Obesity and FTO: Changing Focus at a Complex Locus
2014; Cell Press; Volume: 20; Issue: 5 Linguagem: Inglês
10.1016/j.cmet.2014.09.010
ISSN1932-7420
AutoresY. C. Loraine Tung, Giles S.H. Yeo, Stephen O’Rahilly, Anthony P. Coll,
Tópico(s)Genetic Associations and Epidemiology
ResumoThe fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits. The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits. When first cloned in 1999, Fto was postulated to have a role in programmed cell death and development. It was identified in the study of the “fused toe” (Ft) mouse, a model organism created by insertional mutagenesis that had a 1.6 Mb deletion on chromosome 8 (van der Hoeven et al., 1994van der Hoeven F. Schimmang T. Volkmann A. Mattei M.G. Kyewski B. Rüther U. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft).Development. 1994; 120: 2601-2607PubMed Google Scholar). Mice heterozygous for the Ft mutation developed fusion of the first to fourth toes of the forelimbs and thymic hyperplasia (Peters et al., 1999Peters T. Ausmeier K. Ruther U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation.Mamm. Genome. 1999; 10: 983-986Crossref PubMed Scopus (4) Google Scholar). This deletion eliminated six genes (Peters et al., 2002Peters T. Ausmeier K. Dildrop R. Ruther U. The mouse Fused toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster.Mamm. Genome. 2002; 13: 186-188Crossref PubMed Scopus (76) Google Scholar) and three members of the Iroquois gene family (Irx3, Irx5, and Irx6) that form the IrxB cluster, as well as three other genes (Fts, Ftm, and Fto), which, at the time, were poorly characterized. Fts was initially called “Ft1,” being the first of the three to be identified; the second proved to be an elusive sequence to characterize technically, so it was labeled the Fantom (Ftm); the third gene was named “Fatso” (Fto) because of its large size (Fischer et al., 2008Fischer J. Emmerling C. Ruther U. On the history of Fto.Obesity Facts. 2008; 1: 43-44Crossref PubMed Scopus (8) Google Scholar). Setting a theme that plays throughout the studies of Fto biology, subsequent studies of the Ft mouse were taken up in trying to determine which of the affected genes in the larger deleted locus were responsible for the component parts of the diverse phenotypes seen in the animal. Furthermore, these initially mysterious genes underwent name changes to reflect evolving knowledge. Ftm was found to be a novel basal body protein of cilia involved in Hedgehog (Hh) signaling (Vierkotten et al., 2007Vierkotten J. Dildrop R. Peters T. Wang B. Rüther U. Ftm is a novel basal body protein of cilia involved in Shh signalling.Development. 2007; 134: 2569-2577Crossref PubMed Scopus (158) Google Scholar). Sequence analysis revealed Ftm to be highly homologous to RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein 1, a gene encoding a protein with a role in photoreceptor cells of the eye), and it was renamed Rpgrip1-like (Rpgrip1l). In mice, inactivation of Rpgrip1l causes a multiorgan syndromic phenotype with cerebral, renal, and hepatic defects (Vierkotten et al., 2007Vierkotten J. Dildrop R. Peters T. Wang B. Rüther U. Ftm is a novel basal body protein of cilia involved in Shh signalling.Development. 2007; 134: 2569-2577Crossref PubMed Scopus (158) Google Scholar), while mutations in RPGRIP1L are the cause of a group of developmental disorders such as Joubert syndrome type B and Meckel syndrome (Delous et al., 2007Delous M. Baala L. Salomon R. Laclef C. Vierkotten J. Tory K. Golzio C. Lacoste T. Besse L. Ozilou C. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat. Genet. 2007; 39: 875-881Crossref PubMed Scopus (369) Google Scholar). With the coming of age of technologically advanced genetic association studies, Fto underwent a more subtle, but no less significant, name change, with the roots of the labeling acronym reflecting its new association with obesity and metabolism. In the first half of 2007, three independent studies demonstrated a strong association between genetic variance within FTO and human obesity. The gene name morphed into “fat mass and obesity associated,” and the metabolic community had, at last, an example of common genetic variance with robust evidence of association with obesity in the general population. The Frayling et al., 2007Frayling T.M. Timpson N.J. Weedon M.N. Zeggini E. Freathy R.M. Lindgren C.M. Perry J.R. Elliott K.S. Lango H. Rayner N.W. