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  • Review Article
  • Published:

The bigger picture of FTO—the first GWAS-identified obesity gene

Key Points

  • A cluster of single nucleotide polymorphisms (SNPs) in intron 1 of fat mass and obesity associated (FTO) gene was the first obesity susceptibility locus identified by a genome-wide association study (GWAS)

  • FTO is an RNA demethylase that links amino acid availability and mTORC1 signalling to regulate growth and mRNA translation

  • Of all GWAS-identified obesity susceptibility loci, the FTO locus has the largest effect; SNPs in the FTO locus are associated with obesity traits, throughout life and across diverse ancestries

  • SNPs in FTO are also associated with non-adiposity traits, such as cardiometabolic traits, type 2 diabetes mellitus and osteoarthritis; most of these associations are mediated through FTO's effect on BMI

  • Evidence from epidemiological and functional studies suggests that FTO confers an increased risk of obesity through subtle changes in food intake and preference

Abstract

Single nucleotide polymorphisms (SNPs) that cluster in the first intron of fat mass and obesity associated (FTO) gene are associated obesity traits in genome-wide association studies. The minor allele increases BMI by 0.39 kg/m2 (or 1,130 g in body weight) and risk of obesity by 1.20-fold. This association has been confirmed across age groups and populations of diverse ancestry; the largest effect is seen in young adulthood. The effect of FTO SNPs on obesity traits in populations of African and Asian ancestry is similar or somewhat smaller than in European ancestry populations. However, the BMI-increasing allele in FTO is substantially less prevalent in populations with non-European ancestry. FTO SNPs do not influence physical activity levels; yet, in physically active individuals, FTO's effect on obesity susceptibility is attenuated by approximately 30%. Evidence from epidemiological and functional studies suggests that FTO confers an increased risk of obesity by subtly changing food intake and preference. Moreover, emerging data suggest a role for FTO in nutrient sensing, regulation of mRNA translation and general growth. In this Review, we discuss the genetic epidemiology of FTO and discuss how its complex biology might link to the regulation of body weight.

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Figure 1: A cluster of BMI-associated SNPs in the first intron of FTO.
Figure 2: Genotype frequencies for rs17817964 within and across ancestries based on the 1000 Genomes Project.176
Figure 3: Hypothetical role of FTO in amino-acid sensing.

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References

  1. Elks, C. E. et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front. Endocrinol. (Lausanne) 3, 29 (2012).

    Article  Google Scholar 

  2. Maes, H. H., Neale, M. C. & Eaves, L. J. Genetic and environmental factors in relative body weight and human obesity. Behav. Genet. 27, 325–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Loos, R. J. F. in Adipose Tissue Biology (ed. Symonds, M. E.) 317–378 (Springer, 2012).

    Book  Google Scholar 

  4. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hindorff, L. A., MacArthur, J., Morales, J., Junkins, H. A., Hall, P. N., Klemm, A. K. & Manolio, T. A. A catalog of published genome-wide association studies [online], (2013).

  6. Day, F. R. & Loos, R. J. Developments in obesity genetics in the era of genome-wide association studies. J. Nutrigenet. Nutrigenomics 4, 222–238 (2011).

