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 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; 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; Andrew D. Morris; Colin N. A. Palmer; Wellcome Trust Case Control Consor, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA

doi:10.1038/ng.140

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, 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, 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, Andrew D. Morris, Colin N. A. Palmer, Wellcome Trust Case Control Consor, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA

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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 language	English
Pages (from-to)	768-775
Number of pages	8
Journal	Nature Genetics
Volume	40
Issue number	6
DOIs	https://doi.org/10.1038/ng.140
Publication status	Published - Jun 2008

Keywords

GENOME-WIDE ASSOCIATION
MELANOCORTIN-4 RECEPTOR GENE
EARLY-ONSET OBESITY
FRAMESHIFT MUTATION
ADULT OBESITY
FTO GENE
EXPRESSION
DEFICIENCY
CHILDHOOD
DOMINANT

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Loos, R. J. F., Lindgren, C. M., Li, S., Wheeler, E., Zhao, J. H., Prokopenko, I., Inouye, M., Freathy, R. M., Attwood, A. P., Beckmann, J. S., Berndt, S. I., Bergmann, S., Bennett, A. J., Bingham, S. A., Bochud, M., Brown, M., Cauchi, S., Connell, J. M., Cooper, C., ... Wellcome Trust Case Control Consor, 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, 40(6), 768-775. https://doi.org/10.1038/ng.140

@article{55016aa5c562422facaa323d0f213b79,

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

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.",

keywords = "GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, EARLY-ONSET OBESITY, FRAMESHIFT MUTATION, ADULT OBESITY, FTO GENE, EXPRESSION, DEFICIENCY, CHILDHOOD, DOMINANT",

author = "Loos, {Ruth J. F.} and Lindgren, {Cecilia M.} and Shengxu Li and Eleanor Wheeler and Zhao, {Jing Hua} and Inga Prokopenko and Michael Inouye and Freathy, {Rachel M.} and Attwood, {Antony P.} and Beckmann, {Jacques S.} and Berndt, {Sonja I.} and Sven Bergmann and Bennett, {Amanda J.} and Bingham, {Sheila A.} and Murielle Bochud and Morris Brown and Stephane Cauchi and Connell, {John M.} and Cyrus Cooper and Smith, {George Davey} and Ian Day and Christian Dina and Subhajyoti De and Dermitzakis, {Emmanouil T.} and Doney, {Alex S. F.} and Elliott, {Katherine S.} and Paul Elliott and Evans, {David M.} and Farooqi, {I. Sadaf} and Philippe Froguel and Jilur Ghori and Groves, {Christopher J.} and Rhian Gwilliam and David Hadley and Hall, {Alistair S.} and Hattersley, {Andrew T.} and Johannes Hebebrand and Heid, {Iris M.} and Blanca Herrera and Anke Hinney and Hunt, {Sarah E.} and Marjo-Riitta Jarvelin and Toby Johnson and Jolley, {Jennifer D. M.} and Fredrik Karpe and Andrew Keniry and Kay-Tee Khaw and Luben, {Robert N.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and {Wellcome Trust Case Control Consor, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA}",

year = "2008",

month = jun,

doi = "10.1038/ng.140",

language = "English",

volume = "40",

pages = "768--775",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

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, ASF, Elliott, KS, Elliott, P, 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, Morris, AD, Palmer, CNA & Wellcome Trust Case Control Consor, 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

TY - JOUR

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, Alex S. F.

AU - Elliott, Katherine S.

AU - Elliott, Paul

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 - Morris, Andrew D.

AU - Palmer, Colin N. A.

AU - Wellcome Trust Case Control Consor, Nurses' Health Study, FUSION, Diabetes Genetics Initiative, SardiNIA Study, Prostate Lung Colorectal Ovarian, KORA

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 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.

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 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.

KW - GENOME-WIDE ASSOCIATION

KW - MELANOCORTIN-4 RECEPTOR GENE

KW - EARLY-ONSET OBESITY

KW - FRAMESHIFT MUTATION

KW - ADULT OBESITY

KW - FTO GENE

KW - EXPRESSION

KW - DEFICIENCY

KW - CHILDHOOD

KW - DOMINANT

U2 - 10.1038/ng.140

DO - 10.1038/ng.140

M3 - Article

C2 - 18454148

SN - 1061-4036

VL - 40

SP - 768

EP - 775

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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