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 Stančáková; Ravinder Abrol; Céline 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; Kristine H Allin; Torben Jørgensen; Allan Linneberg; Torben Hansen; Oluf Pedersen; EPIC-InterAct Consortium

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 Stančáková, Ravinder Abrol, Céline 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, Kristine H Allin, Torben Jørgensen, Allan Linneberg, Torben Hansen, Oluf Pedersen, EPIC-InterAct Consortium

121 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	6
Pages (from-to)	5897
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms6897
Publication status	Published - Feb 2015

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

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, 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, Allin, KH, Jørgensen, T, Linneberg, A , Hansen, T , Pedersen, O & EPIC-InterAct Consortium 2015, 'Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility', Nature Communications, vol. 6, pp. 5897. https://doi.org/10.1038/ncomms6897

@article{60057cc1dede4896bdd4b78b5296b2eb,

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 (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.",

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 Stan{\v c}{\'a}kov{\'a} and Ravinder Abrol and C{\'e}line 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 {Hua Zhao}, Jing 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 Allin, {Kristine H} and Torben J{\o}rgensen and Allan Linneberg and Torben Hansen and Oluf Pedersen and {EPIC-InterAct Consortium}",

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doi = "10.1038/ncomms6897",

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journal = "Nature Communications",

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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 - Stančáková, Alena

AU - Abrol, Ravinder

AU - Besse, Céline

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 - Hua Zhao, Jing

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 - Allin, Kristine H

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - EPIC-InterAct Consortium

PY - 2015/2

Y1 - 2015/2

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 (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.

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 (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.

U2 - 10.1038/ncomms6897

DO - 10.1038/ncomms6897

M3 - Journal article

C2 - 25631608

SN - 2041-1723

VL - 6

SP - 5897

JO - Nature Communications

JF - Nature Communications

ER -

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

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