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, Sven Bergmann, Amanda J Bennett, Sheila A. Bingham, Murielle Bochud, Morris Brown, Stephane Cauchi, John M. Connell, Cyrus Cooper, George Davey SmithIan Day, Christian Dina, Subhajyoti De, Emmanouil T. Dermitzakis, A Doney, Paul Elliott, Katherine S. 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, 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, Wellcome Trust Case Control Consortium, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)768-775
Number of pages8
JournalNature Genetics
Volume40
Issue number6
Early online date4 May 2008
DOIs
Publication statusPublished - Jun 2008

Keywords

  • genome-wide association
  • melanocortin-4 receptor gene
  • early-onset obesity
  • frameshift mutation
  • adult obesity
  • expression
  • deficiency
  • childhood
  • dominant
  • humans

Cite this

Loos, R. J. F., Lindgren, C. M., Li, S., Wheeler, E., Zhao, J. H., Prokopenko, I., ... KORA (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.; 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, Subhajyoti; Dermitzakis, Emmanouil T.; Doney, A; Elliott, Paul; Elliott, Katherine S. ; Evans, David M. ; Farooqi, I. Sadaf; Froguel, Philippe; Ghori, Jilur; Groves, Christopher J.; Gwilliam, Rhian; Hadley, David; Hall, Alistair S. ; Hattersley, Andrew T.; Hebebrand, Johannes; Heid, Iris M.; 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; Wellcome Trust Case Control Consortium; Nurses' Health Study; FUSION; Diabetes Genetics Initiative; SardiNIA Study; Prostate Lung Colorectal Ovarian; KORA.

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, 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, A, Elliott, P, Elliott, KS, Evans, DM, Farooqi, IS, Froguel, P, Ghori, J, Groves, CJ, Gwilliam, R, Hadley, D, Hall, AS, Hattersley, AT, Hebebrand, J, Heid, IM, Herrera, B, Hinney, A, Hunt, SE, Jarvelin, M-R, Johnson, T, Jolley, JDM, Karpe, F, Keniry, A, Khaw, K-T, Luben, RN, Mangino, M, Marchini, J, Wellcome Trust Case Control Consortium, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian & KORA 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. ; 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, Subhajyoti ; Dermitzakis, Emmanouil T. ; Doney, A ; Elliott, Paul ; Elliott, Katherine S. ; Evans, David M. ; Farooqi, I. Sadaf ; Froguel, Philippe ; Ghori, Jilur ; Groves, Christopher J. ; Gwilliam, Rhian ; Hadley, David ; Hall, Alistair S. ; Hattersley, Andrew T. ; Hebebrand, Johannes ; Heid, Iris M. ; 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 ; Wellcome Trust Case Control Consortium ; Nurses' Health Study ; FUSION ; Diabetes Genetics Initiative ; SardiNIA Study ; Prostate Lung Colorectal Ovarian ; KORA. / 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 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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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 - Bergmann, Sven

AU - Bennett, Amanda J

AU - Bingham, Sheila A.

AU - Bochud, Murielle

AU - Brown, Morris

AU - Cauchi, Stephane

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, A

AU - Elliott, Paul

AU - Elliott, Katherine S.

AU - Evans, David M.

AU - Farooqi, I. Sadaf

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 - 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 - Wellcome Trust Case Control Consortium

AU - Nurses' Health Study

AU - FUSION

AU - Diabetes Genetics Initiative

AU - SardiNIA Study

AU - Prostate Lung Colorectal Ovarian

AU - KORA

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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.

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KW - genome-wide association

KW - melanocortin-4 receptor gene

KW - early-onset obesity

KW - frameshift mutation

KW - adult obesity

KW - expression

KW - deficiency

KW - childhood

KW - dominant

KW - humans

U2 - 10.1038/ng.140

DO - 10.1038/ng.140

M3 - Article

VL - 40

SP - 768

EP - 775

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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