A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese

Abstract

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54x10(-10); odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36-1.82), and serine racemase (SRR) (P = 3.06x10(-9); OR = 1.28; 95% CI = 1.18-1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65x10(-10); OR = 1.29, 95% CI = 1.19-1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

Figure 1. Graphical summary of T2D GWAS in a Han Chinese population.

T2D association was determined for SNPs on the Illumina HumanHap550K-Duo chip. The y-axis represents the −log₁₀ P value and the x-axis represents each of the 516,212 SNPs used in the primary scan of 995 T2D cases and 894 controls.

Figure 2. Regional plots of three significant associations.

For each of the (A) PTPRD, (B) SRR, and (C) KCNQ1 regions, the −log₁₀ P values for the trend test from the primary scan were plotted as a function of genomic position (NCBI Build 36). The SNPs with the strongest signal and neighboring genotyped SNPs in the joint analysis are denoted by blue diamonds. Green diamonds in the KCNQ1 region (C) represent reported T2D–associated SNPs genotyped in all samples of joint analysis. Estimated recombination rates (right y-axis) based on the Chinese HapMap population was plotted to reflect the local LD structure around the significant SNPs. Gene annotations were taken from NCBI.

Figure 3. Q–Q plot for the trend test.

Q–Q plots are shown for the trend test based on the 516,212 quality SNPs of the initial analysis of 995 cases and 894 controls. The red lines represent the upper and lower boundaries of the 95% confidence bands.