    Article  PubMed  Google Scholar 

  7. Lu, Y. & Loos, R. J. Obesity genomics: assessing the transferability of susceptibility loci across diverse populations. Genome Med. 5, 55 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Loos, R. J. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Lindgren, C. M. et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Heard-Costa, N. L. et al. NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet. 5, e1000539 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kilpelainen, T. O. et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat. Genet. 43, 753–760 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Berndt, S. I. et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat. Genet. 45, 501–512 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Meyre, D. et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat. Genet. 41, 157–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Scherag, A. et al. Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet. 6, e1000916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bradfield, J. P. et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat. Genet. 44, 526–531 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wheeler, E. et al. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat. Genet. 45, 513–517 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cho, Y. S. et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Wen, W. et al. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat. Genet. 44, 307–311 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Okada, Y. et al. Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat. Genet. 44, 302–306 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Monda, K. L. et al. A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat. Genet. 45, 690–696 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Peters, U. et al. A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet. 9, e1003171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stratigopoulos, G. et al. Regulation of Fto/Ftm gene expression in mice and humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1185–R1196 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Stratigopoulos, G., LeDuc, C. A., Cremona, M. L., Chung, W. K. & Leibel, R. L. Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling. J. Biol. Chem. 286, 2155–2170 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Li, S. et al. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Am. J. Clin. Nutr. 91, 184–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Tan, J. T. et al. FTO variants are associated with obesity in the Chinese and Malay populations in Singapore. Diabetes 57, 2851–2857 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu, Y. et al. Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. Obesity 18, 1619–1624 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Ng, M. C. Y. et al. Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN17C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, AND KCTD15 with obesity and type 2 diabetes in 7,705 Chinese. J. Clin. Endocrinol. Metab. 95, 2418–2425 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Chang, Y. C. et al. Common variation in the fat mass and obesity-associated (FTO) gene confers risk of obesity and modulates BMI in the Chinese population. Diabetes 57, 2245–2252 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi, J. et al. Evaluation of genetic susceptibility loci for obesity in Chinese women. Am. J. Epidemiol. 172, 244–254 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sun, Y., Sun, J., Wang, X., You, W. & Yang, M. Variants in the fat mass and obesity associated (FTO) gene are associated with obesity and C-reactive protein levels in Chinese Han populations. Clin. Invest. Med. 33, E405–E412 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, J. et al. Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty. Int. J. Obes. (Lond.) 36, 542–547 (2012).

    Article  CAS  Google Scholar 

  38. Wu, L. et al. Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes 59, 3085–3089 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xi, B. et al. Associations of obesity susceptibility loci with hypertension in Chinese children. Int. J. Obes. (Lond.) 37, 926–930 (2013).

    Article  CAS  Google Scholar 

  40. Hotta, K. et al. Variations in the FTO gene are associated with severe obesity in the Japanese. J. Hum. Genet. 53, 546–553 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Omori, S. et al. Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes 57, 791–795 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Tabara, Y. et al. Prognostic significance of FTO genotype in the development of obesity in Japanese: the J-SHIPP study. Int. J. Obes. 33, 1243–1248 (2009).

    Article  CAS  Google Scholar 

  43. Karasawa, S. et al. Association of the common fat mass and obesity associated (FTO) gene polymorphism with obesity in a Japanese population. Endocr. J. 57, 293–301 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Takeuchi, F. et al. Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals. Diabetologia 54, 1350–1359 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Cha, S. W. et al. Replication of genetic effects of FTO polymorphisms on BMI in a Korean population. Obesity (Silver Spring) 16, 2187–2189 (2008).

    Article  CAS  Google Scholar 

  46. Hong, K. W. & Oh, B. Recapitulation of genome-wide association studies on body mass index in the Korean population. Int. J. Obes. (Lond.) 36, 1127–1130 (2012).

    Article  CAS  Google Scholar 

  47. Binh, T. Q. et al. Association of the common FTO-rs9939609 polymorphism with type 2 diabetes, independent of obesity-related traits in a Vietnamese population. Gene 513, 31–35 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Croteau-Chonka, D. C. et al. Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women. Obesity (Silver Spring) 19, 1019–1027 (2010).

    Article  CAS  Google Scholar 

  49. Yajnik, C. et al. FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians. Diabetologia 52, 247–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Ramya, K., Radha, V., Ghosh, S., Majumder, P. P. & Mohan, V. Genetic variations in the FTO gene are associated with type 2 diabetes and obesity in south Indians (CURES-79). Diabetes Technol. Ther. 13, 33–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Taylor, A. E. et al. Associations of FTO and MC4R variants with obesity traits in indians and the role of rural/urban environment as a possible effect modifier. J. Obes. 2011, 307542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chauhan, G. et al. Common variants of FTO and the risk of obesity and type 2 diabetes in Indians. J. Hum. Genet. 56, 720–726 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Vasan, S. K. et al. Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians. Obesity (Silver Spring) 20, 2268–2277 (2012).

