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

Wessel, J. et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nature Communications, 6, 5897. (doi: 10.1038/ncomms6897) (PMID:25631608) (PMCID:PMC4311266)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Padmanabhan, Professor Sandosh and Strawbridge, Dr Rona
• Authors: 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., Stančáková, 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., Hua Zhao, J., 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., Allin, K. H., Amin, N., Aponte, J. L., Aung, T., Barbieri, C., Bihlmeyer, N. A., Boehnke, M., Bombieri, C., Bowden, D. W., Burns, S. M., Chen, Y., Chen, Y.-D., Cheng, C.-Y., Correa, A., Czajkowski, J., Dehghan, A., Ehret, G. B., Eiriksdottir, G., Escher, S. A., Farmaki, A.-E., Frånberg, M., Gambaro, G., Giulianini, F., Goddard, W. A., Goel, A., Gottesman, O., Grove, M. L., Gustafsson, S., Hai, Y., Hallmans, G., Heo, J., Hoffmann, P., Ikram, M. K., Jensen, R. A., Jørgensen, M. E., Jørgensen, T., Karaleftheri, M., Khor, C. C., Kirkpatrick, A., Kraja, A. T., Kuusisto, J., Lange, E. M., Lee, I. T., Lee, W.-J., Leong, A., Liao, J., Liu, C., Liu, Y., Lindgren, C. M., Linneberg, A., Malerba, G., Mamakou, V., Marouli, E., Maruthur, N. M., Matchan, A., McKean-Cowdin, R., McLeod, O., Metcalf, G. A., Mohlke, K. L., Muzny, D. M., Ntalla, I., Palmer, N. D., Pasko, D., Peter, A., Rayner, N. W., Renström, F., Rice, K., Sala, C. F., Sennblad, B., Serafetinidis, I., Smith, J. A., Soranzo, N., Speliotes, E. K., Stahl, E. A., Stirrups, K., Tentolouris, N., Thanopoulou, A., Torres, M., Traglia, M., Tsafantakis, E., Javad, S., Yanek, L. R., Zengini, E., Becker, D. M., Bis, J. C., Brown, J. B., Adrienne Cupples, L., Hansen, T., Ingelsson, E., Karter, A. J., Lorenzo, C., Mathias, R. A., Norris, J. M., Peloso, G. M., Sheu, W. H.-H., Toniolo, D., Vaidya, D., Varma, R., Wagenknecht, L. E., Boeing, H., Bottinger, E. P., Dedoussis, G., Deloukas, P., Ferrannini, E., Franco, O. H., Franks, P. W., Gibbs, R. A., Gudnason, V., Hamsten, A., Harris, T. B., Hattersley, A. T., Hayward, C., Hofman, A., Jansson, J.-H., Langenberg, C., Launer, L. J., Levy, D., Oostra, B. A., O’Donnell, C. J., O’Rahilly, S., Padmanabhan, S., Pankow, J. S., Polasek, O., Province, M. A., Rich, S. S., Ridker, P. M., Rudan, I., Schulze, M. B., Smith, B. H., Uitterlinden, A. G., Walker, M., Watkins, H., Wong, T. Y., Zeggini, E., Sharp, S. J., Forouhi, N. G., Kerrison, N. D., Lucarelli, D. M., Sims, M., Barroso, I., McCarthy, M. I., Arriola, L., Balkau, B., Barricarte, A., Gonzalez, C., Grioni, S., Kaaks, R., Key, T. J., Navarro, C., Nilsson, P. M., Overvad, K., Palli, D., Panico, S., Quirós, J. R., Rolandsson, O., Sacerdote, C., Sánchez, M.–J., Slimani, N., Tjonneland, A., Tumino, R., van der A, D. L., van der Schouw, Y. T., Riboli, E., Laakso, M., Borecki, I. B., Chasman, D. I., Pedersen, O., Psaty, B. M., Shyong Tai, E., van Duijn, C. M., Wareham, N. J., Waterworth, D. M., Boerwinkle, E., Linda Kao, W. H., Florez, J. C., Loos, R. J.F., Wilson, J. G., Frayling, T. M., Siscovick, D. S., Dupuis, J., Rotter, J. I., Meigs, J. B., Scott, R. A., and Goodarzi, M. O.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2015 Macmillan Publishers Limited
• First Published: First published in Nature Communications 6:5897
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
38172	1	Generation Scotland	Anna Dominiczak	Scottish Executive Health Department (SEHHD-CSO)	CZD/16/6	RI CARDIOVASCULAR & MEDICAL SCIENCES
38172	4	Generation Scotland	Anna Dominiczak	Scottish Executive Health Department (SEHHD-CSO)	CZD/16/6	RI CARDIOVASCULAR & MEDICAL SCIENCES