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, Kevin B. Jacobs, Stephen J. Chanock, Richard B. Hayes, Sven Bergmann, Amanda J. Bennett, Sheila A. Bingham, Murielle Bochud, Morris Brown, Stéphane CauchiJohn 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, 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, 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, Peter Kraft, Susan E. Hankinson, David J. Hunter, Frank B. Hu, Joshua C. Randall, Nigel W. Rayner, Susan M. Ring, Manjinder S. Sandhu, André Scherag, Matthew A. Sims, Kijoung Song, Nicole Soranzo, Elizabeth K. Speliotes, Helen N. Lyon, Benjamin F. Voight, Martin Ridderstrale, Leif Groop, Holly E. Syddall, Sarah A. Teichmann, Nicholas J. Timpson, Jonathan H. Tobias, Manuela Uda, Paul Scheet, Serena Sanna, Goncalo R. Abecasis, Giuseppe Albai, Ramaiah Nagaraja, David Schlessinger, Carla I. Ganz Vogel, Chris Wallace, Dawn M. Waterworth, Michael N. Weedon, Cristen J. Willer, Anne U. Jackson, Jaakko Tuomilehto, Francis S. Collins, Michael Boehnke, Karen L. Mohlke, 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, Inês Barroso

Research output: Contribution to journalArticle

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 × 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 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 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 × 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.

Original languageEnglish (US)
Pages (from-to)768-775
Number of pages8
JournalNature Genetics
Volume40
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Fingerprint

Receptor, Melanocortin, Type 4
Morbid Obesity
Obesity
Pediatric Obesity
Fats
Weights and Measures
Body Mass Index
Alleles
Pedigree
Single Nucleotide Polymorphism
Genome
Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Loos, R. J. F., Lindgren, C. M., Li, S., Wheeler, E., Zhao, J. H., Prokopenko, I., ... Barroso, I. (2008). Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics, 40(6), 768-775. https://doi.org/10.1038/ng.140

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

In: Nature Genetics, Vol. 40, No. 6, 06.2008, p. 768-775.

