Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, Arg192His increased risk of T2D and Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, = 4.47 × 10 and OR 0.84, = 3.55 × 10 , respectively). Another variant at 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, = 5.18 × 10 ). In T2D patients, Arg192His was associated with earlier age at diagnosis, and Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the Arg192His was associated with higher fasting glucose and Arg131Gln was associated with lower fasting glucose and HbA level. Gene-based analysis revealed that was most significantly associated with decreased risk of T2D ( = 1.0 × 10 ). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.