The analysis of rare GSVs for association with complex traits represents a complementary approach to SNP- or sequence-based methods for identifying novel loci that can account for the ‘missing heritability’ of multiple complex traits [3], [9]. Even though causal GSVs themselves may be rare and found only in individuals with extreme phenotypes, the identification of such GSVs can enable a more focussed search for rare causal sequence variants. This logic lay behind the elucidation of the impact on obesity of defects in SIM1. The original identification of SIM1 as a possible obesity gene was as a result of its disruption due to a chromosomal rearrangement (a balanced translocation) in a single individual with profound obesity [24]; this was followed by the identification, by exon sequencing, of rare SIM1 variants that co-segregate with syndromic obesity and of common variants implicated in common obesity [25], [26]. The potential of this approach to reveal additional novel obesity-associated loci is supported by our analysis, which provides evidence to support reported GSV associations at 3 loci [10], [16].
