A Nonsynonymous Variant in GLP-1R Is Associated with Decreased Risk of Type 2 Diabetes in Koreans

Type 2 diabetes (T2D) is a common complex disorder with strong genetic predisposition. Although different ethnic groups share most of the common variants of T2D, there might be nonsynonymous variants that are specific to an ethnic group. In this study, we used whole exome sequencing (N=917) and exome genotyping array (N=3,026) to identify nonsynonymous variants in Korean T2D cases and controls (stage 1) and validated the findings in an independent set of 15,095 T2D cases and controls (stage 2). Whole exome capture was prepared using Agilent SureSelect version 4+UTR and sequencing was performed by Illumina HiSeq 2000. Nonsynonymous variants were incorporated into customized Axiom Biobank Plus Genotyping array. Genotype imputation was performed with 1,000 Genomes Project phase 3 reference. In silico data look-up was done for stage 2 analyses. EPACTS software was used for association testing and METAL was used for meta-analysis of stage 1 and 2 results. We identified 728,838 variants using whole exome sequencing, which include 258,463 novel variants. A nonsynonymous variant in GLP-1R (rs3765467, R131Q) was associated with decreased risk of T2D in genome-wide significance (OR = 0.85, P = 3.01x10^-8). This variant was associated with lower fasting glucose concentration (P = 0.00020) and lower HbA1c level (P = 0.0085) in nondiabetic controls. The minor allele frequency of this variant was 21.1% in Koreans but it was monomorphic in Europeans. We also validated the previous association between PAX4 nonsynonymous variant (rs2233580, R192H) and increased risk of T2D (OR = 1.52, P = 6.41x10^-15). This variant was associated with lower age at diagnosis and decreased C-peptide level in T2D cases (P < 0.05). Gene-wise analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 0.00010) by Madsen and Browning method.

In summary, we have identified East Asian specific nonsynonymous variants in GLP-1R and PAX4 to be associated with T2D in genome-wide significance.