In a first application of this strategy for the identification of novel obesity loci, we showed that a 593 kb deletion on chromosome 16p11.2 (at 29.5–30.1 Mb) directly causes obesity [12]: this association was demonstrated by comparing two cohorts with developmental delay (DD), with or without additional ascertainment for obesity, and was then replicated by retrospective analysis of case-control and population cohorts. We have also shown that duplications of the same locus have the opposite effect, being associated with underweight [13]. Several genes whose altered dosage might plausibly account for the observed phenotype lie within the deleted region, and their potential role in obesity can now be investigated in a hypothesis-driven manner, rather than by the more statistically-challenging hypothesis-free approach applicable to GWAS. Indeed, there are no GWAS signals overlapping this locus [14], [15], illustrating the potential of strategies based on identification of rare GSVs for the identification of novel obesity loci.
