Importantly, in addition to the established T2D-associated loci TCF7L2, SLC30A8 and MTNR1B, five of the loci that are associated with elevated FG levels in non-diabetic individuals (ADCY5, GCK, GCKR, PROX1 and DGKB/TMEM195) also increase the risk of T2D in separate T2D case-control studies. However, this overlap is incomplete and highlights that the magnitude of the effect on FG is not predictive of the effect on T2D risk, as shown when comparing FG and T2D effect sizes for MTNR1B and TCF7L2, or for ADCY5 and MADD (Table 2). The latter two loci have similar effect sizes on FG and similar allele frequencies, and yet the former is robustly associated with T2D risk (OR 1.12, P=5.5×10−21) while the latter is not (OR 1.01, P=0.3) in the same samples. This suggests that not all loci associated with FG within the “physiological” range are also associated with “pathological” FG levels and T2D risk. Thus, variation in FG in healthy individuals is not necessarily an endophenotype for T2D, which posits the hypothesis that the mechanism by which glucose is raised, rather than a mere elevation
