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

Nat Commun. 2015 Jan 29;6:5897. doi: 10.1038/ncomms6897.

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 (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=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 (β=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.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • African Continental Ancestry Group / genetics
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • European Continental Ancestry Group / genetics
  • Exome / genetics*
  • Fasting / blood*
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucose-6-Phosphatase / genetics
  • Humans
  • Insulin / blood
  • Mutation Rate*
  • Oligonucleotide Array Sequence Analysis*
  • Polymorphism, Single Nucleotide / genetics

Substances

  • Blood Glucose
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Glucose-6-Phosphatase
  • G6PC2 protein, human

Grant support