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

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 Stancakova; Ravinder Abrol; Celine 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; Lorraine Southam; Marcus H. Stoiber; Rona J. Strawbridge; Kent D. Taylor; Tibor V. Varga; Yvonne T. van der Schouw

doi:10.1038/ncomms6897

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

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. BaldridgeAlena Stancakova, Ravinder Abrol, Celine 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, Lorraine Southam, Marcus H. Stoiber, Rona J. Strawbridge, Kent D. Taylor, Tibor V. Varga, Yvonne T. van der Schouw,

^*Corresponding author for this work

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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.

Original language	English
Article number	5897
Number of pages	16
Journal	Nature Communications [E]
Volume	6
DOIs	https://doi.org/10.1038/ncomms6897
Publication status	Published - Jan 2015

Keywords

GLUCAGON-LIKE PEPTIDE-1
GENOME-WIDE ASSOCIATION
RECEPTOR GENE
TRIGLYCERIDE LEVELS
GERMLINE MUTATIONS
INSULIN-RESISTANCE
CODING VARIATION
GLYCEMIC TRAITS
SEQUENCING DATA
PLASMA-GLUCOSE

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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. (2015). Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nature Communications [E], 6, Article 5897. https://doi.org/10.1038/ncomms6897

@article{807ea9ed6bf64f99bcea0b0a707242b6,

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

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",

author = "Jennifer Wessel and Chu, {Audrey Y.} and Willems, {Sara M.} and Shuai Wang and Hanieh Yaghootkar and Brody, {Jennifer A.} and Marco Dauriz and Marie-France Hivert and Sridharan Raghavan and Leonard Lipovich and Bertha Hidalgo and Keolu Fox and Huffman, {Jennifer E.} and Ping An and Yingchang Lu and Rasmussen-Torvik, {Laura J.} and Niels Grarup and Ehm, {Margaret G.} and Li Li and Baldridge, {Abigail S.} and Alena Stancakova and Ravinder Abrol and Celine Besse and Anne Boland and Jette Bork-Jensen and Myriam Fornage and Freitag, {Daniel F.} and Garcia, {Melissa E.} and Xiuqing Guo and Kazuo Hara and Aaron Isaacs and Johanna Jakobsdottir and Lange, {Leslie A.} and Layton, {Jill C.} and Man Li and Zhao, {Jing Hua} and Karina Meidtner and Morrison, {Alanna C.} and Nalls, {Mike A.} and Peters, {Marjolein J.} and Maria Sabater-Lleal and Claudia Schurmann and Angela Silveira and Smith, {Albert V.} and Lorraine Southam and Stoiber, {Marcus H.} and Strawbridge, {Rona J.} and Taylor, {Kent D.} and Varga, {Tibor V.} and {van der Schouw}, {Yvonne T.}",

year = "2015",

month = jan,

doi = "10.1038/ncomms6897",

language = "English",

volume = "6",

journal = "Nature Communications [E]",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, M-F, 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, Stancakova, 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, Zhao, JH, 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, van der Schouw, YT 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

TY - JOUR

T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

AU - Wessel, Jennifer

AU - Chu, Audrey Y.

AU - Willems, Sara M.

AU - Wang, Shuai

AU - Yaghootkar, Hanieh

AU - Brody, Jennifer A.

AU - Dauriz, Marco

AU - Hivert, Marie-France

AU - Raghavan, Sridharan

AU - Lipovich, Leonard

AU - Hidalgo, Bertha

AU - Fox, Keolu

AU - Huffman, Jennifer E.

AU - An, Ping

AU - Lu, Yingchang

AU - Rasmussen-Torvik, Laura J.

AU - Grarup, Niels

AU - Ehm, Margaret G.

AU - Li, Li

AU - Baldridge, Abigail S.

AU - Stancakova, Alena

AU - Abrol, Ravinder

AU - Besse, Celine

AU - Boland, Anne

AU - Bork-Jensen, Jette

AU - Fornage, Myriam

AU - Freitag, Daniel F.

AU - Garcia, Melissa E.

AU - Guo, Xiuqing

AU - Hara, Kazuo

AU - Isaacs, Aaron

AU - Jakobsdottir, Johanna

AU - Lange, Leslie A.

AU - Layton, Jill C.

AU - Li, Man

AU - Zhao, Jing Hua

AU - Meidtner, Karina

AU - Morrison, Alanna C.

AU - Nalls, Mike A.

AU - Peters, Marjolein J.

AU - Sabater-Lleal, Maria

AU - Schurmann, Claudia

AU - Silveira, Angela

AU - Smith, Albert V.

AU - Southam, Lorraine

AU - Stoiber, Marcus H.

AU - Strawbridge, Rona J.

AU - Taylor, Kent D.

AU - Varga, Tibor V.

AU - van der Schouw, Yvonne T.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - GLUCAGON-LIKE PEPTIDE-1

KW - GENOME-WIDE ASSOCIATION

KW - RECEPTOR GENE

KW - TRIGLYCERIDE LEVELS

KW - GERMLINE MUTATIONS

KW - INSULIN-RESISTANCE

KW - CODING VARIATION

KW - GLYCEMIC TRAITS

KW - SEQUENCING DATA

KW - PLASMA-GLUCOSE

U2 - 10.1038/ncomms6897

DO - 10.1038/ncomms6897

M3 - Article

C2 - 25631608

SN - 2041-1723

VL - 6

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 5897

ER -

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

Abstract

Keywords

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