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3354) Google Scholar study initially set out to search for type 2 diabetes mellitus susceptibility genes. In doing so, they identified a common variant in the FTO gene that, indeed, predisposed to diabetes but through an effect on body mass index (BMI). This effect on BMI was driven entirely through fat mass and, although not detectable at birth, was fully present by the age of 7 years and persisted through adulthood (Frayling et al., 2007Frayling T.M. Timpson N.J. Weedon M.N. Zeggini E. Freathy R.M. Lindgren C.M. Perry J.R. Elliott K.S. Lango H. Rayner N.W. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3354) Google Scholar). The major signal for association with BMI was a cluster of SNPs in the first intron of FTO. All BMI-associated SNPs were highly correlated with each other, but SNP rs9939609, having the highest genotyping success rate, was studied further. The 16% of adults who were homozygous for the risk allele A weighed close to 3 kg more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele (Frayling et al., 2007Frayling T.M. Timpson N.J. Weedon M.N. Zeggini E. Freathy R.M. Lindgren C.M. Perry J.R. Elliott K.S. Lango H. Rayner N.W. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3354) Google Scholar). Complementing and confirming these findings, a contemporaneous report by Dina et al., 2007Dina C. Meyre D. Gallina S. Durand E. Körner A. Jacobson P. Carlsson L.M. Kiess W. Vatin V. Lecoeur C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1245) Google Scholar took a different approach to discover this association, initially setting out to analyze the distribution of 48 neutral SNPs in a case-control obesity cohort collected from French individuals of European ancestry. While 47 of the 48 showed uniform distribution, the T allele of SNP rs 1121980 (located within the first intron of FTO) was strongly associated with severe adult obesity. Building on this observation, Dina et al. demonstrated that several SNPs in the FTO locus were highly associated not only with severe obesity in other adult, European populations but also with severe childhood obesity. The last of this triumvirate undertook a genome-wide association study in the genetically isolated population of Sardinia to identify genetic variants associated with obesity-related quantitative traits (Scuteri et al., 2007Scuteri A. Sanna S. Chen W.M. Uda M. Albai G. Strait J. Najjar S. Nagaraja R. Orrú M. Usala G. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1314) Google Scholar). Again, a number of common variants in FTO were associated with BMI, hip circumference, and total body weight. The significant challenges were clear from the beginning. FTO was widely expressed throughout the body (Frayling et al., 2007Frayling T.M. Timpson N.J. Weedon M.N. Zeggini E. Freathy R.M. Lindgren C.M. Perry J.R. Elliott K.S. Lango H. Rayner N.W. et al.A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.Science. 2007; 316: 889-894Crossref PubMed Scopus (3354) Google Scholar, Dina et al., 2007Dina C. Meyre D. Gallina S. Durand E. Körner A. Jacobson P. Carlsson L.M. Kiess W. Vatin V. Lecoeur C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1245) Google Scholar, Gerken et al., 2007Gerken T. Girard C.A. Tung Y.C. Webby C.J. Saudek V. Hewitson K.S. Yeo G.S. McDonough M.A. Cunliffe S. McNeill L.A. et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.Science. 