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

Common variants near MC4R are associated with fat mass, weight and risk of obesity
Common variants near MC4R are associated with fat mass, weight and risk of obesity
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
1061-4036
768-775
Loos, Ruth J.F.
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Lindgren, Cecilia M.
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Li, Shengxu
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Wheeler, Eleanor
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Zhao, Jing Hua
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Prokopenko, Inga
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Inouye, Michael
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Freathy, Rachel M.
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Attwood, Antony P.
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Beckmann, Jacques S.
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Jacobs, Kevin B.
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Chanock, Stephen J.
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Wichmann, H-Erich
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Herrera, Blanca
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Hinney, Anke
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Hunt, Sarah E.
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Johnson, Toby
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Jolley, Jennifer D.M.
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Marchini, Jonathan
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Qi, Lu
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Randall, Joshua C.
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Scherag, Andre
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Sims, Mathew A.
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Song, Kijoung
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Soranzo, Nicole
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Tobias, Jonathan H.
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Ganz Vogel, Carla I.
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Wallace, Chris
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Hirschhorn, Joel N.
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Strachan, David P.
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Wallace, Chris
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Wraight, Vicki L
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Zeggini, Eleftheria
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Frayling, Timothy M.
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Vollenweider, Peter
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Waeber, Gerard
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Mooser, Vincent
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Deloukas, Panos
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McCarthy, Mark I.
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Wareham, Nicholas J.
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Barroso, Ines
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Kraft, Peter
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Hankinson, Susan E.
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Hunter, David J.
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Hu, Frank B.
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Lyon, Helen N.
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Voight, Benjamin F.
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Ridderstrale, Midderstrale
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Groop, Leif
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Scheet, Paul
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Sanna, Serena
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Abecasis, Goncalo R.
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Albai, Giuseppe
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Nagaraja, Ramaiah
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Schlessinger, David
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Jackson, Anne U.
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Tuomilehto, Jaakko
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Collins, Francis S.
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Boehnke, Michael
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Mohlke, Karen L
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Hebebrand, Johannes
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Yuan, Xin
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Ouwehand, Willem H.
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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, Stephane, Connell, John M., Cooper, Cyrus, Smith, George Davey, Day, Ian, Dina, Christian, De, Subhayoti, Dermitzakis, Emmanouil T., Doney, Alex S.F., Elliott, Katherine S., Elliott, Paul, Evans, David M., Farooqi, I.Sadaf, Froguel, Phillipe, Ghori, Jilur, Groves, Christopher J., Gwilliam, Rhian, Hadley, David, Hall, Alistair S., Hattersley, A. T. J., Heid, Iris M., Lamina, Claudia, Gieger, Christian, Illig, Thomas, Meitinger, Thomas, Wichmann, H-Erich, Herrera, Blanca, Hinney, Anke, Hunt, Sarah E., Jarvelin, Manjo-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, A.lexandra C., Ong, Ken K., O'Rahilly, Stephen, Owen, Katharine R., Palmer, Colin N., Papadakis, Konstantinos, Potter, Simon, Pouta, Anneli, Qi, Lu, Randall, Joshua C., Rayner, Nigel W., Ring, Susan M., Sandhu, Manjinder S., Scherag, Andre, Sims, Mathew A., Song, Kijoung, Soranzo, Nicole, Speliotes, Elizabeth K., Syddall, Holly E., Teichmann, Sarah A., Timpson, Nicholas J., Tobias, Jonathan H., Uda, Manuela, Ganz Vogel, Carla I., Wallace, Chris, Waterworth, Dawn M., Weedon, Michael N., Willer, Cristen J., Wraight, Vicki L, Zeggini, Eleftheria, Hirschhorn, Joel N., Strachan, David P., Caulfield, Mark J., Samani, Nilesh J., Frayling, Timothy M., Vollenweider, Peter, Waeber, Gerard, Mooser, Vincent, Deloukas, Panos, McCarthy, Mark I., Wareham, Nicholas J., Barroso, Ines, Kraft, Peter, Hankinson, Susan E., Hunter, David J., Hu, Frank B., Lyon, Helen N., Voight, Benjamin F., Ridderstrale, Midderstrale, Groop, Leif, Scheet, Paul, Sanna, Serena, Abecasis, Goncalo R., Albai, Giuseppe, Nagaraja, Ramaiah, Schlessinger, David, Jackson, Anne U., Tuomilehto, Jaakko, Collins, Francis S., Boehnke, Michael, Mohlke, Karen L, Hebebrand, Johannes, Yuan, Xin and Ouwehand, Willem H. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics, 40 (6), 768-775. (doi:10.1038/ng.140).

Record type: Article

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

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Published date: May 2008
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Identifiers

Local EPrints ID: 61340
URI: http://eprints.soton.ac.uk/id/eprint/61340
DOI: doi:10.1038/ng.140
ISSN: 1061-4036
PURE UUID: 3b621549-edd0-4b3a-b979-1a382ba30a34
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Holly E. Syddall: ORCID iD orcid.org/0000-0003-0171-0306

Catalogue record

Date deposited: 25 Mar 2009
Last modified: 18 Mar 2024 02:48

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Contributors

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

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