Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Figure 1

Genome-wide Manhattan plots for the DIAGRAM+ stage 1 meta-analysis. Top panel summarizes the results of the unconditional meta-analysis. Previously established loci are denoted in red and loci identified by the current study are denoted in green. The ten signals in blue are those taken forward but not confirmed in stage 2 analyses. The genes used to name signals have been chosen on the basis of proximity to the index SNP and should not be presumed to indicate causality. The lower panel summarizes the results of equivalent meta-analysis after conditioning on 30 previously established and newly identified autosomal T2D-associated SNPs (denoted by the dotted lines below these loci in the upper panel). Newly discovered conditional signals (outside established loci) are denoted with an orange dot if they show suggestive levels of significance (P < 10⁻⁵), whereas secondary signals close to already confirmed T2D loci are shown in purple (P < 10⁻⁴).

Figure 2

Regional plots of the 12 newly discovered T2D loci. Genotyped and imputed SNPs passing quality control measures across all stage 1 studies are plotted with their meta-analysis P values (as −log₁₀ values) as a function of genomic position (NCBI Build 36). In each panel, the index association SNP is represented by a diamond, with stage 1 meta-analysis results denoted by a red diamond and the combined stage 1 and stage 2 meta-analysis results denoted with a clear symbol. Estimated recombination rates (taken from HapMap CEU) are plotted to reflect the local LD structure. Color of remaining SNPs (circles) indicates LD with the index SNP according to a scale from r² = 0 to r² = 1 based on pairwise r² values from HapMap CEU (red, r² = 0.8–1.0; orange, r² = 0.6–0.8; green, r² = 0.4–0.6; blue, r² = 0.2–0.4; black, r² < 0.2; gray, no r² value available). Gene annotations were taken from the University of California Santa Cruz genome browser.

Figure 3

Plots of fasting blood glucose, insulin and derived indices for the established and new T2D loci. (a,b) Plots of fasting glucose (x axis) and fasting insulin (y axis). (c,d) Plots of HOMA-B (an index of beta cell function; x axis) and HOMA-IR (an index of insulin sensitivity; y axis). Each point refers to a single T2D association signal, with colors denoting the strength of the association to either the x-axis variable (left-hand of each pair of plots) or y-axis variable (right-hand of each pair) (red, P < 10⁻³; orange, 10⁻³ < P < 10⁻²; yellow, 0.01 < P < 0.05; green, 0.05 < P < 0.20; blue, P > 0.20). The two KCNQ1 associations are distinguished by the notation KCNQ1 for rs163184 and KCNQ1* for rs231362. The gene names associated with each signal have been chosen on the basis of proximity to the index SNP and should not be presumed to indicate causality.