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; Marcus H Stoiber; Rona J Strawbridge; Kent D Taylor; Tibor V Varga; Kristine H Allin; 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, Marcus H Stoiber, Rona J Strawbridge, Kent D Taylor, Tibor V Varga, Kristine H Allin, EPIC-InterAct Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

130 Citations (Web of Science)

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
Pages (from-to)	5897
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms6897
Publication status	Published - 29 Jan 2015
Externally published	Yes

Keywords

African Continental Ancestry Group/genetics
Blood Glucose/metabolism
Diabetes Mellitus, Type 2/blood
European Continental Ancestry Group/genetics
Exome/genetics
Fasting/blood
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Genetic Variation
Glucagon-Like Peptide-1 Receptor/genetics
Glucose-6-Phosphatase/genetics
Humans
Insulin/blood
Mutation Rate
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide/genetics

Access to Document

10.1038/ncomms6897Licence: CC BY

Cite this

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

@article{a3218f04c6714557b05a02a5ee819a8f,

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. ",

keywords = "African Continental Ancestry Group/genetics, Blood Glucose/metabolism, Diabetes Mellitus, Type 2/blood, European Continental Ancestry Group/genetics, Exome/genetics, Fasting/blood, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor/genetics, Glucose-6-Phosphatase/genetics, Humans, Insulin/blood, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics",

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 Stoiber, {Marcus H} and Strawbridge, {Rona J} and Taylor, {Kent D} and Varga, {Tibor V} and Allin, {Kristine H} and {EPIC-InterAct Consortium}",

year = "2015",

month = jan,

day = "29",

doi = "10.1038/ncomms6897",

language = "English",

volume = "6",

pages = "5897",

journal = "Nature Communications",

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, 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, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH & 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

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 - 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 - Stoiber, Marcus H

AU - Strawbridge, Rona J

AU - Taylor, Kent D

AU - Varga, Tibor V

AU - Allin, Kristine H

AU - EPIC-InterAct Consortium

PY - 2015/1/29

Y1 - 2015/1/29

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.

KW - African Continental Ancestry Group/genetics

KW - Blood Glucose/metabolism

KW - Diabetes Mellitus, Type 2/blood

KW - European Continental Ancestry Group/genetics

KW - Exome/genetics

KW - Fasting/blood

KW - Genetic Association Studies

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Glucagon-Like Peptide-1 Receptor/genetics

KW - Glucose-6-Phosphatase/genetics

KW - Humans

KW - Insulin/blood

KW - Mutation Rate

KW - Oligonucleotide Array Sequence Analysis

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1038/ncomms6897

DO - 10.1038/ncomms6897

M3 - Article

C2 - 25631608

SN - 2041-1723

VL - 6

SP - 5897

JO - Nature Communications

JF - Nature Communications

ER -