One interesting implication of our study relates to the hypothesized genetic architecture of obesity. Although it is well known that obesity results from multiple genetic risk factors as well as environmental factors, it is not clear what and how many genetic risk factors are involved. Recent GWASs identified a few obesity genes, but they collectively only explain a minor fraction of interindividual differences in obesity (5). Therefore, even though more common susceptibility variants may be identified by increasing sample size, they will be very unlikely to account for a significant proportion of genetic risk. On the other hand, our study suggests that rare variants with much higher ORs may also contribute to risk of obesity. Given the rare nature of the CNVs, we could not discern which one of these large CNVs are truly causal for obesity, so some less penetrant or noncausal large CNVs will dilute the effect sizes. Therefore, the observed effect sizes for large CNVs may represent underestimation of the true effect size of causal CNVs for obesity.
