Genome-Wide Association Study on Longitudinal Change in Fasting Plasma Glucose in Korean Population

Abstract

Background: Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time.

Methods: We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project.

Results: A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level.

Conclusion: We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

Keywords: Genome-wide association study; Hyperglycemia; Longitudinal studies.

Fig. 1.

Manhattan and quantile-quantile (Q-Q) plot for single nucleotide polymorphism (SNP) and SNP×time effects in meta-analysis. (A) Manhattan plot of the P values in the genome-wide association studies (GWAS) for fasting glucose. The horizontal lines represent the genome-wide significance (red; P<5.0×10⁻⁸) and suggestively significant (blue; P<1.0×10⁻⁵) SNPs. (B) Q-Q plot showing expected versus observed (–log10 P value). The expected line is shown in red and confidence bands are shown in gray. (C) Manhattan plot of the P values in the GWAS for longitudinal change of fasting glucose. (D) Q-Q plot GWAS results of longitudinal change of fasting plasma glucose.

Fig. 2.

LocusZoom plot of suggestive single nucleotide polymorphism (SNP)×time association in meta-analysis (P<1.0×10⁻⁵). (A, B, C, D) Vertical axis is –log₁₀ of the P value, the horizontal axis is the chromosomal position. Each dot represents a SNP tested for association with longitudinal change of fasting plasma glucose in 10,528 Korean population. Approximate linkage disequilibrium between the most significant SNP, listed at the top of each plot, and the other SNPs in the plot is shown by the r2 legend in each plot.