si, Berndt; Vogel, Carla I. Ganz; Hebebrand, Johannes; Study, Nurses' Health; Heid, Iris M.; Nw, Rayner; Sm, Ring; Lung,; Herrera, Blanca; Prostate, Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial; Hinney, Anke; Ms, Sandhu; Ma, Sims; Johnson, Toby; Hunt, Sarah E.; Kk, Ong; Jarvelin, Marjo-Riitta; Karpe, Fredrik; Sa, Teichmann; Kr, Owen; Keniry, Andrew; Nj, Timpson; Jolley, Jennifer D. M.; Initiative, Diabetes Genetics; Freathy, Rachel M.; SardiNIA, Study; Mangino, Massimo; Is, Farooqi; Attwood, Antony P.; Jc, Randall; Beckmann, Jacques S.; Marchini, Jonathan; Khaw, Kay-Tee; Berndt, Sonja I.; Mn, Weedon; Mcginnis, Ralph; Luben, Robert N.; Bergmann, Sven; Meyre, David; Ness, Andrew R.; Bennett, Amanda J.; Bochud, Murielle; Bingham, Sheila A.; McArdle, Wendy L.; Brown, Morris; He, Syddall; Cauchi, Stéphane; Munroe, Patricia B.; Wh, Ouwehand; Willer, Cristen J.; Connell, John M.; Cooper, Cyrus; Morris, Andrew D.; O'Rahilly, Stephen; Mj, Caulfield; Lamina, C.; Jh, Tobias; Day, Ian; Wraight, Vicki L.; Nj, Samani; Hunter, David J.; Illig, T.; Yuan, Xin; Neville, Matthew J.; Dina, Christian; Meitinger, T.; Chanock, Stephen J.; Zeggini, Eleftheria; Nica, Alexandra C.; Papadakis, Konstantinos; De, Subhajyoti; Tm, Frayling; Hu, Frank B.; Ong, Ken Kk; Dermitzakis, Emmanouil T.; Potter, Simon; Doney, Alex S. F.; Pouta, Anneli; Elliott, P.; Owen, Katharine R.; Health, Study Nurses'; Elliott, Katherine S.; Qi, Lu; Mi, McCarthy; Nj, Wareham; Palmer, Colin N. A.; Hayes, Richard B.; Evans, David M.; Froguel, Philippe; Jn, Hirschhorn; Ghori, Jilur; Gwilliam, Rhian; Groves, Christopher J.; Lyon, Helen N.; Scherag, Andre; Hadley, David; Randall, Joshua C.; Voight, Benjamin F.; Kraft, Peter; Hall, Alistair S.; Rayner, Nigel W.; Song, Kijoung; Hattersley, Andrew T.; Ring, Susan M.; Soranzo, Nicole; Sandhu, Manjinder S.; Sims, Matthew A.; Tobias, Jonathan H.; Hn, Lyon; Speliotes, Elizabeth K.; Uda, Manuela; Ridderstråle, Martin; Gieger, C.; Sardi, N. I. A. Study; Syddall, Holly E.; Teichmann, Sarah A.; Kl, Mohlke; Timpson, Nicholas J.; Wallace, Chris; Cm, Lindgren; Scheet, Paul; Sanna, Serena; Aj, Bennett; Jackson, Anne U.; Nagaraja, Ramaiah; Schlessinger, David; Gd, Smith; Mohlke, Karen L.; Hankinson, Susan E.; As, Doney; Waterworth, Dawn M.; Et, Dermitzakis; Weedon, Michael N.; Tuomilehto, Jaakko; Elliott, Paul; Vollenweider, Peter; Hirschhorn, Joel N.; Dm, Evans; Waeber, Gerard; Strachan, David P.; Mooser, Vincent; Ouwehand, Willem H.; As, Hall; Cj, Groves; Samani, Nilesh J.; Asf, Doney; Gieger, Christian; Groop, Leif; McCarthy, Mark I.; Ap, Attwood; At, Hattersley; Wareham, Nicholas J.; Davey Smith, George; Erich Wichmann, H.; Abecasis, Gonçalo R.; Ad, Morris; Ar, Ness; Cn, Palmer; Ac, Nica; Colorectal,; Albai, Giuseppe; Farooqi, I. Sadaf; Ek, Speliotes; Cna, Palmer; Ci, Vogel; Ganz Vogel, Carla I.; Fusion,; Collins, Francis S.; Consortium, Wellcome Trust Case Control; Dm, Waterworth; Cj, Willer; Dp, Strachan; Boehnke, Michael; Cig, Vogel; Genetics, Initiative Diabetes; Dj, Hunter; Caulfield, Mark J.; Deloukas, Panos; Fb, Hu; Bf, Voight; Frayling, Timothy M.; Barroso, Inês; Gr, Abecasis; Cancer Screening Trial:, Prostate Lung Colorectal and Ovarian (PLCO); Au, Jackson; Breen, Gerome; Fs, Collins; Control, Consortium Wellcome Trust Case; Al, Et; Bradbury, Linda A.