    Article  CAS  Google Scholar 

  54. Sanghera, D. et al. Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF12BP2, TCF7L2 and FTO variants confer a significant risk. BMC Med. Genet. 9, 59 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Moore, S. C. et al. Common genetic variants and central adiposity among Asian-Indians. Obesity (Silver Spring) 20, 1902–1908 (2012).

    Article  CAS  Google Scholar 

  56. Dwivedi, O. P. et al. Common variants of FTO are associated with childhood obesity in a cross-sectional study of 3,126 urban Indian children. PLoS ONE 7, e47772 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rees, S. D. et al. An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabet. Med. 28, 673–680 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li, H. et al. Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians. Diabetologia 55, 981–995 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Grant, S. F. et al. Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS ONE 3, e1746 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu, G. et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med. Genet. 11, 57 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Graff, M. et al. Estimation of genetic effects on BMI during adolescence in an ethnically diverse cohort: The National Longitudinal Study of Adolescent Health. Nutr. Diabetes 2, e47 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Adeyemo, A. et al. FTO genetic variation and association with obesity in west africans and african americans. Diabetes 59, 1549–1554 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hennig, B. et al. FTO gene variation and measures of body mass in an African population. BMC Med. Genet. 10, 21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hassanein, M. T. et al. Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum. Mol. Genet. 19, 2907–2916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bressler, J., Kao, W. H., Pankow, J. S. & Boerwinkle, E. Risk of type 2 diabetes and obesity is differentially associated with variation in fto in whites and african-americans in the ARIC Study. PLoS ONE 5, e10521 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Avery, C. L. et al. A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains. PLoS Genet. 7, e1002322 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cauchi, S. et al. European genetic variants associated with type 2 diabetes in North African Arabs. Diabetes Metab. 38, 316–323 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Hallman, D. M. et al. The association of variants in the FTO gene with longitudinal body mass index profiles in non-Hispanic white children and adolescents. Int. J. Obes (Lond.) 36, 61–68 (2012).

    Article  CAS  Google Scholar 

  69. Lombard, Z. et al. Appetite regulation genes are associated with body mass index in black South African adolescents: a genetic association study. BMJ Open 2, e000873 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Hester, J. M. et al. Implication of European-derived adiposity loci in African Americans. Int. J. Obes. (Lond.) 36, 465–473 (2012).

    Article  CAS  Google Scholar 

  71. Ng, M. C. et al. Genome-wide association of BMI in African Americans. Obesity (Silver Spring) 20, 622–627 (2012).

    Article  CAS  Google Scholar 

  72. Fesinmeyer, M. D. et al. Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study. BMC Med. Genet. 14, 6 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Demerath, E. W. et al. Interaction of FTO and physical activity level on adiposity in African-American and European-American adults: the ARIC study. Obesity (Silver Spring) 19, 1866–1872 (2011).

    Article  CAS  Google Scholar 

  74. Wing, M. R. et al. Analysis of FTO gene variants with measures of obesity and glucose homeostasis in the IRAS Family Study. Hum. Genet. 125, 615–626 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Villalobos-Comparan, M. et al. The FTO gene is associated with adulthood obesity in the Mexican population. Obesity (Silver Spring) 16, 2296–2301 (2008).

    Article  CAS  Google Scholar 

  76. Dong, C. et al. Genome-wide linkage and peak-wide association study of obesity-related quantitative traits in Caribbean Hispanics. Hum. Genet. 129, 209–219 (2011).

    Article  PubMed  Google Scholar 

  77. Song, Y. et al. FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women. Obesity (Silver Spring) 16, 2472–2480 (2008).

    Article  CAS  PubMed Central  Google Scholar 

  78. Rong, R. et al. Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF32BP2, LOC387761 and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes 58, 478–488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Haworth, C. M. A. et al. Increasing heritability of BMI and stronger associations with the FTO Gene over childhood. Obesity 16, 2663–2668 (2008).

