From an interim analysis of our ongoing GWA study of childhood obesity, we have investigated variation in the FTO
locus previously reported to be associated with both the adult and pediatric forms of the disease
. Consequently, we have replicated association of this gene with obesity by further demonstrating its effect in the childhood form of the disorder. More specifically, the common non-coding variants, rs8050136 and rs3751812 (perfect surrogates for the previously reported rs9939609 i.e. both r2
1 in Caucasians), were shown to confer risk for the disorder with comparable odds ratios to that previously observed.
Although the size of the cohort in the original genome wide association study was larger
, the amount of testing in our cohort was restricted to a focused effort of specifically investigating if SNPs in the FTO
gene also yield association in the same direction as previously reported. Our cohort is therefore sufficiently powered to ask this straight-forward validation question.
As the association we observe is indeed of a very similar magnitude to that of the original reports
, this independent replication confirms FTO
as a genuine childhood obesity susceptibility gene. As such, the “winner's curse” that is often seen for other complex trait susceptibility genes
is not observed in this instance.
What is worth particular note is that the association observed in children is almost identical to that of adults. With the gene-environment interaction
models in mind, we have been motivated to look at the genetics of childhood disease in order to more readily distill the genetic component in these phenotypes due to the fact that environmental exposure and impact has been for a relatively short period of their lifetime. However, with the magnitude of the association being so comparable between children and adults, this particular research outcome suggests that the environmental interaction with this variant over time is negligible and in fact this variant may be primarily associated with early onset obesity.
Studying populations of different ancestry will also help us to globally identify and understand the genetic and environmental factors associated with estimates of obesity, as variants found in populations of both African and Caucasian ancestry may represent more universally important genes and pathways for subsequent diagnosis, prevention and treatment of obesity and its complications. As such, a cohort of African ancestry in many instances can aid in refining the anticipated association(s) made in our GWA approach. Therefore, analysis of key markers specifically in an AA cohort is part of our study design in order to help investigate if any of the association signals can be refined and localized further due to lower LD in this ethnicity. Such an instance occurred for FTO in our AA cohort of obese children and controls. Self-reported African ethnicity proved to be accurate, as the resulting genomic inflation factor was only 1.06. SNP rs3751812 yielded association, whereas the other SNP rs8050136, which showed evidence of association in Caucasians, was not associated in the AA cohort.
In addition, the other 11 SNPs at the locus failed to show any evidence of association in the AA cohort. These results demonstrate the impact of variation at this locus in AA and how we have refined the signal to rs3751812, which it is potentially closer to the causative underlying mutational event. demonstrates this point, where in Caucasians there are multiple SNPs in LD showing nominally significant association () while in the AA, all but one falls away (). Interestingly, the associated rs3751812 is not in strong LD with the originally reported rs9939609 in African ancestry populations (r2
0.058) while rs8050136, which failed to show association in AA, is in strong LD (r2
0.819). However, the minor allele frequency of rs3751812 differs substantially between the two ethnicities, suggesting that the underlying causative variant is being tagged differently by this SNP in these populations.
Importantly, if investigators only analyze rs9939609 in their cohorts of African ancestry, they would miss the association of obesity with this locus, as has already been reported
. As such investigators should test both rs3751812 and rs9939609 in their obese cohorts around the world in order to thoroughly assess the influence of this locus on the phenotype globally. For example, Li et al
showed no association of rs8050136 and rs9939609 with obesity in a Chinese population so testing rs3751812 in these populations needs to be addressed before strong conclusions can be drawn on the role of variation in FTO
in obesity predisposition in this ethnicity.
This is similar to what occurred in the case of association of variants in the TCF7L2
gene with T2D. In Caucasians, one microsatellite and five SNPs were reported to capture the association
while all but one failed to show association in a T2D cohort from West Africa, namely rs7903146
, thus also getting closer to the underlying variant.
Our results lend further support for the role of the FTO
gene in obesity, suggesting that interventions at the FTO pathway level may be of value in patients who suffer from this disease. The FTO
gene encodes the fat mass and obesity associated protein, Fatso
and has been recently shown to be a 2-Oxoglutarate–Dependent Nucleic Acid Demethylase
. The variants that we observe association to may directly dictate splicing or some other regulatory mechanism but more likely are in LD with the causative variant(s).
Once our GWA study is complete, we will have the opportunity to look for other variants in the genome that are associated with childhood obesity, as a consequence of our use of a high resolution BeadChip. In addition, we will explore the FTO gene further to elucidate other potential variants that may confer genetic susceptibility to this disorder in our cohort.