New insights into the genetics of body weight

These last months, the wave of genome-wide association scans finally reached the shores of body weight and obesity complex trait. In parallel, thanks to the increasing sequencing and genotyping capacities, large studies on rare mutations can now be carried out.

In this review, I tried to cover the most recent findings in genome-wide association analyses, the outcome of conclusions subsequently not replicated, and the weight of rare mutations with strong effects on common obesity. The strongest predictor of obesity, FTO, is responsible for 1% of the total heritability, and results from other genome-wide scans do not provide, so far, any clue of other variants of this effect size. Thus, monogenic obesity studies might well reinstall the importance of rare nonsynonymous mutations of already known genes, especially melanocortin-4 receptor gene, in the general population. Nevertheless, additional genome-wide association analyses and replication are expected to confirm these first intuitions.

Initial results both support the common variant-common disease hypothesis because at least one such variant exists in FTO, and also tone down its importance because such variants may be fewer than expected. Moreover, having a polymorphism associated with body weight is clearly not the end but rather the beginning of a long search for the gene function and pathway.