Shared obesity variant in kids of European and African ancestry

I'll be talking more about obesity genetics later this week; for now, check out this paper published this week in PLoS ONE (open access). The FTO gene is the poster child for genetic variants underlying human variable traits: it has a reasonably strong effect on body weight and obesity risk, and has been replicated ad nauseum in a variety of cohorts, including in children. What's missing at this stage is an understanding of exactly which variant within this gene underlies the effect on body weight.

This study takes a clever approach to zoom in on the causative variant, using obese children and non-obese controls from two populations with different ancestral backgrounds (one of European and one of African ancestry). That's a powerful strategy: the pattern of genetic variation around the FTO gene is likely to be quite different between these two populations, and markers that stand out in both populations must thus be physically close to the true causative variant.

The study looked at eleven markers within the FTO gene and found two that - in Europeans - are very closely linked to the marker previously associated with obesity ("closely linked" means that these markers are almost always inherited together, so that knowing someone's sequence at one marker allows you to predict, with very high confidence, their sequence at the other marker).

Reassuringly, both of these markers were significantly associated with obesity in their European cohort; importantly, only one of them (rs3751812) showed a significant association in the African-American cohort. None of the other eleven markers - including the variant previously strongly associated with obesity in other studies - showed a signal in the Africans. The implication is that rs3751812 is very close to the real genetic variant underlying the obesity association in this region.

If this result holds up - and it's best not to put too much weight on it (heh) until it's been replicated in a separate African-ancestry cohort - it's quite an exciting finding, because it gives us a much better idea of where the precise obesity-related variant in this region actually lies. It also illustrates the currently hugely under-utilised power of using individuals with African ancestry for fine-mapping: Africans typically have much lower associations between nearby markers, so if you find a marker associated with a given trait, it's likely to be pretty close to the real trait-affecting variation.

I've checked out the positions of these markers using the UCSC Genome Browser. All three of the markers - the two looked at in this study, and the original obesity marker - are found within a few thousand bases of each other in the first intron of the FTO gene. Both the original marker and the new marker (i.e. the one that is associated in Africans) are found in highly evolutionarily conserved regions, suggestive of regions that may regulate the expression of this gene. It seems likely that the causal variant rests in one of these conserved islands; no doubt these regions are being closely examined for clues as I write this.

You can bet we'll be hearing a lot more about this gene during 2008. In fact, I can guarantee you'll hear more about it from me later this week...

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Grant, S.F., Li, M., Bradfield, J.P., Kim, C.E., Annaiah, K., Santa, E., Glessner, J.T., Casalunovo, T., Frackelton, E.C., Otieno, F.G., Shaner, J.L., Smith, R.M., Imielinski, M., Eckert, A.W., Chiavacci, R.M., Berkowitz, R.I., Hakonarson, H., Maedler, K. (2008). Association Analysis of the FTO Gene with Obesity in Children of Caucasian and African Ancestry Reveals a Common Tagging SNP. PLoS ONE, 3(3), e1746. DOI: 10.1371/journal.pone.0001746