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

Publication ,  Journal Article
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 ...
Published in: Nat Commun
January 29, 2015

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

January 29, 2015

Volume

6

Start / End Page

5897

Location

England

Related Subject Headings

  • White People
  • Polymorphism, Single Nucleotide
  • Oligonucleotide Array Sequence Analysis
  • Mutation Rate
  • Insulin
  • Humans
  • Glucose-6-Phosphatase
  • Glucagon-Like Peptide-1 Receptor
  • Genetic Variation
  • Genetic Predisposition to Disease
 

Citation

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Wessel, J., Chu, A. Y., Willems, S. M., Wang, S., Yaghootkar, H., Brody, J. A., … Goodarzi, M. O. (2015). Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun, 6, 5897. https://doi.org/10.1038/ncomms6897
Wessel, Jennifer, Audrey Y. Chu, Sara M. Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A. Brody, Marco Dauriz, et al. “Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.Nat Commun 6 (January 29, 2015): 5897. https://doi.org/10.1038/ncomms6897.
Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015 Jan 29;6:5897.
Wessel, Jennifer, et al. “Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.Nat Commun, vol. 6, Jan. 2015, p. 5897. Pubmed, doi: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, Stoiber MH, Strawbridge RJ, Taylor KD, Varga TV, Allin KH, Amin N, Aponte JL, Aung T, Barbieri C, Bihlmeyer NA, Boehnke M, Bombieri C, Bowden DW, Burns SM, Chen Y, Chen Y-D, Cheng C-Y, Correa A, Czajkowski J, Dehghan A, Ehret GB, Eiriksdottir G, Escher SA, Farmaki A-E, Frånberg M, Gambaro G, Giulianini F, Goddard WA, Goel A, Gottesman O, Grove ML, Gustafsson S, Hai Y, Hallmans G, Heo J, Hoffmann P, Ikram MK, Jensen RA, Jørgensen ME, Jørgensen T, Karaleftheri M, Khor CC, Kirkpatrick A, Kraja AT, Kuusisto J, Lange EM, Lee IT, Lee W-J, Leong A, Liao J, Liu C, Liu Y, Lindgren CM, Linneberg A, Malerba G, Mamakou V, Marouli E, Maruthur NM, Matchan A, McKean-Cowdin R, McLeod O, Metcalf GA, Mohlke KL, Muzny DM, Ntalla I, Palmer ND, Pasko D, Peter A, Rayner NW, Renström F, Rice K, Sala CF, Sennblad B, Serafetinidis I, Smith JA, Soranzo N, Speliotes EK, Stahl EA, Stirrups K, Tentolouris N, Thanopoulou A, Torres M, Traglia M, Tsafantakis E, Javad S, Yanek LR, Zengini E, Becker DM, Bis JC, Brown JB, Cupples LA, Hansen T, Ingelsson E, Karter AJ, Lorenzo C, Mathias RA, Norris JM, Peloso GM, Sheu WH-H, Toniolo D, Vaidya D, Varma R, Wagenknecht LE, Boeing H, Bottinger EP, Dedoussis G, Deloukas P, Ferrannini E, Franco OH, Franks PW, Gibbs RA, Gudnason V, Hamsten A, Harris TB, Hattersley AT, Hayward C, Hofman A, Jansson J-H, Langenberg C, Launer LJ, Levy D, Oostra BA, O’Donnell CJ, O’Rahilly S, Padmanabhan S, Pankow JS, Polasek O, Province MA, Rich SS, Ridker PM, Rudan I, Schulze MB, Smith BH, Uitterlinden AG, Walker M, Watkins H, Wong TY, Zeggini E, EPIC-InterAct Consortium, Laakso M, Borecki IB, Chasman DI, Pedersen O, Psaty BM, Tai ES, van Duijn CM, Wareham NJ, Waterworth DM, Boerwinkle E, Kao WHL, Florez JC, Loos RJF, Wilson JG, Frayling TM, Siscovick DS, Dupuis J, Rotter JI, Meigs JB, Scott RA, Goodarzi MO. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015 Jan 29;6:5897.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

January 29, 2015

Volume

6

Start / End Page

5897

Location

England

Related Subject Headings

  • White People
  • Polymorphism, Single Nucleotide
  • Oligonucleotide Array Sequence Analysis
  • Mutation Rate
  • Insulin
  • Humans
  • Glucose-6-Phosphatase
  • Glucagon-Like Peptide-1 Receptor
  • Genetic Variation
  • Genetic Predisposition to Disease