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Inga Prokopenko
Rjf et al., 2008

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Nature Research, Nature Genetics, 6(40), p. 768-775, 2008

DOI: 10.1038/ng.140

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@article{Rjf2008,
  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. ; 20477},
  author = {Rjf, Loos and et A. L. Willer Cristen, J. and Wl, McArdle and Zhao, Jing Hua and Loos, Ruth J. F. and Lindgren, Cecilia M. and Sx, Li and Li, Shengxu X. and Rj, Loos and Jh, Zhao and Trial, and Ovarian (PLCO) Cancer Screening and Wheeler, Eleanor and Kb, Jacobs and Se, Hunt and Sj, Chanock and Rb, Hayes and Prokopenko, Inga and Sa, Bingham and Ovarian Cancer Screening, Trial and Inouye, Michael and Screening, Trial Ovarian Cancer and Jm, Connell and Ks, Elliott and Kora,  and Wellcome Trust Case Control Consor, Nurses' Health Study FUSION Diabetes Genetics Initiative SardiNIA Study Prostate Lung Colorectal Ovarian KORA and Mr, Järvelin and Rm, Freathy and Smith, George Davey and Lamina, Claudia and Im, Heid and He, Wichmann and Rn, Luben and Jacobs, Kevin B. and Illig, Thomas and Meitinger, Thomas and Jd, Jolley and Pb, Munroe and Wichmann, He-Erich and Sadaf Farooqi, I. and Vl, Wraight and Mj, Neville and Js, Beckmann and Value], Kora [No and Kt, Khaw and Jdm, Jolley and Si, Berndt and Vogel, Carla I. Ganz and Hebebrand, Johannes and Study, Nurses' Health and Heid, Iris M. and Nw, Rayner and Sm, Ring and Lung,  and Herrera, Blanca and Prostate, Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial and Hinney, Anke and Ms, Sandhu and Ma, Sims and Johnson, Toby and Hunt, Sarah E. and Kk, Ong and Jarvelin, Marjo-Riitta and Karpe, Fredrik and Sa, Teichmann and Kr, Owen and Keniry, Andrew and Nj, Timpson and Jolley, Jennifer D. M. and Initiative, Diabetes Genetics and Freathy, Rachel M. and SardiNIA, Study and Mangino, Massimo and Is, Farooqi and Attwood, Antony P. and Jc, Randall and Beckmann, Jacques S. and Marchini, Jonathan and Khaw, Kay-Tee and Berndt, Sonja I. and Mn, Weedon and Mcginnis, Ralph and Luben, Robert N. and Bergmann, Sven and Meyre, David and Ness, Andrew R. and Bennett, Amanda J. and Bochud, Murielle and Bingham, Sheila A. and McArdle, Wendy L. and Brown, Morris and He, Syddall and Cauchi, Stéphane and Munroe, Patricia B. and Wh, Ouwehand and Willer, Cristen J. and Connell, John M. and Cooper, Cyrus and Morris, Andrew D. and O'Rahilly, Stephen and Mj, Caulfield and Lamina, C. and Jh, Tobias and Day, Ian and Wraight, Vicki L. and Nj, Samani and Hunter, David J. and Illig, T. and Yuan, Xin and Neville, Matthew J. and Dina, Christian and Meitinger, T. and Chanock, Stephen J. and Zeggini, Eleftheria and Nica, Alexandra C. and Papadakis, Konstantinos and De, Subhajyoti and Tm, Frayling and Hu, Frank B. and Ong, Ken Kk and Dermitzakis, Emmanouil T. and Potter, Simon and Doney, Alex S. F. and Pouta, Anneli and Elliott, P. and Owen, Katharine R. and Health, Study Nurses' and Elliott, Katherine S. and Qi, Lu and Mi, McCarthy and Nj, Wareham and Palmer, Colin N. A. and Hayes, Richard B. and Evans, David M. and Froguel, Philippe and Jn, Hirschhorn and Ghori, Jilur and Gwilliam, Rhian and Groves, Christopher J. and Lyon, Helen N. and Scherag, Andre and Hadley, David and Randall, Joshua C. and Voight, Benjamin F. and Kraft, Peter and Hall, Alistair S. and Rayner, Nigel W. and Song, Kijoung and Hattersley, Andrew T. and Ring, Susan M. and Soranzo, Nicole and Sandhu, Manjinder S. and Sims, Matthew A. and Tobias, Jonathan H. and Hn, Lyon and Speliotes, Elizabeth K. and Uda, Manuela and Ridderstråle, Martin and Gieger, C. and Sardi, N. I. A. Study and Syddall, Holly E. and Teichmann, Sarah A. and Kl, Mohlke and Timpson, Nicholas J. and Wallace, Chris and Cm, Lindgren and Scheet, Paul and Sanna, Serena and Aj, Bennett and Jackson, Anne U. and Nagaraja, Ramaiah and Schlessinger, David and Gd, Smith and Mohlke, Karen L. and Hankinson, Susan E. and As, Doney and Waterworth, Dawn M. and Et, Dermitzakis and Weedon, Michael N. and Tuomilehto, Jaakko and Elliott, Paul and Vollenweider, Peter and Hirschhorn, Joel N. and Dm, Evans and Waeber, Gerard and Strachan, David P. and Mooser, Vincent and Ouwehand, Willem H. and As, Hall and Cj, Groves and Samani, Nilesh J. and Asf, Doney and Gieger, Christian and Groop, Leif and McCarthy, Mark I. and Ap, Attwood and At, Hattersley and Wareham, Nicholas J. and Davey Smith, George and Erich Wichmann, H. and Abecasis, Gonçalo R. and Ad, Morris and Ar, Ness and Cn, Palmer and Ac, Nica and Colorectal,  and Albai, Giuseppe and Farooqi, I. Sadaf and Ek, Speliotes and Cna, Palmer and Ci, Vogel and Ganz Vogel, Carla I. and Fusion,  and Collins, Francis S. and Consortium, Wellcome Trust Case Control and Dm, Waterworth and Cj, Willer and Dp, Strachan and Boehnke, Michael and Cig, Vogel and Genetics, Initiative Diabetes and Dj, Hunter and Caulfield, Mark J. and Deloukas, Panos and Fb, Hu and Bf, Voight and Frayling, Timothy M. and Barroso, Inês and Gr, Abecasis and Cancer Screening Trial:, Prostate Lung Colorectal and Ovarian (PLCO) and Au, Jackson and Breen, Gerome and Fs, Collins and Control, Consortium Wellcome Trust Case and Al, Et and Bradbury, Linda A.},
  doi = {10.1038/ng.140},
  journal = {Nature Genetics},
  month = {may},
  pages = {768-775},
  title = {Common variants near MC4R are associated with fat mass, weight and risk of obesity},
  url = {http://www.nature.com/articles/ng.140.pdf},
  volume = {40},
  year = {2008}
}

