Impairment of glucose homeostasis may be characterized by elevated FG or FI, elevated 2-hour glucose or 2-hour insulin post-oral glucose tolerance test (OGTT), or elevated glycated hemoglobin (HbA1c). We tested associations of each of the 17 loci in a subset of MAGIC cohorts with GWAS data informative for these traits. Since HbA1c is a measure of average glycemia over the preceding 2–3 months, we hypothesized that if an association with additional traits was present it should be directionally consistent. The three loci with the largest effect sizes on FG (G6PC2, MTNR1B and GCK) all showed genome-wide significant and directionally consistent associations with HbA1c, with DGKB/TMEM195, ADCY5, SLC2A2, PROX1, SLC30A8 and TCF7L2 showing nominal (P<0.05) evidence of directionally consistent association (Table 2). The FG-raising alleles at TCF7L2, SLC30A8, GCK and ADCY5 were associated (P<0.0002) with increased 2-hour glucose (Table 2); a parallel MAGIC project reports the genome-wide significant association with 2-hour glucose of another ADCY5 SNP in strong linkage disequilibrium (LD) with our lead SNP (r2=0.82)29. Consistent with previous reports that the FG-raising allele is associated with greater insulin release during OGTT11,12,30, the FG-raising allele in GCKR was associated with lower 2-hour glucose.
