In a re-analysis of the data from 3 GWA studies on type 2 diabetes, we found that for 5 of the 11 genetic variants that are considered “confirmed” susceptibility loci for type 2 diabetes there was still moderate to very large between-study heterogeneity across the different GWA investigations. Given the between-study heterogeneity, the level of statistical significance was more conservative with random effects calculations. Further examination of these potentially heterogeneous associations suggested possible explanations for the observed inconsistency. In several cases, this probably reflected either the fact that the identified marker was not the culprit polymorphism, but had a different linkage disequilibrium pattern with the culprit polymorphism across different studies. In the case of FTO, it probably reflected the fact it was associated with type 2 diabetes through its effect on the correlated phenotype of obesity; the phenotype correlation varied across different studies. Additional possibilities may need to be considered also for the heterogeneity, as discussed below. Conversely, we should caution that homogeneity of effects for the other 6 variants provides limited information on whether a causative locus has been identified. Lack of heterogeneity is not proof of causality.
