Genetic-risk assessment of GWAS-derived susceptibility loci for type 2 diabetes in a 10 year follow-up of a population-based cohort study

To date, genome-wide meta-analyses have identified genetic susceptibility to type 2 diabetes mellitus (t2d) predominantly in populations of european ancestry. however, comprehensive genetic-risk assessment based on previous gwas loci has not been fully tested in non-european populations. to evaluate whether a genetic-risk score (grs) could improve t2d-risk prediction in the korean population, a grs (grs-55) was constructed by summing 55 risk alleles based on the 1000 genomes imputation in the korean association resource study (t2d cases=1042 and controls=2943 at baseline). we also constructed another grs (grs-19) based on nominal significance and consistent direction of effect. in mean difference tests, the mean value of the grs-19 was significantly higher in t2d cases than in controls at baseline examination. in a model adjusted for area, age, sex and body mass index, weighted grs-19 was found to be associated with enhanced effect sizes of t2d risk under consistent c-statistics. in addition, we confirmed cumulative risk effects on incidence rates of t2d, fasting plasma glucose and glycated hemoglobin (hba1c) levels in a longitudinal 10 year of follow-up study. these findings highlight that a genotype score comprised of 19 common variants contributed to t2d-risk prediction in the korean population. further multi-locus epistatic interactions may provide the possibility to improve risk prediction in c-statistics for discrimination or reclassification.