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

Journal article published in 2008 by Loos Rjf, J. et A. L. Willer Cristen, McArdle Wl, Jing Hua Zhao, Ruth J. F. Loos, Cecilia M. Lindgren, Li Sx, Shengxu X. Li, Loos Rj, Zhao Jh, and Ovarian (PLCO) Cancer Screening Trial, Eleanor Wheeler, Jacobs Kb, Hunt Se, Chanock Sj and other authors. Loos Rjf, J. et A. L. Willer Cristen, McArdle Wl, Jing Hua Zhao, Ruth J. F. Loos, Cecilia M. Lindgren, Li Sx, Shengxu X. Li, Loos Rj, Zhao Jh, and Ovarian (PLCO) Cancer Screening Trial, Eleanor Wheeler, Jacobs Kb, Hunt Se, Chanock Sj, Hayes Rb, Inga Prokopenko

, Bingham Sa, Trial Ovarian Cancer Screening, Michael Inouye, Trial Ovarian Cancer Screening, Connell Jm, Elliott Ks, Kora, Nurses' Health Study FUSION Diabetes Genetics Initiative SardiNIA Study Prostate Lung Colorectal Ovarian KORA Wellcome Trust Case Control Consor, Järvelin Mr, Freathy Rm, George Davey Smith, Claudia Lamina, Heid Im, Wichmann He, Luben Rn, Kevin B. Jacobs, Thomas Illig, Thomas Meitinger, Jolley Jd, Munroe Pb, He-Erich Wichmann, I. Sadaf Farooqi, Wraight Vl, Neville Mj, Beckmann Js, Kora [No Value], Khaw Kt, Jolley Jdm, Berndt Si, Carla I. Ganz Vogel, Johannes Hebebrand, Nurses' Health Study, Iris M. Heid, Rayner Nw, Ring Sm, Lung, Blanca Herrera, Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial Prostate, Anke Hinney, Sandhu Ms, Sims Ma, Toby Johnson