    Article  PubMed  Google Scholar 

  80. Cecil, J. E., Tavendale, R., Watt, P., Hetherington, M. M. & Palmer, C. N. A. An obesity-associated fto gene variant and increased energy intake in children. N. Engl. J. Med. 359, 2558–2566 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Zhao, J. et al. Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI. Diabetes 59, 751–755 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Melen, E. et al. Genome-wide association study of body mass index in 23,000 individuals with and without asthma. Clin. Exp. Allergy 43, 463–474 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. den Hoed, M. et al. Genetic susceptibility to obesity and related traits in childhood and adolescence. Diabetes 59, 2980–2988 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lauria, F. et al. Prospective analysis of the association of a common variant of FTO (rs9939609) with adiposity in children: results of the IDEFICS study. PLoS ONE 7, e48876 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhao, J. et al. Role of BMI-associated loci identified in GWAS meta-analyses in the context of common childhood obesity in European Americans. Obesity (Silver Spring) 19, 2436–2439 (2011).

    Article  CAS  Google Scholar 

  86. Graff, M. et al. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. Hum. Mol. Genet. 22, 3597–3607 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hardy, R. et al. Life course variations in the associations between FTO and MC4R gene variants and body size. Hum. Mol. Genet. 19, 545–552 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Rzehak, P. et al. Associations between BMI and the FTO gene are age dependent: results from the GINI and LISA birth cohort studies up to age 6 years. Obes. Facts 3, 180 (2010).

    Article  Google Scholar 

  89. Cauchi, S. et al. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J. Mol. Med. 87, 537–546 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Jess, T. et al. Impact on weight dynamics and general growth of the common FTO rs9939609: a longitudinal Danish cohort study. Int. J. Obes 32, 1388–1394 (2008).

    Article  CAS  Google Scholar 

  91. Kilpelainen, T. O. et al. Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals. Am. J. Clin. Nutr. 93, 851–860 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Horikoshi, M. et al. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat. Genet. 45, 76–82 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Qi, L. et al. Fat mass-and obesity-associated (FTO) gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test. Diabetes 57, 3145–3151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sovio, U. et al. Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development. PLoS Genet. 7, e1001307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Speakman, J. R., Rance, K. A. & Johnstone, A. M. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity 16, 1961–1965 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Timpson, N. J. et al. The fat mass-and obesity-associated locus and dietary intake in children. Am. J. Clin. Nutr. 88, 971–978 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Sonestedt, E. et al. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am. J. Clin. Nutr. 90, 1418–1425 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Lee, H. J. et al. Effects of common FTO gene variants associated with BMI on dietary intake and physical activity in Koreans. Clin. Chim. Acta 411, 1716–1722 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Park, S. L. et al. Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: The PAGE Study. Am. J. Epidemiol. 178, 780–790 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ahmad, T. et al. Lifestyle interaction with fat mass and obesity-associated (FTO) genotype and risk of obesity in apparently healthy, U. S. women. Diabetes Care 34, 675–680 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wardle, J. et al. Obesity associated genetic variation in FTO is associated with diminished satiety. J. Clin. Endocr. Metab. 93, 3640–3643 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Wardle, J., Llewellyn, C., Sanderson, S. & Plomin, R. The FTO gene and measured food intake in children. Int. J. Obes 33, 42–45 (2008).

    Article  CAS  Google Scholar 

  103. McCaffery, J. M. et al. Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. Am. J. Clin. Nutr. 95, 1477–1486 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brunkwall, L. et al. Genetic variation in the fat mass and obesity-associated gene (FTO) in association with food preferences in healthy adults. Food Nutr. Res. 57, 20028 (2013).

    Article  CAS  Google Scholar 

  105. Tanofsky-Kraff, M. et al. The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am. J. Clin. Nutr. 90, 1483–1488 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tanaka, T. et al. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am. J. Clin. Nutr. 97, 1395–1402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bauer, F. et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am. J. Clin. Nutr. 90, 951–959 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Corella, D. et al. A high intake of saturated fatty acids strengthens the association between the fat mass and obesity-associated gene and BMI. J. Nutr. 141, 2219–2225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hubacek, J. A., Pikhart, H., Peasey, A., Kubinova, R. & Bobak, M. FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. The HAPIEE study. Physiol. Res. 60, 175–183 (2010).

    PubMed  Google Scholar 

  110. Holzapfel, C. et al. Genes and lifestyle factors in obesity: results from 12,462 subjects from MONICA/KORA. Int. J. Obes. 34, 1538–1545 (2010).

