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

Lookup NU author(s): Professor Mark Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


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Author(s): Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, Dauriz M, Hivert MF, Raghavan S, Lipovich L, Hidalgo B, Fox K, Huffman JE, An P, Lu YC, Rasmussen-Torvik LJ, Grarup N, Ehm MG, Li L, Baldridge AS, Stancakova A, Abrol R, Besse CL, Boland A, Bork-Jensen J, Fornage M, Freitag DF, Garcia ME, Guo XQ, 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, Allin KH, Amin N, Aponte JL, Aung T, Barbieri C, Bihlmeyer NA, Boehnke M, Bombieri C, Bowden DW, Burns SM, Chen YN, Chen YD, Cheng CY, Correa A, Czajkowski J, Dehghan A, Ehret GB, Eiriksdottir G, Escher SA, Farmaki AE, Franberg 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, Jorgensen ME, Jorgensen T, Karaleftheri M, Khor CC, Kirkpatrick A, Kraja AT, Kuusisto J, Lange EM, Lee IT, Lee WJ, Leong A, Liao JM, Liu CY, Liu YM, 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, Renstrom 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 WHH, 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 JH, 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, 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, Sharp SJ, Forouhi NG, Kerrison ND, Lucarelli DM, Sims M, Barroso I, McCarthy MI, Arriola L, Balkau B, Barricarte A, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Rolandsson O, Sacerdote C, Sanchez MJ, Slimani N, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, Riboli E, The EPIC-InterAct Consortium

