Table 2

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

GWAS meta-analysis	Nominal MAGENTA enrichment P value^*	Number of OBS genes/loci above enrichment cutoff	Number of EXP genes/loci above enrichment cutoff	Excess number of genes/loci above enrichment cutoff (OBS − EXP)^†	Enrichment fold (OBS/EXP)	Number of genes near validated GWAS SNPs^‡	Genes near validated GWAS SNPs^‡
T2D	1.7 × 10⁻⁵	41^**	23	18	1.78	6^***	PPARG, IRS1^§, KCNJ11/ABCC8^‖, IDE, GIPR^¶
Fasting glucose	0.078	31	24	7	1.29	1	SLC2A2
HOMA-IR	0.11	29	24	5	1.21	0	—
2-h insulin	0.24	27	24	3	1.13	1	IRS1
HOMA-B	0.27	26	23	3	1.13	0	—
Fasting insulin	0.29	26	24	2	1.08	0	—
2-h glucose	0.74	20	23	0	0.87	0	—
HbA_1c	0.75	20	23	0	0.87	0	—

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).