Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Publication date
2015-01
Authors
Wessel, Jennifer
Chu, Audrey Y.
Willems, Sara M.
Wang, Shuai
Yaghootkar, Hanieh
Brody, Jennifer A.
Dauriz, Marco
Hivert, Marie-France
Raghavan, Sridharan
Lipovich, Leonard
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Document Type
Article
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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 (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.
Keywords
GLUCAGON-LIKE PEPTIDE-1, GENOME-WIDE ASSOCIATION, RECEPTOR GENE, TRIGLYCERIDE LEVELS, GERMLINE MUTATIONS, INSULIN-RESISTANCE, CODING VARIATION, GLYCEMIC TRAITS, SEQUENCING DATA, PLASMA-GLUCOSE, Journal Article, Research Support, American Recovery and Reinvestment Act, 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, Non-P.H.S.
Citation
Wessel, J, Chu, A Y, Willems, S M, Wang, S, Yaghootkar, H, Brody, J A, Dauriz, M, Hivert, M-F, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, J E, An, P, Lu, Y, Rasmussen-Torvik, L J, Grarup, N, Ehm, M G, Li, L, Baldridge, A S, Stancakova, A, Abrol, R, Besse, C, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, D F, Garcia, M E, Guo, X, Hara, K, Isaacs, A, Jakobsdottir, J, Lange, L A, Layton, J C, Li, M, Zhao, J H, Meidtner, K, Morrison, A C, Nalls, M A, Peters, M J, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, A V, Southam, L, Stoiber, M H, Strawbridge, R J, Taylor, K D, Varga, T V, van der Schouw, Y T & The EPIC-InterAct Consortium 2015, 'Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility', Nature Communications [E], vol. 6, 5897. https://doi.org/10.1038/ncomms6897