Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4

Abstract

Aims/hypothesis: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.

Methods: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.

Results: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.

Conclusions/interpretation: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Fig. 1

Summary of study design. CHB, Han Chinese in Beijing, China; JPT, Japanese in Tokyo, Japan

Fig. 2

Manhattan plot of combined genome-wide association results from the Hong Kong 1, Hong Kong 2 and Shanghai studies based on the random effect models. The y-axis represents the −log₁₀ p value, and the x-axis represents the 2,925,090 analysed SNPs. The dashed horizontal line indicates the threshold of significance p < 1 × 10⁻⁵. There are 44 points with p < 1 × 10⁻⁵, and the arrow and labels localise the susceptibility loci to type 2 diabetes uncovered in the present study

Fig. 3

Regional plots for the identified variant rs10229583, including results for both genotyped and imputed SNPs in the Chinese population. The purple circle and diamond represent the sentinel SNP in meta-analysis of three GWAS in the stage 1 and the East Asian meta-analysis in stages 1 + 2 + 3, respectively. Other SNPs are coloured according to their level of LD, which is measured by r ², with the sentinel SNP. The recombination rates estimated from the 1000 Genomes project JPT + CHB data are shown. CHB, Han Chinese in Beijing, China; JPT, Japanese in Tokyo, Japan

Fig. 4

Forest plot for meta-analysis of the association between type 2 diabetes and rs10229583 for all populations in the present study. ORs and 95% CIs were reported with respect to the type 2 diabetes-related risk alleles (G)

Fig. 5

Associations of the risk variant (G allele) of rs10229583 with measures of insulin secretion in Chinese controls. (a) Association with reduced HOMA-B in a Hong Kong Chinese adolescent cohort (p = 0.0221). (b) Association with a reduced Stumvoll Index of beta cell function in healthy Shanghai controls (p = 0.0303). (c) Association of the risk variant with higher FPG in healthy Shanghai controls (p = 0.0460). Data are expressed as mean (for FPG) or geometric mean (for HOMA-B and Stumvoll Index). SDs or 95% CIs are expressed as error bars. The number of individuals analysed for each genotype is shown in parentheses under each column