splicing event in RPS26. This observation extends what was recently reported by Schadt et al. [9] by specifically identifying RPS26 splicing as responsible for the expression association with the implicated polymorphism in type 1 diabetes. More generally, however, these results illustrate the exceptional difficulty of moving from phenotypic associations to underlying biological mechanisms. While the strong splicing association with RPS26 makes it a convincing candidate for being responsible for the diabetes risk, the originally reported polymorphism is located in the ERBB3 gene, which also has been suggested as having direct relevance in type 1 diabetes [19]. Fortunately, the effects may in this case be resolvable because rs10876864 has a stronger association with the splicing change than does rs2292239. The association between these polymorphisms, while high, is not complete and it should be possible to resolve which SNP is the more likely causal variant by testing whether the originally identified polymorphism has a stronger association with type 1 diabetes than does the polymorphism more strongly associated with the splicing change.
