Obesity is a growing health concern, yet little is known about common genetic variants that predispose to it. Two groups have now shown that variation in the FTO (fat mass and obesity associated) gene is associated with both adult and childhood obesity.
Changes in lifestyle mean that the incidence of obesity is increasing worldwide, and this trend is a major cause of diseases such as type 2 diabetes, heart disease, stroke and cancer. Genetic factors are also known to be important, which means that certain individuals will be more at risk from the environmental trend towards increased weight. However, so far only rare monogenic forms of obesity have been genetically dissected and the genetic factors behind obesity in the vast majority of the population remain obscure.
Frayling et al. carried out a genome-wide association study for type 2 diabetes. They found an association between SNPs in the first intron of FTO and the disease. However, when they looked at body mass index (BMI) in these individuals, they found that in fact it was this phenotype that was directly associated with the variants and the effect on diabetes was just a consequence. Tests on more than 38,000 individuals from 13 further populations convincingly showed that one particular haplotype had an additive effect on BMI — heterozygotes were on average 0.4 kg m-2 heavier and for homozygotes the figure was twice this. In the European population that they studied, 16% of individuals are homozygous for the high-risk allele and 47% are heterozygous. The difference of 3 kg between the two homozygous genotypes in adults reflected a difference in fat mass that was associated with an odds ratio of 1.67 for obesity.
In a similar study that used family-based data in another European population, Dina et al. found a similar strong association between obesity risk and different SNPs in the same region of FTO. Both groups found that their variants were also associated with childhood BMI and obesity, although not with weight at birth.
FTO is expressed in a range of tissues including the brain, adipose tissue, pancreas and hypothalamus. However, the mechanistic basis for the association remains unclear, although Dina et al. suggest that two of their SNPs might have functional consequences. Frayling et al. point out that the first intron of FTO is also part of the control region for another adjacent gene, KIA1005, which might be involved.
Both groups highlight the need for new mouse models, as the only model at present has a large deletion of several genes so it is hard to assess which, if any, phenotype results from loss of FTO. Understanding how these common variants predispose to obesity will be an important step in unravelling the pathways that regulate fat mass in response to both genetic and environmental cues.