LAUSR

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.