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

ABSTRACT

Background@#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. @*Methods@#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. @*Results@#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 ). @*Conclusion@#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.