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 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a
novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492;
MAF ¼ 1.4%) with lower FG (b ¼ 0.09±0.01 mmol l 1
, P ¼ 3.4 10 12), T2D risk
(OR[95%CI] ¼ 0.86[0.76–0.96], P ¼ 0.010), early insulin secretion (b ¼ 0.07±0.035
pmolinsulin mmolglucose
1 , P ¼ 0.048), but higher 2-h glucose (b ¼ 0.16±0.05 mmol l 1
,
P ¼ 4.3 10 4). We identify a gene-based association with FG at G6PC2
(pSKAT ¼ 6.8 10 6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and
S324P). We identify rs651007 (MAF ¼ 20%) in the first intron of ABO at the putative
promoter of an antisense lncRNA, associating with higher FG (b ¼ 0.02±0.004 mmol l 1
,
P ¼ 1.3 10 8). Our approach identifies novel coding variant associations and extends
the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D
susceptibility.
DOI: 10.103