Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

Abstract

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Figure 1

Genome-wide Manhattan plots for the GUARDIAN Discovery meta-analysis. A: MCRI. B: Insulin sensitivity (S_I + M). C: S_I. D: M. E: AIR_g. F: DI. G: S_G.

Figure 1

Genome-wide Manhattan plots for the GUARDIAN Discovery meta-analysis. A: MCRI. B: Insulin sensitivity (S_I + M). C: S_I. D: M. E: AIR_g. F: DI. G: S_G.

Figure 2

Regional plot of the MTNR1B locus in the GUARDIAN Discovery cohort meta-analysis. A: DI. B: AIR_g. C: S_I. Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted with their Discovery meta-analysis P values (as −log₁₀ values) as a function of genomic position (hg19). In each panel, the index variant is represented by a purple diamond. Color of additional variants indicates correlation with the index SNP (red, r² ≥ 0.80; orange, 0.60 ≤ r² < 0.80; green, 0.40 ≤ r² < 0.60; light blue, 0.20 ≤ r² < 0.40; dark blue, r² < 0.20; gray, no r² value available) based on pairwise r² values from HapMap. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Gene annotations were taken from the UCSC genome browser.

Figure 3

Regional plots of loci attaining genome-wide significance (P < 5.00 × 10⁻⁸) in the combined Discovery and Translation meta-analysis. A: KCNQ1 rs2237897 with DI/T2D. B: MTNR1B rs10830963 with AIR_g/T2D. C: CDKAL1 rs2206734 and AIR_g/T2D. D: 6p24.3 rs2064197 and S_G/T2D. Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted with their Discovery meta-analysis P values (as −log₁₀ values) as a function of genomic position (hg19). In each panel, the index variant from the Discovery cohort is represented by a purple circle, and the Discovery and Translation meta-analysis is represented by a purple square. Color of additional variants indicates correlation with the index SNP (red, r² ≥ 0.80; orange, 0.60 ≤ r² < 0.80; green, 0.40 ≤ r² < 0.60; light blue, 0.20 ≤ r² < 0.40; dark blue, r² < 0.20; gray, no r² value available) based on pairwise r² values from HapMap. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Gene annotations were taken from the UCSC genome browser. chr, chromosome.