Three New Genetic Loci for Severe Obesity

Yesterday, Nature Genetics published an early online release of a paper by a large team of European researchers, headed by Philippe Froguel from the Pasteur Institute, Lille, France, that identifies three new genetic loci that account for a substantial amount of childhood-onset and severe adult obesity.

The genome-wide association study analysed data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to the previously identified FTO and MC4R genes, the researchers detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene), near MAF (encoding the transcription factor c-MAF) and near PTER (phosphotriesterase-related gene).

Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. Based on the present study, the near-NPC1 variant may account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.

The locus located near the PTER gene, the function of which is not known, is estimated to account for up to a third of all childhood obesity, and a fifth of all cases of adult obesity.

MAF controls the production of insulin, glucagon and glucagon-like peptides, which play a role both in carbohydrate metabolism as well as food intake. The MAF variant accounts for about 6 per cent of early-onset obesity in children, and 16 per cent of adult morbid obesity.

What is surprising is not that these genetic variants exist, but that they have such strong population effects (at least in Europeans). Together with the previously identified FTO and MC4R genes, which were once again confirmed in this study, it appears that the researchers are slowly but steadily circling in on the genetic factors that account for a substantial proportion of early-onset and adult severe obesity.

So far, most of these genes appear linked to the regulation of food intake. Even, if it is far from straightforward to use this information for developing new treatments for obesity – we may be one step nearer to better demonstrating that obesity is not a homogeneous entity and that obesity is not simply a matter of “choice”.

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