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Originally published in Science Express on 12 April 2007
Science 11 May 2007:
Vol. 316. no. 5826, pp. 889 - 894
DOI: 10.1126/science.1141634
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A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity

Timothy M. Frayling,1,2* Nicholas J. Timpson,3,4* Michael N. Weedon,1,2* Eleftheria Zeggini,3,5* Rachel M. Freathy,1,2 Cecilia M. Lindgren,3,5 John R. B. Perry,1,2 Katherine S. Elliott,3 Hana Lango,1,2 Nigel W. Rayner,3,5 Beverley Shields,2 Lorna W. Harries,2 Jeffrey C. Barrett,3 Sian Ellard,2,6 Christopher J. Groves,5 Bridget Knight,2 Ann-Marie Patch,2,6 Andrew R. Ness,7 Shah Ebrahim,8 Debbie A. Lawlor,9 Susan M. Ring,9 Yoav Ben-Shlomo,9 Marjo-Riitta Jarvelin,10,11 Ulla Sovio,10,11 Amanda J. Bennett,5 David Melzer,1,12 Luigi Ferrucci,13 Ruth J. F. Loos,14 Inês Barroso,15 Nicholas J. Wareham,14 Fredrik Karpe,5 Katharine R. Owen,5 Lon R. Cardon,3 Mark Walker,16 Graham A. Hitman,17 Colin N. A. Palmer,18 Alex S. F. Doney,19 Andrew D. Morris,19 George Davey Smith,4 The Wellcome Trust Case Control Consortium{dagger} Andrew T. Hattersley,1,2{ddagger}§ Mark I. McCarthy3,5{ddagger}

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

1 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter, UK.
2 Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, UK.
3 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK.
4 MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol, UK.
5 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
6 Molecular Genetics Laboratory, Royal Devon and Exeter National Health Service Foundation Trust, Old Pathology Building, Barrack Road, Exeter, UK.
7 Department of Oral and Dental Science, University of Bristol Dental School, Lower Maudlin Street, Bristol, UK.
8 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
9 Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK.
10 Department of Epidemiology and Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
11 Department of Public Health Science and General Practice, Fin-90014, University of Oulu, Finland.
12 Epidemiology and Public Health Group, Peninsula Medical School, Barrack Road, Exeter, UK.
13 Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
14 Medical Research Council Epidemiology Unit, Strangeways Research Laboratories, Cambridge, UK.
15 Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
16 Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
17 Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, UK.
18 Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
19 Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

* These authors contributed equally to this work.

{dagger} Membership of the Wellcome Trust Case Control Consortium is listed in the Supporting Online Material.

{ddagger} These authors contributed equally to this work.

§ To whom correspondence should be addressed. E-mail: Andrew.Hattersley{at}pms.ac.uk

