A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants

Abstract

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.

Fig. 1

Plots of T2D association and LD in FUSION stage 1 samples for regions surrounding IGF2BP2 (A) and rs9300039 (B). (A) and (B) each contain six panels. The top panels display RefSeq genes; there are none in the rs9300039 region. The second panels (i.e., directly below the top panels) show the T2D association −log₁₀ P values in FUSION stage 1 samples for SNPs genotyped in the GWA panel (closed blue circles) or imputed (open blue circles). The third panels show T2D association −log₁₀ P values for each SNP in a logistic regression model correcting for the reference SNP [indicated by the red circle for rs4402960 in (A) and for rs9300039 in (B)]. SNP rs7480010, reported by Sladek et al. (7), is also labeled in the rs9300039 plot (B) (green circle). A decrease in the −log₁₀ P value from the second to the third panels indicates that the association signal of the tested SNPs can be explained, at least in part, by the reference SNP. In both regions, the reference SNP was chosen for convenience; the choice of another strongly associated SNP nearby would have resulted in a similar picture. The fourth panels show recombination rate in centimorgans per megabase for the HapMap CEU sample (14). The fifth and sixth panels show LD r² and D’ based on FUSION stage 1–genotyped and FUSION stage 1–imputed data.

Fig. 2

Prediction of T2D risk in the FUSION sample with the use of 10 T2D susceptibility variants. T2D cases and NGT controls with complete genotype data were included in the analysis. To obtain a sample with a T2D prevalence of ~10%, we included nine copies of each of 2176 NGT controls and one copy of each of 2102 T2D cases. The predicted risk for each individual was estimated from a logistic regression model containing the 10 risk variants listed in Table 1. The proportion of T2D cases is shown for 20 equal intervals of predicted T2D risk. We constructed 95% confidence intervals (CIs) for the proportion of T2D cases in each interval using the original sample of 2102 cases and 2176 controls. The constructed sample T2D prevalence (0.096) is shown as a horizontal line. The proportion of T2D cases increases from ~5% in the lowest to 20% in the highest predicted risk categories.