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

EPIC-InterAct Consortium, Jennifer Wessel, Audrey Y Chu, Sara M Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A Brody, Marco Dauriz, Marie-France Hivert, Sridharan Raghavan, Leonard Lipovich, Bertha Hidalgo, Keolu Fox, Jennifer E Huffman, Ping An, Yingchang Lu, Laura J Rasmussen-Torvik, Niels Grarup, Margaret G Ehm, Li LiAbigail S Baldridge, Alena Stančáková, Ravinder Abrol, Céline Besse, Anne Boland, Jette Bork-Jensen, Myriam Fornage, Daniel F Freitag, Melissa E Garcia, Xiuqing Guo, Kazuo Hara, Aaron Isaacs, Johanna Jakobsdottir, Leslie A Lange, Jill C Layton, Man Li, Jing Hua Zhao, Karina Meidtner, Alanna C Morrison, Mike A Nalls, Marjolein J Peters, Maria Sabater-Lleal, Claudia Schurmann, Angela Silveira, Albert V Smith, Lorraine Southam, Marcus H Stoiber, Rona J Strawbridge, Kent D Taylor, Tibor V Varga, Kristine H Allin, James Brown

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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.

Original languageEnglish
Article number5897
Number of pages16
JournalNature Communications
Publication statusPublished - 29 Jan 2015


  • African Continental Ancestry Group/genetics
  • Blood Glucose/metabolism
  • Diabetes Mellitus, Type 2/blood
  • 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


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