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

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/m(2) (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.

Figure 1. A cluster of BMI-associated SNPs in FTO’s first intron.

a | Regional plot of the FTO locus in European ancestry populations. SNPs are plotted by position on chromosome 16 against association with BMI (−log10 P-value). Recombination rates (from CEU HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the rs17817964 (in purple) are color coded to reflect their LD with this SNP (r2 values from the HapMap CEU data). b | The LD structure of SNPs surrounding rs17817964, color coded to reflect their LD with this SNP in European (CEU), East Asian (CHBJPT) and African (YRI) ancestry populations. Based on LD r2 values from the HapMap CEU, CHBJPT and YRI data. Each “cell” represents a SNP in the first intron of FTO (between position 52,355,019 and 52,407,580 according to NCBI Build 36). SNPs in “red” are highly correlated (r²>0.80) with rs17817964.

Figure 2. Genotype frequencies for rs17817964 across populations of different ancestry based on data from the 1000 Genomes Project. The T-allele is the BMI-increasing allele.

Figure 3. Model of FTO’s role in the cellular sensing of amino acids (AAs).