The reported disproportionate hyperinsulinaemia in carriers of these deletions is reminiscent of the phenotype of SH2B1 knockout mice [30], which previously led to the suggestion that haploinsufficiency of SH2B1 is the primary cause of obesity in these individuals [10]. However, the absence of evidence in our data to support this phenotype reopens the possibility that haploinsufficiency of one of the other genes in the region is responsible for the observed GSV-associated obesity phenotype (although SH2B1 remains a strong candidate). It also highlights the caution required when interpreting data derived from a heavily-selected cohort – carriers of a GSV drawn from such a cohort do not necessarily accurately reflect the phenotypic effect of a GSV in the general population. We suggest that, if possible, attempts to investigate additional phenotypes that may be associated with a variant should not use individuals that have been ascertained on the basis of the phenotype of interest; instead, they should be drawn from independent cohorts and selected solely on the basis of being a carrier of the variant under study.
