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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
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2015 (English)In: Nature Communications, ISSN 2041-1723, Vol. 6, 5897Article in journal (Refereed) Published
Abstract [en]

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 (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 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 (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Place, publisher, year, edition, pages
2015. Vol. 6, 5897
National Category
Endocrinology and Diabetes
URN: urn:nbn:se:uu:diva-247330DOI: 10.1038/ncomms6897ISI: 000348741700001PubMedID: 25631608OAI: oai:DiVA.org:uu-247330DiVA: diva2:797057
Available from: 2015-03-22 Created: 2015-03-17 Last updated: 2016-01-25Bibliographically approved

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Gustafsson, StefanIngelsson, Erik
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Molecular epidemiologyScience for Life Laboratory, SciLifeLab
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