    Article  CAS  Google Scholar 

  111. Franks, P. W. et al. Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia 51, 2214–2223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rampersaud, E. et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch. Intern. Med. 168, 1791–1797 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ahmad, T. et al. The Fat-Mass and Obesity-Associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am. Heart J. 160, 1163–1169 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Vimaleswaran, K. S. et al. Physical activity attenuates the body mass index increasing influence of genetic variation in the FTO gene. Am. J. Clin. Nutr. 90, 425–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Kilpelainen, T. O. Physical activity attenuates the influence of FTO variants on obesity risk; a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 8, e1001116 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Andreasen, C. H. et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 57, 264–268 (2008).

    Article  CAS  Google Scholar 

  117. Sonestedt, E. et al. Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int. J. Obes (Lond.) 35, 1041–1049 (2010).

    Article  Google Scholar 

  118. Bell, C. G. et al. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE 5, e14040 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Toperoff, G. et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum. Mol. Genet. 21, 371–383 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Almen, M. S. et al. Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics 99, 132–137 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Heid, I. M. et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 42, 949–960 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fox, C. S. et al. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet. 8, e1002695 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fall, T. et al. The role of adiposity in cardiometabolic traits: a mendelian randomization analysis. PLoS Med. 10, e1001474 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Hertel, J. K. et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies. Diabetes 60, 1637–1644 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Brennan, P. et al. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. Int. J. Epidemiol. 38, 971–975 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Delahanty, R. J. et al. Association of obesity-related genetic variants with endometrial cancer risk: a report from the Shanghai Endometrial Cancer Genetics Study. Am. J. Epidemiol. 174, 1115–1126 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Machiela, M. J. et al. Association of type 2 diabetes susceptibility variants with advanced prostate cancer risk in the Breast and Prostate Cancer Cohort Consortium. Am. J. Epidemiol. 176, 1121–1129 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Lurie, G. et al. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PLoS ONE 6, e16756 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Long, J. et al. Evaluating genome-wide association study-identified breast cancer risk variants in African-American women. PLoS ONE 8, e58350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Pierce, B. L., Austin, M. A. & Ahsan, H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 22, 877–83 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Lewis, S. J. et al. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS ONE 5, e13485 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gaudet, M. M. et al. No association between FTO or HHEX and endometrial cancer risk. Cancer Epidemiol. Biomarkers Prev. 19, 2106–2109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lim, U. et al. Susceptibility variants for obesity and colorectal cancer risk: the multiethnic cohort and PAGE studies. Int. J. Cancer 131, E1038–E1043 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Li, G., Chen, Q., Wang, L., Ke, D. & Yuan, Z. Association between FTO gene polymorphism and cancer risk: evidence from 16,277 cases and 31,153 controls. Tumour Biol. 33, 1237–1243 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Zheng, W. et al. Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23,637 breast cancer cases and 25,579 controls. Hum. Mol. Genet. 22, 2539–2550 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Garcia-Closas, M. et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat. Genet. 45, 392–398 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Iles, M. M. et al. A variant in FTO shows association with melanoma risk not due to BMI. Nat. Genet. 45, 428–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Meyre, D. et al. Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes 59, 311–318 (2010).

    Article  CAS  PubMed  Google Scholar 

  139. Deliard, S. et al. The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry. Obesity (Silver Spring) 21, 159–63 (2013).

    Article  CAS  Google Scholar 

  140. Zheng, Z. et al. Screening for Coding Variants in FTO and SH2B1 Genes in Chinese Patients with Obesity. PLoS ONE 8, e67039 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Jia, G. et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 582, 3313–3319 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Han, Z. et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464, 1205–1209 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Desrosiers, R., Friderici, K. & Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl Acad. Sci. USA 71, 3971–3975 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kowalak, J. A., Pomerantz, S. C., Crain, P. F. & McCloskey, J. A. A novel method for the determination of post-transcriptional modification in RNA by mass spectrometry. Nucleic Acids Res. 21, 4577–4585 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chambers, J. C. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716–718 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. Challis, B. G. et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum. Mol. Genet. 11, 1997–2004 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Gray, J. et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55, 3366–3371 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Benzinou, M. et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat. Genet. 40, 943–945 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306 (1997).

