Fasting ​glucose and ​insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 nondiabetic individuals and in 16,491 type 2 diabetes cases and 81,877 controls.

We identify a novel association of a low-frequency nonsynonymous SNV in ​GLP1R (A316T; rs10305492; MAF=1.4%) with lower fasting glucose (beta=−0.09±0.01 mmol l−1, P=3.4 × 10−12), type 2 diabetes risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early ​insulin secretion (beta=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h ​glucose (beta=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at ​G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P).

We identify rs651007 (MAF=20%) in the first intron of ​ABO at the putative promoter of an antisense lncRNA, associating with higher fasting glucose (beta=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and type 2 diabetes susceptibility.

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