Research output: Contribution to journalArticle

Loos, RJF, Lindgren, CM, Li, S, Wheeler, E, Zhao, JH, Prokopenko, I, Inouye, M, Freathy, RM, Attwood, AP, Beckmann, JS, Berndt, SI, 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, ASF, 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, Lamina, C, Gieger, C, Illig, T, Meitinger, T, Wichmann, HE, Herrera, B, Hinney, A, Hunt, SE, Jarvelin, MR, Johnson, T, Jolley, JDM, 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, CNA, Papadakis, K, Potter, S, Pouta, A, Qi, L, Kraft, P, Hankinson, SE, Hunter, DJ, Hu, FB, Randall, JC, Rayner, NW, Ring, SM, Sandhu, MS, Scherag, A, Sims, MA, Song, K, Soranzo, N, Speliotes, EK, Lyon, HN, Voight, BF, Ridderstrale, M, Groop, L, Syddall, HE, Teichmann, SA, Timpson, NJ, Tobias, JH, Uda, M, Scheet, P, Sanna, S, Abecasis, GR, Albai, G, Nagaraja, R, Schlessinger, D, Ganz Vogel, CI, Wallace, C, Waterworth, DM, Weedon, MN, Willer, CJ, Jackson, AU, Tuomilehto, J, Collins, FS, Boehnke, M, Mohlke, KL, Wraight, VL, 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 2008, 'Common variants near MC4R are associated with fat mass, weight and risk of obesity', Nature Genetics, vol. 40, no. 6, pp. 768-775. https://doi.org/10.1038/ng.140
Loos RJF, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics. 2008 Jun;40(6):768-775. https://doi.org/10.1038/ng.140
Loos, Ruth J F ; Lindgren, Cecilia M. ; Li, Shengxu ; Wheeler, Eleanor ; Zhao, Jing Hua ; Prokopenko, Inga ; Inouye, Michael ; Freathy, Rachel M. ; Attwood, Antony P. ; Beckmann, Jacques S. ; Berndt, Sonja I. ; Jacobs, Kevin B. ; Chanock, Stephen J. ; Hayes, Richard B. ; Bergmann, Sven ; Bennett, Amanda J. ; Bingham, Sheila A. ; Bochud, Murielle ; Brown, Morris ; Cauchi, Stéphane ; Connell, John M. ; Cooper, Cyrus ; Smith, George Davey ; Day, Ian ; Dina, Christian ; De, Subhajyoti ; Dermitzakis, Emmanouil T. ; Doney, Alex S F ; Elliott, Katherine S. ; Elliott, Paul ; Evans, David M. ; Sadaf Farooqi, I. ; Froguel, Philippe ; Ghori, Jilur ; Groves, Christopher J. ; Gwilliam, Rhian ; Hadley, David ; Hall, Alistair S. ; Hattersley, Andrew T. ; Hebebrand, Johannes ; Heid, Iris M. ; Lamina, Claudia ; Gieger, Christian ; Illig, Thomas ; Meitinger, Thomas ; Wichmann, H. Erich ; Herrera, Blanca ; Hinney, Anke ; Hunt, Sarah E. ; Jarvelin, Marjo Riitta ; Johnson, Toby ; Jolley, Jennifer D M ; Karpe, Fredrik ; Keniry, Andrew ; Khaw, Kay Tee ; Luben, Robert N. ; Mangino, Massimo ; Marchini, Jonathan ; McArdle, Wendy L. ; McGinnis, Ralph ; Meyre, David ; Munroe, Patricia B. ; Morris, Andrew D. ; Ness, Andrew R. ; Neville, Matthew J. ; Nica, Alexandra C. ; Ong, Ken K. ; O'Rahilly, Stephen ; Owen, Katharine R. ; Palmer, Colin N A ; Papadakis, Konstantinos ; Potter, Simon ; Pouta, Anneli ; Qi, Lu ; Kraft, Peter ; Hankinson, Susan E. ; Hunter, David J. ; Hu, Frank B. ; Randall, Joshua C. ; Rayner, Nigel W. ; Ring, Susan M. ; Sandhu, Manjinder S. ; Scherag, André ; Sims, Matthew A. ; Song, Kijoung ; Soranzo, Nicole ; Speliotes, Elizabeth K. ; Lyon, Helen N. ; Voight, Benjamin F. ; Ridderstrale, Martin ; Groop, Leif ; Syddall, Holly E. ; Teichmann, Sarah A. ; Timpson, Nicholas J. ; Tobias, Jonathan H. ; Uda, Manuela ; Scheet, Paul ; Sanna, Serena ; Abecasis, Goncalo R. ; Albai, Giuseppe ; Nagaraja, Ramaiah ; Schlessinger, David ; Ganz Vogel, Carla I. ; Wallace, Chris ; Waterworth, Dawn M. ; Weedon, Michael N. ; Willer, Cristen J. ; Jackson, Anne U. ; Tuomilehto, Jaakko ; Collins, Francis S. ; Boehnke, Michael ; Mohlke, Karen L. ; Wraight, Vicki L. ; Yuan, Xin ; Zeggini, Eleftheria ; Hirschhorn, Joel N. ; Strachan, David P. ; Ouwehand, Willem H. ; Caulfield, Mark J. ; Samani, Nilesh J. ; Frayling, Timothy M. ; Vollenweider, Peter ; Waeber, Gerard ; Mooser, Vincent ; Deloukas, Panos ; McCarthy, Mark I. ; Wareham, Nicholas J. ; Barroso, Inês. / Common variants near MC4R are associated with fat mass, weight and risk of obesity. In: Nature Genetics. 2008 ; Vol. 40, No. 6. pp. 768-775.
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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 × 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 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 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 × 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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T1 - Common variants near MC4R are associated with fat mass, weight and risk of obesity

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 - 2008/6

Y1 - 2008/6

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 × 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 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 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 × 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.

AB - 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 × 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 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 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 × 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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