Wednesday, May 16, 2007

Genetics of obesity   posted by p-ter @ 5/16/2007 02:45:00 PM

I realize I'm sort of beating a dead horse by reporting every single high-profile genome-wide association scan (for example), but it's worth pointing out their successes, as there was serious opposition to the HapMap project that laid the groundwork for these studies. So in that spirit, I'll point out this paper, which identifies a common variant in the FTO gene as being associated with obesity:
An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
One of the most important points about genome-wide association studies is that they're (more or less) unbiased-- that is, you don't have to think about which genes could be involved in the phenotype before studying it. Some people consider this a liability, some a blessing. I'm in the latter group, as a strong signal in a genome-wide association can in some cases lead to new candidate genes, new hypotheses and expose interesting biology. This is precisely one of those cases. Here's what's known about the gene identified in this study:
FTO is a gene of unknown function in an unknown pathway that was originally cloned as a result of the identification of a fused-toe (Ft) mutant mouse that results from a 1.6-Mb deletion of mouse chromosome 8. Three genes of unknown function (Fts, Ftm and Fto), along with three members of the Iroquois gene family (Irx3, Irx5, and Irx6 from the IrxB gene cluster), are deleted in Ft mice. The homozygous Ft mouse is embryonically lethal and shows abnormal development, including left/right asymmetry. Heterozygous animals survive and are characterized by fused toes on the forelimbs and thymic hyperplasia but have not been reported to have altered body weight or adiposity. The fused-toe mutant is a poor model for studying the role of altered Fto activity, because multiple genes are deleted. Neither isolated inactivation nor overexpression of Fto has been described.
So essentially, nothing is known about this gene. Thanks to this study, this is unlikely to be the case for long.

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