2007; 318: 1469-1472Crossref PubMed Scopus (1177) Google Scholar), and, at the time, nothing was known about function or potential pathways. All of these initial reports made it clear that there was no ready mechanism to explain how the predisposing intronic variants affected function or expression of FTO. Indeed, right from the start, the possibility that the underlying mechanism involved neighboring genes or other, as-yet-unidentified, more distant genes was raised. However, hot on the heels of these initial findings, there followed a report that gave some important clues to FTO biology. Bioinformatics analysis indicated that FTO shared sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases, with assays using recombinant murine Fto showing that the protein could catalyze Fe(II)- and 2OG-dependent DNA demethylation, the preferred substrate being 3-methylthymine in DNA. Fto was also found to be localized to the nucleus and highly expressed in hypothalamic regions with critical roles for the control of energy balance in a nutritionally dependent manner (Gerken et al., 2007Gerken T. Girard C.A. Tung Y.C. Webby C.J. Saudek V. Hewitson K.S. Yeo G.S. McDonough M.A. Cunliffe S. McNeill L.A. et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.Science. 2007; 318: 1469-1472Crossref PubMed Scopus (1177) Google Scholar). Subsequently, genome-wide association studies (GWASs) for obesity-related traits in a myriad of European ancestry populations confirmed that multiple SNPs at the FTO locus were associated with BMI (Graff et al., 2013Graff M. Ngwa J.S. Workalemahu T. Homuth G. Schipf S. Teumer A. Völzke H. Wallaschofski H. Abecasis G.R. Edward L. et al.GIANT ConsortiumGenome-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. 2013; 22: 3597-3607Crossref PubMed Scopus (100) Google Scholar, Bradfield et al., 2012Bradfield J.P. Taal H.R. Timpson N.J. Scherag A. Lecoeur C. Warrington N.M. Hypponen E. Holst C. Valcarcel B. 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Many other reports found the association of FTO SNPs with BMI in non-European-derived populations, including most populations of Asian ancestry, as well as Hispanic/Latino populations and Pima Indians (reviewed by Loos and Yeo, 2014Loos R.J. Yeo G.S. The bigger picture of FTO—the first GWAS-identified obesity gene.Nat. Rev. Endocrinol. 2014; 10: 51-61Crossref PubMed Scopus (366) Google Scholar). Studies in populations of African ancestry, in which the FTO gene shows significant differences in allele frequency and linkage disequilibrium (LD) patterns, have proven to be insightful. Although several of the previously identified variants appear not to have significant association with BMI in these populations, other intronic variations around the FTO locus (such as rs3751812 and rs9941349) show strong evidence of association (Adeyemo et al., 2010Adeyemo A. Chen G. Zhou J. Shriner D. Doumatey A. Huang H. Rotimi C. 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Rajkovic A. 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. 2013; 9: e1003171Crossref PubMed Scopus (53) Google Scholar came from a SNP (rs56137030) that had not been highlighted in previous studies. A recent meta-analysis by Monda et al., 2013Monda K.L. Chen G.K. Taylor K.C. Palmer C. Edwards T.L. Lange L.A. Ng M.C. Adeyemo A.A. Allison M.A. Bielak L.F. et al.NABEC ConsortiumUKBEC ConsortiumBioBank Japan ProjectAGEN ConsortiumA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.Nat. Genet. 2013; 45: 690-696Crossref PubMed Scopus (195) Google Scholar of data derived from populations of African ancestry also provided support for shared BMI loci across populations. The association of FTO SNPs with obesity-related traits in children and adolescents was also extended (Bradfield et al., 2012Bradfield J.P. Taal H.R. Timpson N.J. Scherag A. Lecoeur C. Warrington N.M. Hypponen E. Holst C. Valcarcel B. Thiering E. et al.Early Growth Genetics ConsortiumA genome-wide association meta-analysis identifies new childhood obesity loci.Nat. Genet. 2012; 44: 526-531Crossref PubMed Scopus (276) Google Scholar, Meyre et al., 2009Meyre D. Delplanque J. Chèvre J.C. Lecoeur C. Lobbens S. Gallina S. Durand E. Vatin V. Degraeve F. Proença C. et al.Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.Nat. Genet. 2009; 41: 157-159Crossref PubMed Scopus (516) Google Scholar, Scherag et al., 2010Scherag A. Dina C. Hinney A. Vatin V. Scherag S. Vogel C.I. Müller T.D. Grallert H. Wichmann H.E. 