Genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a korean population

Abstract

Background: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.

Methods: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.

Results: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study.

Conclusion: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Keywords: Genome-wide association study; Glycemic trait; Sex-specific; Type 2 diabetes.

Fig. 1

Genome-wide association of single nucleotide polymorphisms (SNPs) with type 2 diabetes mellitus (T2DM) in Korea Association Resource (KARE) study samples. (A) Quantile-quantile plot for test statistics. The observed P values were plotted as a function of the expected P values of the null distribution for T2DM. The shaded region represents the 95% concentration band. (B) Scatter plots of P values derived from genome-wide scan results for T2DM. Single-marker tests of association with T2DM were scrutinized by the 1 degree of freedom trend test. The trend test P value of each SNP is plotted (Y axis) as -log₁₀ (P) according to its chromosomal location (X axis). SNPs from the KARE genome-wide association study with P value <10^-4 are shown in red.

Fig. 2

Signal region on chromosome 12q24 covering type 2 diabetes mellitus (T2DM)-associated loci. (A) Signal plot of -log₁₀ (P values) using the trend test for T2DM association in a genomic region (in Mb). Black and gray dots indicate genotyped single nucleotide polymorphisms (SNPs) in Korea Association Resource genome-wide association study and imputed SNPs, respectively. Red diamonds indicate the strongest association signals detected in the genome-wide scan. Genomic positions are based on National Center for Biotechnology Information (NCBI) genome build 36 and dbSNP build 128. In the bottom of the signal plot, the locations of known genes are indicated with red boxes and green lines, which indicate exons and introns, respectively. Genetic information was obtained from NCBI build 36. (B) Plot of linkage disequilibrium (r²) for all SNPs across the region from Japanese in Tokyo, Japan and Han Chinese in Beijing, China founders in HapMap (release 22). This plot was generated using the Haploview 4.1 program.