, Sarah E. Hunt, Ong Kk, Marjo-Riitta Jarvelin, Fredrik Karpe, Teichmann Sa, Owen Kr, Andrew Keniry, Timpson Nj, Jennifer D. M. Jolley, Diabetes Genetics Initiative, Rachel M. Freathy

, Study SardiNIA, Massimo Mangino, Farooqi Is, Antony P. Attwood, Randall Jc, Jacques S. Beckmann, Jonathan Marchini, Kay-Tee Khaw, Sonja I. Berndt, Weedon Mn, Ralph Mcginnis, Robert N. Luben

, Sven Bergmann, David Meyre, Andrew R. Ness, Amanda J. Bennett, Murielle Bochud, Sheila A. Bingham, Wendy L. McArdle, Morris Brown, Syddall He, Stéphane Cauchi, Patricia B. Munroe, Ouwehand Wh, Cristen J. Willer, John M. Connell, Cyrus Cooper, Andrew D. Morris, Stephen O'Rahilly, Caulfield Mj, C. Lamina, Tobias Jh, Ian Day, Vicki L. Wraight, Samani Nj, David J. Hunter, T. Illig, Xin Yuan, Matthew J. Neville, Christian Dina, T. Meitinger, Stephen J. Chanock, Eleftheria Zeggini

, Alexandra C. Nica, Konstantinos Papadakis, Subhajyoti De, Frayling Tm, Frank B. Hu, Ken Kk Ong, Emmanouil T. Dermitzakis, Simon Potter, Alex S. F. Doney, Anneli Pouta, P. Elliott, Katharine R. Owen, Study Nurses' Health, Katherine S. Elliott, Lu Qi, McCarthy Mi, Wareham Nj, Colin N. A. Palmer, Richard B. Hayes

, David M. Evans, Philippe Froguel, Hirschhorn Jn, Jilur Ghori, Rhian Gwilliam, Christopher J. Groves, Helen N. Lyon, Andre Scherag, David Hadley, Joshua C. Randall, Benjamin F. Voight, Peter Kraft, Alistair S. Hall, Nigel W. Rayner, Kijoung Song, Andrew T. Hattersley, Susan M. Ring, Nicole Soranzo, Manjinder S. Sandhu, Matthew A. Sims, Jonathan H. Tobias

, Lyon Hn, Elizabeth K. Speliotes, Manuela Uda, Martin Ridderstråle, C. Gieger

, N. I. A. Study Sardi, Holly E. Syddall, Sarah A. Teichmann

, Mohlke Kl, Nicholas J. Timpson

, Chris Wallace, Lindgren Cm, Paul Scheet, Serena Sanna

, Bennett Aj, Anne U. Jackson, Ramaiah Nagaraja, David Schlessinger, Smith Gd, Karen L. Mohlke, Susan E. Hankinson, Doney As, Dawn M. Waterworth, Dermitzakis Et, Michael N. Weedon, Jaakko Tuomilehto, Paul Elliott, Peter Vollenweider, Joel N. Hirschhorn, Evans Dm, Gerard Waeber, David P. Strachan, Vincent Mooser, Willem H. Ouwehand, Hall As, Groves Cj, Nilesh J. Samani, Doney Asf, Christian Gieger, Leif Groop, Mark I. McCarthy, Attwood Ap, Hattersley At, Nicholas J. Wareham, George Davey Smith, H. Erich Wichmann, Gonçalo R. Abecasis, Morris Ad, Ness Ar, Palmer Cn, Nica Ac, Colorectal, Giuseppe Albai, I. Sadaf Farooqi, Speliotes Ek, Palmer Cna, Vogel Ci, Carla I. Ganz Vogel, Fusion, Francis S. Collins, Wellcome Trust Case Control Consortium, Waterworth Dm, Willer Cj, Strachan Dp, Michael Boehnke, Vogel Cig, Initiative Diabetes Genetics, Hunter Dj, Mark J. Caulfield, Panos Deloukas

, Hu Fb, Voight Bf, Timothy M. Frayling, Inês Barroso, Abecasis Gr, Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial:, Jackson Au, Gerome Breen, Collins Fs, Consortium Wellcome Trust Case Control, Et Al, Linda A. Bradbury

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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. ; 20477

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

Abstract