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

Go MJ, Hwang JY, Park TJ, Kim YJ, Oh JH, Kim YJ, Han BG, Kim BJ - Diabetes Metab J (2014)

Bottom Line: A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function.We further observed that two novel loci with multiple diverse effects were highly specific to males.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural and Functional Genomics, Center for Genome Science, Korea National Institute of Health, Cheongwon, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

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  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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4209352&req=5

Figure 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 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.

Mentions: Stage 1 KARE GWA for T2DM was analyzed using the trend test while controlling for age, sex, BMI, and recruitment area as covariates. The quantile-quantile plot of the observed P values derived from the trend test showed a significant deviation from the distribution only in the tail, which suggested an association of these SNPs with T2DM (Fig. 1A). The estimated genomic control inflation factor (λ) was 1.008, which indicated limited evidence of population stratification in the KARE study samples. Stage 1 association results revealed 24 independent SNPs (pair-wise linkage disequilibrium [LD] statistic r2 <0.2 within a genomic region 500-Kb window) that passed our arbitrary stage 1 threshold for replication (GWAS P value of <10-4 and MAF of ≥0.01 in T2DM cases and controls) (Fig. 1B). We were able to genotype 21 of 24 selected SNPs in our stage 2 samples of 1,216 patients and 1,352 controls recruited to the Health2 study cohort from five different regions of the country; we analyzed their association with T2DM and performed a meta-analysis of the stage 1 and stage 2 results (Appendix 1).


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

Go MJ, Hwang JY, Park TJ, Kim YJ, Oh JH, Kim YJ, Han BG, Kim BJ - Diabetes Metab J (2014)

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  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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209352&req=5

Figure 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 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.
Mentions: Stage 1 KARE GWA for T2DM was analyzed using the trend test while controlling for age, sex, BMI, and recruitment area as covariates. The quantile-quantile plot of the observed P values derived from the trend test showed a significant deviation from the distribution only in the tail, which suggested an association of these SNPs with T2DM (Fig. 1A). The estimated genomic control inflation factor (λ) was 1.008, which indicated limited evidence of population stratification in the KARE study samples. Stage 1 association results revealed 24 independent SNPs (pair-wise linkage disequilibrium [LD] statistic r2 <0.2 within a genomic region 500-Kb window) that passed our arbitrary stage 1 threshold for replication (GWAS P value of <10-4 and MAF of ≥0.01 in T2DM cases and controls) (Fig. 1B). We were able to genotype 21 of 24 selected SNPs in our stage 2 samples of 1,216 patients and 1,352 controls recruited to the Health2 study cohort from five different regions of the country; we analyzed their association with T2DM and performed a meta-analysis of the stage 1 and stage 2 results (Appendix 1).

Bottom Line: A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function.We further observed that two novel loci with multiple diverse effects were highly specific to males.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural and Functional Genomics, Center for Genome Science, Korea National Institute of Health, Cheongwon, Korea.

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.

No MeSH data available.


Related in: MedlinePlus