New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Figure 1

Regional plots of ten novel genome-wide significant associations. For each of the ADCY5 (a), MADD (b), ADRA2A (c), FADS1 (d), CRY2 (e), SLC2A2 (f), GLIS3 (g), PROX1 (h), FAM148B (i) and IGF1 (j) regions, directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as –log10 values) as a function of genomic position (NCBI Build 35). In each panel, the Stage 1 discovery SNP taken forward to Stage 2 replication is represented by a blue diamond (with global meta-analysis P value), with its Stage 1 discovery P value denoted by a red diamond. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (according to a white to red scale from r² = 0 to 1, based on pairwise r² values from HapMap CEU). Gene annotations were taken from the University of California Santa Cruz genome browser.

Figure 2

Quantile-quantile (Q-Q) plots for fasting glucose (FG) (a), β-cell function by homeostasis model assessment (HOMA-B) (b), fasting insulin (FI) (c), and insulin resistance by homeostasis model assessment (HOMA-IR) (d). In each plot, the expected null distribution is plotted along the red diagonal, the entire distribution of observed P values is plotted in black, and a distribution that excludes the ten novel findings in Figure 1 is plotted in green. For FG and HOMA-B, the distribution that excludes the four genome-wide significant FG-associated loci (GCK, GCKR, G6PC2 and MTNR1B) is plotted in blue. A comparison of the observed P values for each trait shows that FG/HOMA-B associations are much more likely to be detected than FI/HOMA-IR associations.

Figure 3

Variation in levels of fasting glucose depending on the number of risk alleles at novel loci, weighted by effect size in an aggregate genotype score for the Framingham Heart Study. The bar plots show the average and standard error of fasting glucose in mmol/L for each value of the genotype score based on the regression coefficient (right Y axis), and the histogram denotes the number of individuals in each genotype score category (left Y axis). Comparable results were obtained for the NFBC 1966 and ARIC cohorts. On average, the range spans ~0.4 mmol/L (~7.2 mg/dl) from low to high genotype score.