[HTML][HTML] Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

J Wessel, AY Chu, SM Willems, S Wang… - Nature …, 2015 - nature.com
J Wessel, AY Chu, SM Willems, S Wang, H Yaghootkar, JA Brody, M Dauriz, MF Hivert…
Nature communications, 2015nature.com
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= 1.4%) with lower FG (β=− 0.09±0.01 mmol l− 1, P= 3.4× 10− 12), T2D
risk (OR [95% CI]= 0.86 [0.76–0.96], P= 0.010), early insulin secretion (β=− 0.07±0.035 …
Abstract
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=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion =−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose =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 FG =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 T2D susceptibility.
nature.com