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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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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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