    Article  CAS  PubMed  Google Scholar 

  155. Peters, T., Ausmeier, K. & Ruther, U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm. Genome 10, 983–986 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Anselme, I., Laclef, C., Lanaud, M., Ruther, U. & Schneider-Maunoury, S. Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes. Dev. Biol. 304, 208–220 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. van der Hoeven, F. et al. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120, 2601–2607 (1994).

    CAS  PubMed  Google Scholar 

  158. Fischer, J. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009).

    Article  CAS  PubMed  Google Scholar 

  159. McMurray, F. et al. Adult onset global loss of the fto gene alters body composition and metabolism in the mouse. PLoS Genet. 9, e1003166 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Boissel, S. et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 85, 106–111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Delous, M. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat. Genet. 39, 875–881 (2007).

    Article  CAS  PubMed  Google Scholar 

  162. Wu, Q., Saunders, R. A., Szkudlarek-Mikho, M., Serna Ide, L. & Chin, K. V. The obesity-associated Fto gene is a transcriptional coactivator. Biochem. Biophys. Res. Commun. 401, 390–395 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Church, C. et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat. Genet. 42, 1086–1092 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Tung, Y. C. et al. Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. PLoS ONE 5, e8771 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Gao, X. et al. The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PLoS ONE 5, e14005 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ma, M., Harding, H. P., O'Rahilly, S., Ron, D. & Yeo, G. S. Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate. Biochem. J. 444, 183–187 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Cheung, M. K., Gulati, P., O'Rahilly, S. & Yeo, G. S. FTO expression is regulated by availability of essential amino acids. Int. J. Obes (Lond.) 37, 744–747 (2013).

    Article  CAS  Google Scholar 

  168. Gulati, P. et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl Acad. Sci. USA 110, 2557–2562 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Quevillon, S., Robinson, J. C., Berthonneau, E., Siatecka, M. & Mirande, M. Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein. J. Mol. Biol. 285, 183–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  170. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bokar, J. A., Shambaugh, M. E., Polayes, D., Matera, A. G. & Rottman, F. M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3, 1233–1247 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Hess, M. E. et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat. Neurosci. 16, 1042–1048 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Karra, E. et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J. Clin. Invest. 123, 3539–3551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. Freathy, R. M. et al. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI. Diabetes 57, 1419–1426 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Asselbergs, F. W. et al. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. Am. J. Hum. Genet. 91, 823–838 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Robiou-du-Pont, S. et al. Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population. Int. J. Obes. (Lond.) 37, 980–985 (2013).

    Article  CAS  Google Scholar 

  180. Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Hubacek, J. A. et al. The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population. Nephrol. Dial. Transplant. 27, 1030–1035 (2012).

    Article  CAS  PubMed  Google Scholar 

  182. Franceschini, N. et al. The association of genetic variants of type 2 diabetes with kidney function. Kidney Int. 82, 220–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Timpson, N. J. et al. Does greater adiposity increase blood pressure and hypertension risk?: Mendelian randomization using the FTO/MC4R genotype. Hypertension 54, 84–90 (2009).

    Article  CAS  PubMed  Google Scholar 

  184. Elks, C. E. et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 42, 1077–1085 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Zeggini, E. et al. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380, 815–823 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Panoutsopoulou, K. et al. The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-203772.

  187. Samaan, Z. et al. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2012-178.

  188. Bressler, J. et al. Fat mass and obesity gene and cognitive decline: the Atherosclerosis Risk in Communities Study. Neurology 80, 92–99 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Supplementary Table 1

Association between FTO SNPs and non-adiposity traits and morbidities reported by large-scale (n >3,500) studies. If available, results for adiposity-adjusted analyses are listed as well. (DOC 220 kb)

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Loos, R., Yeo, G. The bigger picture of FTO—the first GWAS-identified obesity gene. Nat Rev Endocrinol 10, 51–61 (2014). https://doi.org/10.1038/nrendo.2013.227

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