Diabetes Metab J.  2021 Mar;45(2):231-240. 10.4093/dmj.2019.0163.

Exome Chip Analysis of 14,026 Koreans Reveals Known and Newly Discovered Genetic Loci Associated with Type 2 Diabetes Mellitus

• Cho SB
• Jang JH
• Chung MG
• Kim SC

• KMID: 2514199
• DOI: http://doi.org/10.4093/dmj.2019.0163

Abstract

Most loci associated with type 2 diabetes mellitus (T2DM) discovered to date are within noncoding regions of unknown functional significance. By contrast, exonic regions have advantages for biological interpretation.

We analyzed the association of exome array data from 14,026 Koreans to identify susceptible exonic loci for T2DM. We used genotype information of 50,543 variants using the Illumina exome array platform.

In total, 7 loci were significant with a Bonferroni adjusted P=1.03×10⁻⁶. rs2233580 in paired box gene 4 (PAX4) showed the highest odds ratio of 1.48 (P=1.60×10⁻¹⁰). rs11960799 in membrane associated ring-CH-type finger 3 (MARCH3) and rs75680863 in transcobalamin 2 (TCN2) were newly identified loci. When we built a model to predict the incidence of diabetes with the 7 loci and clinical variables, area under the curve (AUC) of the model improved significantly (AUC=0.72, P<0.05), but marginally in its magnitude, compared with the model using clinical variables (AUC=0.71, P<0.05). When we divided the entire population into three groups—normal body mass index (BMI; <25 kg/m²), overweight (25≤ BMI <30 kg/m²), and obese (BMI ≥30 kg/m²) individuals—the predictive performance of the 7 loci was greatest in the group of obese individuals, where the net reclassification improvement was highly significant (0.51; P=8.00×10⁻⁵).

We found exonic loci having a susceptibility for T2DM. We found that such genetic information is advantageous for predicting T2DM in a subgroup of obese individuals.

Keyword

Diabetes mellitus, type 2; Exome; Genetic predisposition to disease; Microarray analysis

Figure

• 

  Fig. 1 Manhattan plot of P values from exome-wide association analysis (GWAS). The 6 points that are placed over the red dotted line indicates significant loci with Bonferroni's multiple testing correction (adjusted P=9.83×10−7). OR, odds ratio.

• 

  Fig. 2 Forest plot of meta-analysis with result from Korean exome data and genome-wide association stud (GWAS) catalog summary data. P value indicates P values of meta-analysis with fixed effect model. In the presentation of odds ratio (OR) and confidence interval (CI), upper one is from Korean exome data, and the lower one is from GWAS catalog. Blue line of the forest plot indicates OR and CI of Korean exome data. The whole results were presented in Supplementary Table 2. SNP, single nucleotide polymorphism.

• 

  Fig. 3 Receiver operating curve (ROC) plots of prediction model with or without genotype information in total, normal, overweight, and obese population. The thick line indicated ROC of combined model (clinical variable+genetic marker). The dashed line shows ROC of clinical model that integrated clinical variables in the prediction of incident type 2 diabetes mellitus. (A) There was a small gap between the two ROCs of total population. (B) In the normal weight group, there was a slight gap between the lines, which showed no substantially wider than that of total population. (C) Compared with the plots of normal weight population, there was wider gap between the plots, although still the magnitude is small. (D) In the obese group, area under the curve (AUC) of combined model (0.75) is greater than that of clinical model (0.72), which showed a clear gap between the ROC curves.

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