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2015

Volume: 6

Online publication date: 29/01/2015

Acceptance date: 12/11/2014

Date deposited: 07/04/2015

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms6897

DOI: 10.1038/ncomms6897


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Funder referenceFunder name
Ake-wiberg Foundation
Althingi (the Icelandic Parliament)
Andrea and Charles Bronfman Philanthropies
AstraZeneca
Boehringer-Ingelheim
Cedars-Sinai Winnick Clinical Scholars Award
Danish Centre for Health Technology Assessment
Danish Heart Foundation
Danish Pharmaceutical Association
Doris Duke Charitable Foundation Clinical Scientist Development Award
Erasmus Medical Center
EUR Fellowship
European Union (European Social Fund-ESF)
Faculty of Biology and Medicine of Lausanne
Faculty of Biology and Medicine of Lausanne, Switzerland
Fondazione Compagnia di San Paolo-Torino
Foundation for Strategic Research
German Federal Ministry of Education and Research (BMBF)
GlaxoSmithKline
Heart Foundation of Northern Sweden
Karolinska Institutet Foundation
Knut och Alice Wallenberg Foundation
LillyCo
Magnus Bergvall Foundation
Massachusetts General Hospital Physician Scientist Development Award
Medical Research Council UK
Ministry for Health, Welfare and Sports
Ministry of Education, Culture and Science
Ministry of Internal Affairs and Health
Municipality of Rotterdam
National Heart, Lung and Blood Institute Division of Intramural Research
National Institute of Neurological Disorders and Stroke (NINDS)
National Strategic Reference Framework (NSRF)
NEI
Netherlands Organization for the Health Research and Development (ZonMw)
NIA Intramural Research Program
NIDCD
Novo Nordisk
Pahlssons Foundation
Research Foundation of Copenhagen County
Skane Regional Health Authority
South West NHS Research and Development
Swedish Diabetes Association
Swedish e-science Research Center (SeRC)
Umea Medical Research Foundation
University of Verona, Italy
Uppsala University
Vasterbotten County Council
AstraZeneca (Sweden)
Augustinus Foundation
Becket Foundation
Canadian Diabetes Association Research Fellowship Award
Centre for Medical Systems Biology (CMSB; National Genomics Initiative)
Danish Diabetes Association
Danish Research Council
Darlington Trust
Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai
Diabetes UK
Donald W. Reynolds Foundation
Erasmus MC
Erasmus University Rotterdam
Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study
European Commission (DG XII)
European Research Council
Exeter NHS Research and Development
Fondation Leducq
Fondazione Cariplo-Milano
Foundation for Old Servants
Fredrik and Ingrid Thuring foundation
GlaxoSmithKline (Drug Discovery-Verona, RD)
Hjartavernd (the Icelandic Heart Association)
Ib Henriksen Foundation
Intramural Research Program of the National Institute on Aging
Italian Ministry of Health Progetto Finalizzato
Knut and Alice Wallenberg Foundation
Lundbeck Foundation
National Center for Advancing Translational Sciences
National Heart, Lung, and Blood Institute
National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust
National Institute on Minority Health and Health Disparities
Netherlands Organization for Scientific Research (NWO)
NIH Roadmap for Medical Research
Novo Nordisk Foundation
Novo Nordisk Inc.
NWO
Peninsula NIHR Clinical Research Facility at the University of Exeter
Research Institute for Diseases in the Elderly (RIDE)
Research to Prevent Blindness
Scottish Funding Council
Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet
Swedish Heart Lung Foundation
Swedish Heart-Lung Foundation
Swedish Research Council
Timber Merchant Vilhelm Bang's Foundation
Tore Nilsson foundation
Torsten and Ragnar Soderberg Foundation
01 EA 9401Federal Ministry of Science, Germany
014-93-015; RIDE2Research Institute for Diseases in the Elderly
047.016.009Russian Foundation for Basic research
047.017.043Russian Foundation for Basic research
050-060-810Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)
07-10-R61-A1754-B838-22392FDanish Heart Foundation
0796/2003National Medical Research Council (NMRC), Singapore
08/1/35/19/550Biomedical Research Council (BMRC), Singapore
084723/Z/08/ZWellcome Trust
086596/Z/08/ZWellcome Trust Research Career Development Fellowship
09/1/35/19/616Biomedical Research Council (BMRC), Singapore
108-1080315-0302Ministry of Science, Education and Sport in the Republic of Croatia
098051Wellcome Trust
124243Academy of Finland
12660Swedish Research Council
14-200LDRD
20120197Swedish Heart-Lung Foundation
20653Swedish Research Council
242244CHANCES
257082EU FP7
1R01AG032098-01A1NIA
33CSCO-122661Swiss National Science Foundation
2012B233Health Insurance Foundation (Helsefonden)
2013-024Swedish Diabetes Foundation
4R00HG006698-03LDRD
560183Stockholm County Council
70-2488-Ha IGerman Cancer Aid
7-09-MN-32American Diabetes Association Mentor-Based Postdoctoral Fellowship
77299Academy of Finland
3200B0-105993Swiss National Science Foundation
916.12.154NWO grant veni (veni)
5RC2HL102419NIH through the American Recovery and Reinvestment Act
8691Swedish Research Council
91111025ZonMw
AG023629National Institute on Aging (NIA)
DK062370NIH
DK063491National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC)
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CA047988National Cancer Institute
CCM 2010Italian Ministry of Health Progetto
CG/SERI/2010National Medical Research Council (NMRC), Singapore
EY14684Genetics of Latinos Diabetic Retinopathy (GOLDR)
CZD/16/6Chief Scientist Office of the Scottish Government Health Directorates
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DK081350
ERC-2011-StG 280559-SEPIEuropean Research Council
EY017337Chinese-American Eye Study (CHES)
HEALTH-F5-2011-282510EU FP7
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HHSN268201100007CNational Heart, Lung, and Blood Institute (NHLBI)
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HL047889National Institute of Diabetes and Digestive and Kidney Diseases
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IRG07nov013National Medical Research Council (NMRC), Singapore
IRG09nov014National Medical Research Council (NMRC), Singapore
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LSHM-CT-2007-037273European Commission
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QLG1-CT-2001-01252European Union grant
QLG1-CT-2001-01252EU
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R01-DK-8925601NIH from NIDDK
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PRIN 2009Italian Ministry of Health Progetto
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U01HL72518NIH grants through the National Heart, Lung, and Blood Institute
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WT098051Wellcome Trust
SOC 98200769 05 F02European Community
STaR/0003/2008National Medical Research Council (NMRC), Singapore
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