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This initial wave of association studies was soon followed by reports considering whether FTO SNPs associated with more specific regulators for energy homeostasis, such as food intake or physical activity. Data pointing to a link with food intake began to emerge. Obesity-associated FTO SNPs were found to be associated with increased energy intake (Cecil et al., 2008Cecil J.E. Tavendale R. Watt P. Hetherington M.M. Palmer C.N. An obesity-associated FTO gene variant and increased energy intake in children.N. Engl. J. Med. 2008; 359: 2558-2566Crossref PubMed Scopus (532) Google Scholar, Speakman et al., 2008Speakman 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 (Silver Spring). 2008; 16: 1961-1965Crossref PubMed Scopus (260) Google Scholar, Timpson et al., 2008Timpson N.J. Emmett P.M. Frayling T.M. Rogers I. Hattersley A.T. McCarthy M.I. Davey Smith G. The fat mass- and obesity-associated locus and dietary intake in children.Am. J. Clin. Nutr. 2008; 88: 971-978Crossref PubMed Scopus (214) Google Scholar), increased intake of dietary fat (Park et al., 2013Park S.L. Cheng I. Pendergrass S.A. Kucharska-Newton A.M. Lim U. Ambite J.L. Caberto C.P. Monroe K.R. Schumacher F. Hindorff L.A. 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. 2013; 178: 780-790Crossref PubMed Scopus (49) Google Scholar, Timpson et al., 2008Timpson N.J. Emmett P.M. Frayling T.M. Rogers I. Hattersley A.T. McCarthy M.I. Davey Smith G. The fat mass- and obesity-associated locus and dietary intake in children.Am. J. Clin. Nutr. 2008; 88: 971-978Crossref PubMed Scopus (214) Google Scholar) or protein (Sonestedt et al., 2009Sonestedt E. Roos C. Gullberg B. Ericson U. Wirfält E. Orho-Melander M. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity.Am. J. Clin. Nutr. 2009; 90: 1418-1425Crossref PubMed Scopus (195) Google Scholar), increased appetite and reduced satiety (Wardle et al., 2008Wardle J. Carnell S. Haworth C.M. Farooqi I.S. O’Rahilly S. Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety.J. Clin. Endocrinol. Metab. 2008; 93: 3640-3643Crossref PubMed Scopus (390) Google Scholar, Wardle et al., 2009Wardle J. Llewellyn C. Sanderson S. Plomin R. The FTO gene and measured food intake in children.Int. J. Obes. (Lond.). 2009; 33: 42-45Crossref PubMed Scopus (231) Google Scholar), and loss of control over eating (Tanofsky-Kraff et al., 2009Tanofsky-Kraff M. Han J.C. Anandalingam K. Shomaker L.B. Columbo K.M. Wolkoff L.E. Kozlosky M. Elliott C. Ranzenhofer L.M. Roza C.A. et al.The FTO gene rs9939609 obesity-risk allele and loss of control over eating.Am. J. Clin. Nutr. 2009; 90: 1483-1488Crossref PubMed Scopus (190) Google Scholar). This link with food intake was not seen in every study; for example, a report by Stutzmann et al., 2009Stutzmann F. Cauchi S. Durand E. Calvacanti-Proença C. Pigeyre M. Hartikainen A.L. Sovio U. Tichet J. Marre M. Weill J. et al.Common genetic variation near MC4R is associated with eating behaviour patterns in European populations.Int. J. Obes. (Lond.). 2009; 33: 373-378Crossref PubMed Scopus (85) Google Scholar failed to find an association of the FTO rs 1421085 C allele with eating behavior traits in a large European cohort of children and adults. However, a recent GWAS of macronutrient intake in more than 70,000 individuals identified the BMI-increasing allele of FTO SNPs as highly significantly associated with increased protein intake (Tanaka et al., 2013Tanaka T. Ngwa J.S. van Rooij F.J. Zillikens M.C. Wojczynski M.K. Frazier-Wood A.C. Houston D.K. Kanoni S. Lemaitre R.N. 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Diabetes Prevention Program Research GroupAssessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program.Diabetologia. 2008; 51: 2214-2223Crossref PubMed Scopus (81) Google Scholar, Speakman et al., 2008Speakman 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 (Silver Spring). 2008; 16: 1961-1965Crossref PubMed Scopus (260) Google Scholar, Vimaleswaran et al., 2009Vimaleswaran K.S. Li S. Zhao J.H. Luan J. Bingham S.A. Khaw K.T. Ekelund U. Wareham N.J. Loos R.J. Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene.Am. J. Clin. Nutr. 2009; 90: 425-428Crossref PubMed Scopus (144) Google Scholar). However, low physical activity has been reported to accentuate the effect of FTO risk alleles on obesity in French adults (Cauchi et al., 2009Cauchi S. Stutzmann F. Cavalcanti-Proença C. Durand E. Pouta A. Hartikainen A.L. Marre M. Vol S. Tammelin T. Laitinen J. et al.Combined effects of MC4R and FTO common genetic variants on obesity in European general populations.J. Mol. Med. 2009; 87: 537-546Crossref PubMed Scopus (132) Google Scholar), with a large-scale meta-analysis of published and unpublished data of more than 200,000 adults and 20,000 children (Kilpeläinen et al., 2011bKilpeläinen T.O. Qi L. Brage S. Sharp S.J. Sonestedt E. Demerath E. Ahmad T. Mora S. Kaakinen M. Sandholt C.H. et al.Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.PLoS Med. 2011; 8: e1001116Crossref PubMed Scopus (400) Google Scholar) concluding that the association of FTO SNPs with the odds of obesity are reduced by close to a third in physically active adults. Phenotypic variability in BMI for a given FTO genotype was also reported by Yang et al., 2012Yang J. Loos R.J. Powell J.E. Medland S.E. Speliotes E.K. Chasman D.I. Rose L.M. Thorleifsson G. Steinthorsdottir V. Mägi R. et al.FTO genotype is associated with phenotypic variability of body mass index.Nature. 2012; 490: 267-272Crossref PubMed Scopus (299) Google Scholar report highlighting the potential of environmental modifiers to influence the “genetic burden” of the FTO risk alleles. The phenotype of mice with a global germline loss of Fto was first reported in 2009 (Fischer et al., 2009Fischer J. Koch L. Emmerling C. Vierkotten J. Peters T. Brüning J.C. Rüther U. Inactivation of the Fto gene protects from obesity.Nature. 2009; 458: 894-898Crossref PubMed Scopus (711) Google Scholar). Fto null mice suffered from a high perinatal mortality and a postnatal period characterized by reduction in both body length and body weight, the latter being a result of reduced fat and lean mass. They were reported to have both an increase in food intake and an increase in metabolic rate. Later analyses of several independent murine models of Fto loss also confirmed this pattern of postnatal growth retardation, but one report has shown that, when corrected for alteration in body composition, there was no difference in energy expenditure in mice globally lacking Fto (McMurray et al., 2013McMurray F. Church C.D. Larder R. Nicholson G. Wells S. Teboul L. Tung Y.C. Rimmington D. Bosch F. Jimenez V. et al.Adult onset global loss of the fto gene alters body composition and metabolism in the mouse.PLoS Genet. 2013; 9: e1003166Crossref PubMed Scopus (107) Google Scholar). In 2010, Cox and colleagues in Harwell, UK, generated mice globally expressing additional copies of the Fto gene (Church et al., 2010Church C. Moir L. McMurray F. Girard C. Banks G.T. Teboul L. Wells S. Brüning J.C. Nolan P.M. Ashcroft F.M. Cox R.D. Overexpression of Fto leads to increased food intake and results in obesity.Nat. Genet. 2010; 42: 1086-1092Crossref PubMed Scopus (527) Google Scholar). This ubiquitous overexpression of Fto increased body and fat mass, with the obese phenotype more marked on a high-fat diet. Food intake was significantly increased, but energy expenditure and physical activity were unaltered in these mice. Reports of more specific regional and temporal Fto perturbation soon emerged. Gao et al., 2010Gao X. Shin Y.H. Li M. Wang F. Tong Q. Zhang P. The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice.PLoS ONE. 2010; 5: e14005Crossref PubMed Scopus (165) Google Scholar used a conditional allele to delete Fto in the nervous system. Their findings that this resulted in similar phenotypes as that of the whole body deletion pointed to Fto having a crucial role in the central nervous system to regulate postnatal growth. Following from th
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