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

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    URI
    http://hdl.handle.net/11287/618107
    Author
    Wessel, J. [et al]
    Hattersley, Andrew T.
    Frayling, Timothy M.
    Yaghootkar, Hanieh
    Date
    2015-01
    Journal
    Nature communications
    Type
    Journal Article
    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, P.H.S.
    Publisher
    Nature
    DOI
    10.1038/ncomms6897
    Rights
    Archived with thanks to Nature Communications
    Metadata
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    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.
    Citation
    Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. 2015, 6:5897 Nat Commun
    Publisher URL
    http://dx.doi.org/10.1038/ncomms6897
    Note
    This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text.
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    • 2015 RD&E publications
    • Diabetes/Endocrine Services
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