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

被引：954

作者：

Loos, Ruth J. F. ^{[2
,3
]}

Lindgren, Cecilia M. ^{[1
,4
]}

Li, Shengxu ^{[2
,3
]}

Wheeler, Eleanor ^{[5
]}

Zhao, Jing Hua ^{[2
,3
]}

Prokopenko, Inga ^{[1
,4
]}

Inouye, Michael ^{[5
]}

Freathy, Rachel M. ^{[6
,7
]}

Attwood, Antony P. ^{[5
,8
,9
]}

Beckmann, Jacques S. ^{[10
,11
]}

Berndt, Sonja I. ^{[12
]}

Bergmann, Sven ^{[10
,13
]}

Bennett, Amanda J. ^{[1
,4
]}

Bingham, Sheila A. ^{[14
]}

Bochud, Murielle ^{[15
]}

Brown, Morris ^{[16
]}

Cauchi, Stephane ^{[17
]}

Connell, John M. ^{[18
]}

Cooper, Cyrus ^{[19
]}

Smith, George Davey ^{[20
]}

Day, Ian ^{[19
]}

Dina, Christian ^{[17
]}

De, Subhajyoti ^{[21
]}

Dermitzakis, Emmanouil T. ^{[5
]}

Doney, Alex S. F. ^{[22
]}

Elliott, Katherine S. ^{[1
]}

Elliott, Paul ^{[23
,24
]}

Evans, David M. ^{[1
,20
]}

Farooqi, I. Sadaf ^{[3
,25
]}

Froguel, Philippe ^{[17
,26
]}

Ghori, Jilur ^{[5
]}

Groves, Christopher J. ^{[1
,4
]}

Gwilliam, Rhian ^{[5
]}

Hadley, David ^{[27
]}

Hall, Alistair S. ^{[28
]}

Hattersley, Andrew T. ^{[6
,7
]}

Hebebrand, Johannes ^{[29
]}

Heid, Iris M. ^{[30
,31
]}

Herrera, Blanca ^{[1
,4
]}

Hinney, Anke ^{[29
]}

Hunt, Sarah E. ^{[5
]}

Jarvelin, Marjo-Riitta ^{[23
,32
]}

Johnson, Toby ^{[10
,13
,15
]}

Jolley, Jennifer D. M. ^{[8
,9
]}

Karpe, Fredrik ^{[4
]}

Keniry, Andrew ^{[5
]}

Khaw, Kay-Tee ^{[33
]}

Luben, Robert N. ^{[33
]}

Mangino, Massimo ^{[34
]}

Marchini, Jonathan ^{[35
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[2] Addenbrookes Hosp, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England

[3] Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England

[4] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England

[5] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[6] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England

[7] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England

[8] Univ Cambridge, Dept Haematol, Cambridge, England

[9] Cambridge Ctr, NHS Blood & Transplant, Cambridge, England

[10] Univ Lausanne, Dept Med Genet, CH-1011 Lausanne, Switzerland

[11] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland

[12] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA

[13] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[14] MRC, Dunn Human Nutr Unit, Cambridge CB2 0XY, England

[15] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland

[16] Univ Cambridge, Clin Pharmacol Unit, Addenbrookes Hosp, Cambridge, England

[17] Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France

[18] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland

[19] Univ Southampton, MRC, Epidemiol Resource Ctr, Southampton SO16 6YD, Hants, England

[20] Univ Bristol, MRC, Ctr Causal Analyses Translat Epidemiol, Bristol BS8 2PR, Avon, England

[21] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[22] Univ Dundee, Ninewells Hosp & Med Sch, Diabet Res Grp, Div Med & Therapeut, Dundee DD1 9SY, Scotland

[23] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England

[24] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, FIN-90014 Oulu, Finland

[25] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England

[26] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London W12 0NN, England

[27] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England

[28] Univ Leeds, LIGHT Res Inst, Fac Med & Hlth, Leeds LS2 9JT, W Yorkshire, England

[29] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, D-45147 Essen, Germany

[30] GSF, Inst Epidemiol, D-85764 Neuherberg, Germany

[31] Univ Munich, IBE Chair Epidemiol, D-81377 Munich, Germany

[32] Natl Publ Hlth Inst, Dept Child & Adolescent Hlth, Oulu 90221, Finland

[33] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 2SR, England

[34] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester LE3 9QP, Leics, England

[35] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[36] Univ Bristol, Dept Social Med, Bristol BS8 2PR, Avon, England

[37] Barts & London Queen Marys Sch Med & Dent, Barts & London Genome Ctr, William Harvey Res Inst, London EC1M 6BQ, England

[38] Univ Bristol, Dept Oral & Dent Sci, Bristol Dent Sch, Bristol BS1 2LY, Avon, England

[39] Univ Dundee, Ninewells Hosp & Med Sch, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland

[40] Univ Hosp, Dept Obstet & Gynaecol, Oulu 90221, Finland

[41] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[42] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, D-45122 Essen, Germany

[43] Med Genet Clin Pharmacol & Discovery Med, King Of Prussia, PA 19406 USA

[44] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA

[45] Harvard Univ, Sch Med, Boston, MA 02114 USA

[46] MIT, Broad Inst, Boston, MA 02115 USA

[47] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[48] Univ Bristol, Bristol BS2 8AE, Avon, England

[49] CNR, Ist Neurogenet & Neurofarmacol, I-09100 Cagliari, Italy

[50] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

来源：

NATURE GENETICS | 2008年 / 40卷 / 06期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/ng.140

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：768 / 775

页数：8

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