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Corrigendum.
(2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R1360-R1363
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FTO Variants Are Associated With Obesity in the Chinese and Malay Populations in Singapore.
J. T. Tan, R. Dorajoo, M. Seielstad, X. L. Sim, R. T.-H. Ong, K. S. Chia, T. Y. Wong, S. M. Saw, S. K. Chew, T. Aung, et al. (2008)
Diabetes 57, 2851-2857
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Physical Activity and the Association of Common FTO Gene Variants With Body Mass Index and Obesity.
E. Rampersaud, B. D. Mitchell, T. I. Pollin, M. Fu, H. Shen, J. R. O'Connell, J. L. Ducharme, S. Hines, P. Sack, R. Naglieri, et al. (2008)
Arch Intern Med 168, 1791-1797
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Genes, exercise, growth, and the sedentary, obese child.
M. Teran-Garcia, T. Rankinen, and C. Bouchard (2008)
J Appl Physiol 105, 988-1001
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Obesity Associated Genetic Variation in FTO Is Associated with Diminished Satiety.
J. Wardle, S. Carnell, C. M. A. Haworth, I. S. Farooqi, S. O'Rahilly, and R. Plomin (2008)
J. Clin. Endocrinol. Metab. 93, 3640-3643
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Genomewide Association Analysis Followed by a Replication Study Implicates a Novel Candidate Gene for Neuroticism.
E. J. C. G. van den Oord, P.-H. Kuo, A. M. Hartmann, B. T. Webb, H.-J. Moller, J. M. Hettema, I. Giegling, J. Bukszar, and D. Rujescu (2008)
Arch Gen Psychiatry 65, 1062-1071
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Addictions Biology: Haplotype-Based Analysis for 130 Candidate Genes on a Single Array.
C. A. Hodgkinson, Q. Yuan, K. Xu, P.-H. Shen, E. Heinz, E. A. Lobos, E. B. Binder, J. Cubells, C. L. Ehlers, J. Gelernter, et al. (2008)
Alcohol Alcohol. 43, 505-515
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Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes.
N. Grarup, G. Andersen, N. T. Krarup, A. Albrechtsen, O. Schmitz, T. Jorgensen, K. Borch-Johnsen, T. Hansen, and O. Pedersen (2008)
Diabetes 57, 2534-2540
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Replication of Genome-Wide Association Studies of Type 2 Diabetes Susceptibility in Japan.
Y. Horikawa, K. Miyake, K. Yasuda, M. Enya, Y. Hirota, K. Yamagata, Y. Hinokio, Y. Oka, N. Iwasaki, Y. Iwamoto, et al. (2008)
J. Clin. Endocrinol. Metab. 93, 3136-3141
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Association Analysis in African Americans of European-Derived Type 2 Diabetes Single Nucleotide Polymorphisms From Whole-Genome Association Studies.
J. P. Lewis, N. D. Palmer, P. J. Hicks, M. M. Sale, C. D. Langefeld, B. I. Freedman, J. Divers, and D. W. Bowden (2008)
Diabetes 57, 2220-2225
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Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians.
M. C.Y. Ng, K. S. Park, B. Oh, C. H.T. Tam, Y. M. Cho, H. D. Shin, V. K.L. Lam, R. C.W. Ma, W. Y. So, Y. S. Cho, et al. (2008)
Diabetes 57, 2226-2233
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Common Variation in the Fat Mass and Obesity-Associated (FTO) Gene Confers Risk of Obesity and Modulates BMI in the Chinese Population.
Y.-C. Chang, P.-H. Liu, W.-J. Lee, T.-J. Chang, Y.-D. Jiang, H.-Y. Li, S.-S. Kuo, K.-C. Lee, and L.-M. Chuang (2008)
Diabetes 57, 2245-2252
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Genomics in cardiac metabolism.
J.-L. Samuel, M. C. Schaub, M. Zaugg, M. Mamas, W. B. Dunn, and B. Swynghedauw (2008)
Cardiovasc Res 79, 218-227
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Appetite and adiposity in children: evidence for a behavioral susceptibility theory of obesity.
S. Carnell and J. Wardle (2008)
Am. J. Clinical Nutrition 88, 22-29
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Development of a single tube 640-plex genotyping method for detection of nucleic acid variations on microarrays.
K. Krjutskov, R. Andreson, R. Magi, T. Nikopensius, A. Khrunin, E. Mihailov, V. Tammekivi, H. Sork, M. Remm, and A. Metspalu (2008)
Nucleic Acids Res. 36, e75
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Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation.
J. H. White, M. Chiano, M. Wigglesworth, R. Geske, J. Riley, N. White, S. Hall, G. Zhu, F. Maurio, T. Savage, et al. (2008)
Hum. Mol. Genet. 17, 1890-1903
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Lack of Association of Fatness-Related FTO Gene Variants with Energy Expenditure or Physical Activity.
T. Berentzen, S. I. I. Kring, C. Holst, E. Zimmermann, T. Jess, T. Hansen, O. Pedersen, S. Toubro, A. Astrup, and T. I. A. Sorensen (2008)
J. Clin. Endocrinol. Metab. 93, 2904-2908
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Association of FTO With Obesity-Related Traits in the Cebu Longitudinal Health and Nutrition Survey (CLHNS) Cohort.
A. F. Marvelle, L. A. Lange, L. Qin, L. S. Adair, and K. L. Mohlke (2008)
Diabetes 57, 1987-1991
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