Table 2

GSEA of T2D and glycemic trait associations in the antidiabetes drug target gene set

GWAS meta-analysisNominal MAGENTA enrichment P value*Number of OBS genes/loci above enrichment cutoffNumber of EXP genes/loci above enrichment cutoffExcess number of genes/loci above enrichment cutoff (OBS − EXP)Enrichment fold (OBS/EXP)Number of genes near validated GWAS SNPsGenes near validated GWAS SNPs
T2D1.7 × 10−541**23181.786***PPARG, IRS1§, KCNJ11/ABCC8, IDE, GIPR
Fasting glucose0.078312471.291SLC2A2
HOMA-IR0.11292451.210
2-h insulin0.24272431.131IRS1
HOMA-B0.27262331.130
Fasting insulin0.29262421.080
2-h glucose0.74202300.870
HbA1c0.75202300.870
  • The 2-h glucose and 2-h insulin concentrations were measured after an oral glucose tolerance test. EXP, expected; OBS, observed.

  • *The gene set enrichment P value was calculated by MAGENTA using a 75th percentile enrichment cutoff.

  • **44 genes had scores above the enrichment cutoff, but 3 genes were removed from GSEA to correct for physical clustering along the genome (see Table 4).

  • ***Only 4 loci contributed to enrichment signal. See next two footnotes for explanation.

  • †Estimated number of antidiabetes drug targets that may be true associations with T2D, 14 of which have not yet reached genome-wide significance.

  • ‡Genes were mapped onto 55 established T2D SNPs using the larger of the two boundaries around each SNP: ±100 kb or LD r2 > 0.5 (see research design and methods and Supplementary Table 3).

  • §The gene association P value of IR1S did not surpass the enrichment cutoff because the established T2D GWAS SNP near IRS1 lies farther away than the gene boundaries used in MAGENTA (+110 kb/−40 kb).

  • KCNJ11/ABCC8 were collapsed to one effective gene in the GSEA due to their physical proximity.

  • GIPR was added to our drug target gene list before its association with T2D reached genome-wide significance in a joint meta-analysis of DIAGRAMv3 and Metabochip (3).