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

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>GLP1R</jats:italic> (A316T; rs10305492; MAF=1.4%) with lower FG (<jats:italic>β</jats:italic>=−0.09±0.01 mmol l<jats:sup>−1</jats:sup>, <jats:italic>P</jats:italic>=3.4 × 10<jats:sup>−12</jats:sup>), T2D risk (OR[95%CI]=0.86[0.76–0.96], <jats:italic>P</jats:italic>=0.010), early insulin secretion <jats:italic>(β</jats:italic>=−0.07±0.035 pmol<jats:sub>insulin</jats:sub> mmol<jats:sub>glucose</jats:sub><jats:sup>−1</jats:sup>, <jats:italic>P</jats:italic>=0.048), but higher 2-h glucose <jats:italic>(β</jats:italic>=0.16±0.05 mmol l<jats:sup>−1</jats:sup>, <jats:italic>P</jats:italic>=4.3 × 10<jats:sup>−4</jats:sup>). We identify a gene-based association with FG at <jats:italic>G6PC2</jats:italic> (<jats:italic>p</jats:italic><jats:sub>SKAT</jats:sub>=6.8 × 10<jats:sup>−6</jats:sup>) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of <jats:italic>ABO</jats:italic> at the putative promoter of an antisense lncRNA, associating with higher FG <jats:italic>(β</jats:italic>=0.02±0.004 mmol l<jats:sup>−1</jats:sup>, <jats:italic>P</jats:italic>=1.3 × 10<jats:sup>−8</jats:sup>). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.</jats:p>