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

Research output: Contribution to journalArticle

  • 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 Li
  • Abigail 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
  • I T Lee
  • James B Brown
  • Caroline Hayward
  • Ozren Polasek
  • Igor Rudan
  • James G Wilson
  • EPIC-InterAct Consortium

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)5897
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 29 Jan 2015

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.

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