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

Loos, R.J.; 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.; Prostate Lung, Colorectal; Jacobs, K.B.; Jacobs, K.B.; Chanock, S.J.; Hayes, R.B.; Bergmann, S.; Bennett, A.J.; Bingham, S.A.; Bochud, M.; Brown, M.; Cauchi, S.; Connell, J.M.; Cooper, C.; Smith, G.D.; Day, I.; Dina, C.; De, S.; Dermitzakis, E.T.; Doney, A.S.; Elliott, K.S.; Elliott, P.; Evans, D.M.; Sadaf Farooqi, I.; Froguel, P.; Ghori, J.; Groves, C.J.; Gwilliam, R.; Hadley, D.; Hall, A.S.; Hattersley, A.T.; Hebebrand, J.; Heid, I.M.; Lamina, C.; Lamina, C.; Gieger, C.; Illig, T.; Meitinger, T.; Wichmann, H.E.; Herrera, B.; Hinney, A.; Hunt, S.E.; Jarvelin, M.R.; Johnson, T.; Jolley, J.D.; Karpe, F.; Keniry, A.; Khaw, K.T.; Luben, R.N.; Mangino, M.; Marchini, J.; McArdle, W.L.; McGinnis, R.; Meyre, D.; Munroe, P.B.; Morris, A.D.; Ness, A.R.; Neville, M.J.; Nica, A.C.; Ong, K.K.; O'Rahilly, S.; Owen, K.R.; Palmer, C.N.; Papadakis, K.; Potter, S.; Pouta, A.; Qi, L.; Randall, J.C.; Randall, J.C.; Rayner, N.W.; Ring, S.M.; Sandhu, M.S.; Scherag, A.; Sims, M.A.; Song, K.; Soranzo, N.; Speliotes, E.K.; Syddall, H.E.; Syddall, H.E.; Teichmann, S.A.; Timpson, N.J.; Tobias, J.H.; Uda, M.; Vogel, C.I.; Vogel, C.I.; Wallace, C.; Waterworth, D.M.; Weedon, M.N.; Willer, C.J.; Willer, C.J.; Wraight, X.; Wraight, X.; Yuan, X.; Zeggini, E.; Hirschhorn, J.N.; Strachan, D.P.; Ouwehand, W.H.; Caulfield, M.J.; Samani, N.J.; Frayling, T.M.; Vollenweider, P.; Waeber, G.; Mooser, V.; Deloukas, P.; McCarthy, M.I.; Wareham, N.J.; Barroso, I.; Jacobs, K.B.; Chanock, S.J.; Hayes, R.B.; Lamina, C.; Gieger, C.; Illig, T.; Meitinger, T.; Wichmann, H.E.; Kraft, P.; Hankinson, S.E.; Hunter, D.J.; Hu, F.B.; Lyon, H.N.; Voight, B.F.; Ridderstrale, M.; Groop, L.; Scheet, P.; Sanna, S.; Abecasis, G.R.; Albai, G.; Nagaraja, R.; Schlessinger, D.; Jackson, A.U.; Tuomilehto, J.; Collins, F.S.; Boehnke, M.; Mohlke, K.L.

doi:10.1038/ng.140

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

Details

Download: 5_18454148_Postprint.pdf (1494.21 [Ko])
State: Public
Version: Author's accepted manuscript

Serval ID

serval:BIB_C6AB1518E478

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature Genetics

Author(s)

Loos R.J., 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., Prostate Lung Colorectal, Jacobs K.B., Jacobs K.B., Chanock S.J., Hayes R.B., Bergmann S., Bennett A.J., Bingham S.A., Bochud M., Brown M., Cauchi S., Connell J.M., Cooper C., Smith G.D., Day I., Dina C., De S., Dermitzakis E.T., Doney A.S., Elliott K.S., Elliott P., Evans D.M., Sadaf Farooqi I., Froguel P., Ghori J., Groves C.J., Gwilliam R., Hadley D., Hall A.S., Hattersley A.T., Hebebrand J., Heid I.M., Lamina C., Lamina C., Gieger C., Illig T., Meitinger T., Wichmann H.E., Herrera B., Hinney A., Hunt S.E., Jarvelin M.R., Johnson T., Jolley J.D., Karpe F., Keniry A., Khaw K.T., Luben R.N., Mangino M., Marchini J., McArdle W.L., McGinnis R., Meyre D., Munroe P.B., Morris A.D., Ness A.R., Neville M.J., Nica A.C., Ong K.K., O'Rahilly S., Owen K.R., Palmer C.N., Papadakis K., Potter S., Pouta A., Qi L., Randall J.C., Randall J.C., Rayner N.W., Ring S.M., Sandhu M.S., Scherag A., Sims M.A., Song K., Soranzo N., Speliotes E.K., Syddall H.E., Syddall H.E., Teichmann S.A., Timpson N.J., Tobias J.H., Uda M., Vogel C.I., Vogel C.I., Wallace C., Waterworth D.M., Weedon M.N., Willer C.J., Willer C.J., Wraight X., Wraight X., Yuan X., Zeggini E., Hirschhorn J.N., Strachan D.P., Ouwehand W.H., Caulfield M.J., Samani N.J., Frayling T.M., Vollenweider P., Waeber G., Mooser V., Deloukas P., McCarthy M.I., Wareham N.J., Barroso I., Jacobs K.B., Chanock S.J., Hayes R.B., Lamina C., Gieger C., Illig T., Meitinger T., Wichmann H.E., Kraft P., Hankinson S.E., Hunter D.J., Hu F.B., Lyon H.N., Voight B.F., Ridderstrale M., Groop L., Scheet P., Sanna S., Abecasis G.R., Albai G., Nagaraja R., Schlessinger D., Jackson A.U., Tuomilehto J., Collins F.S., Boehnke M., Mohlke K.L.

