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

  • Author(s): Wessel, J
  • Chu, AY
  • Willems, SM
  • Wang, S
  • Yaghootkar, H
  • Brody, JA
  • Dauriz, M
  • Hivert, MF
  • Raghavan, S
  • Lipovich, L
  • Hidalgo, B
  • Fox, K
  • Huffman, JE
  • An, P
  • Lu, Y
  • Rasmussen-Torvik, LJ
  • Grarup, N
  • Ehm, MG
  • Li, L
  • Baldridge, AS
  • Stančáková, A
  • Abrol, R
  • Besse, C
  • Boland, A
  • Bork-Jensen, J
  • Fornage, M
  • Freitag, DF
  • Garcia, ME
  • Guo, X
  • Hara, K
  • Isaacs, A
  • Jakobsdottir, J
  • Lange, LA
  • Layton, JC
  • Li, M
  • Hua Zhao, J
  • Meidtner, K
  • Morrison, AC
  • Nalls, MA
  • Peters, MJ
  • Sabater-Lleal, M
  • Schurmann, C
  • Silveira, A
  • Smith, AV
  • Southam, L
  • Stoiber, MH
  • Strawbridge, RJ
  • Taylor, KD
  • Varga, TV
  • Allin, KH
  • Amin, N
  • Aponte, JL
  • Aung, T
  • Barbieri, C
  • Bihlmeyer, NA
  • Boehnke, M
  • Bombieri, C
  • Bowden, DW
  • Burns, SM
  • Chen, Y
  • Chen, YD
  • Cheng, CY
  • Correa, A
  • Czajkowski, J
  • Dehghan, A
  • Ehret, GB
  • Eiriksdottir, G
  • Escher, SA
  • Farmaki, AE
  • Frånberg, M
  • Gambaro, G
  • Giulianini, F
  • Goddard, WA
  • et al.
Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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±0.01mmoll-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±0.035pmolinsulinmmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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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