Working group(s)

Ovarian (PLCO) Cancer Screening Trial, KORA, Nurses' Health Study, Diabetes Genetics Initiative, SardiNIA Study, Wellcome Trust Case Control Consortium, FUSION

Contributor(s)

Prostate Lung Colorectal, KORA X., FUSION X., Burton PR., Clayton DG., Cardon LR., Craddock N., Deloukas P., Duncanson A., Kwiatkowski DP., McCarthy MI., Ouwehand WH., Samani NJ., Todd JA., Donnelly P., Barrett JC., Burton PR., Davison D., Donnelly P., Easton D., Evans DM., Leung HT., Marchini JL., Morris AP., Spencer CC., Tobin MD., Cardon LR., Clayton DG., Attwood AP., Boorman JP., Cant B., Everson U., Hussey JM., Jolley JD., Knight AS., Koch K., Meech E., Nutland S., Prowse CV., Stevens HE., Taylor NC., Walters GR., Walker NM., Watkins NA., Winzer T., Todd JA., Ouwehand WH., Jones RW., McArdle WL., Ring SM., Strachan DP., Pembrey M., Breen G., St Clair D., Caesar S., Gordon-Smith K., Jones L., Fraser C., Green EK., Grozeva D., Hamshere ML., Holmans PA., Jones IR., Kirov G., Moskvina V., Nikolov I., O'Donovan MC., Owen MJ., Craddock N., Collier DA., Elkin A., Farmer A., Williamson R., McGuffin P., Young AH., Ferrier IN., Ball SG., Balmforth AJ., Barrett JH., Bishop DT., Iles MM., Maqbool A., Yuldasheva N., Hall AS., Braund PS., Burton PR., Dixon RJ., Mangino M., Stevens S., Tobin MD., Thompson JR., Samani NJ., Bredin F., Tremelling M., Parkes M., Drummond H., Lees CW., Nimmo ER., Satsangi J., Fisher SA., Forbes A., Lewis CM., Onnie CM., Prescott NJ., Sanderson J., Mathew CG., Barbour J., Mohiuddin MK., Todhunter CE., Mansfield JC., Ahmad T., Cummings FR., Jewell DP., Webster J., Brown MJ., Clayton DG., Lathrop GM., Connell J., Dominiczak A., Samani NJ., Marcano CA., Burke B., Dobson R., Gungadoo J., Lee KL., Munroe PB., Newhouse SJ., Onipinla A., Wallace C., Xue M., Caulfield M., Farrall M., Barton A., Bruce IN., Donovan H., Eyre S., Gilbert PD., Hider SL., Hinks AM., John SL., Potter C., Silman AJ., Symmons DP., Thomson W., Worthington J., Clayton DG., Dunger DB., Nutland S., Stevens HE., Walker NM., Widmer B., Todd JA., Frayling TM., Freathy RM., Lango H., Perry JR., Shields BM., Weedon MN., Hattersley AT., Hitman GA., Walker M., Elliott KS., Groves CJ., Lindgren CM., Rayner NW., Timpson NJ., Zeggini E., McCarthy MI., Newport M., Sirugo G., Lyons E., Vannberg F., Hill AV., Bradbury LA., Farrar C., Pointon JJ., Wordsworth P., Brown MA., Franklyn JA., Heward JM., Simmonds MJ., Gough SC., Seal S., Stratton MR., Rahman N., Ban M., Goris A., Sawcer SJ., Compston A., Conway D., Jallow M., Newport M., Sirugo G., Rockett KA., Kwiatkowski DP., Bumpstead SJ., Chaney A., Downes K., Ghori MJ., Gwilliam R., Hunt SE., Inouye M., Keniry A., King E., McGinnis R., Potter S., Ravindrarajah R., Whittaker P., Widden C., Withers D., Deloukas P., Leung HT., Nutland S., Stevens HE., Walker NM., Todd JA., Easton D., Clayton DG., Burton PR., Tobin MD., Barrett JC., Evans DM., Morris AP., Cardon LR., Cardin NJ., Davison D., Ferreira T., Pereira-Gale J., Hallgrimsdóttir IB., Howie BN., Marchini JL., Spencer CC., Su Z., Teo YY., Vukcevic D., Donnelly P., Bentley D., Brown MA., Cardon LR., Caulfield M., Clayton DG., Compston A., Craddock N., Deloukas P., Donnelly P., Farrall M., Gough SC., Hall AS., Hattersley AT., Hill AV., Kwiatkowski DP., Mathew CG., McCarthy MI., Ouwehand WH., Parkes M., Pembrey M., Rahman N., Samani NJ., Stratton MR., Todd JA., Worthington J.

ISSN

1546-1718

ISSN-L

1061-4036

Publication state

Published

Issued date

2008

Peer-reviewed

Oui

Volume

Number

Pages

768-775

Language

english

Notes

Publication types: Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

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

Adiposity/genetics, Adolescent, Adult, Aged, Alleles, Body Mass Index, Body Weight/genetics, Case-Control Studies, Child, Chromosomes, Human, Pair 18/genetics, Cohort Studies, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Linkage Disequilibrium, Male, Meta-Analysis as Topic, Middle Aged, Obesity/epidemiology, Obesity/genetics, Polymorphism, Single Nucleotide, Proteins, Quantitative Trait Loci, Randomized Controlled Trials as Topic, Receptor, Melanocortin, Type 4/genetics

URN

urn:nbn:ch:serval-BIB_C6AB1518E4789

OAI-PMH

oai:serval.unil.ch:BIB_C6AB1518E478

DOI

10.1038/ng.140

Pubmed

18454148

Web of science

000256212000019

Open Access

Yes