期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6897
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资金
- NIH through the American Recovery and Reinvestment Act [5RC2HL102419]
- Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL103612, HL068986, N02-HL-6-4278]
- CHARGE infrastructure grant [HL105756]
- LDRD [14-200, 4R00HG006698-03]
- NIA [N01-AG-12100, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- NEI
- NIDCD
- NIA Intramural Research Program
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-95159, N01-HC-95169, RR-024156]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, U01-HG004729, R01-HL093029, R01-HL084099]
- NIH Roadmap for Medical Research
- National Heart, Lung, and Blood Institute
- University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]
- Northwestern University [HHSN268201300027C]
- University of Minnesota [HHSN268201300028C]
- Kaiser Foundation Research Institute [HHSN268201300029C]
- Johns Hopkins University School of Medicine [HHSN268200900041C]
- Intramural Research Program of the National Institute on Aging
- Chinese-American Eye Study (CHES) [EY017337]
- Research to Prevent Blindness
- Genetics of Latinos Diabetic Retinopathy (GOLDR) [EY14684]
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [AG023629]
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne, Switzerland
- Swiss National Science Foundation [3200B0-105993, 33CSCO-122661]
- GlaxoSmithKline (Drug Discovery-Verona, RD)
- Medical Research Council UK
- Ministry of Science, Education and Sport in the Republic of Croatia [108-1080315-0302]
- South West NHS Research and Development
- Exeter NHS Research and Development
- Darlington Trust
- Peninsula NIHR Clinical Research Facility at the University of Exeter
- European Research Council [SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC, ERC-2011-StG 280559-SEPI]
- German Federal Ministry of Education and Research (BMBF)
- Federal Ministry of Science, Germany [01 EA 9401]
- European Union [SOC 95201408 05 F02]
- German Cancer Aid [70-2488-Ha I]
- European Community [SOC 98200769 05 F02]
- Netherlands Organization for Scientific Research (NWO)
- NWO
- Russian Foundation for Basic research [047.016.009, 047.017.043]
- Erasmus MC
- Centre for Medical Systems Biology (CMSB
- National Genomics Initiative)
- ZonMw [91111025]
- NIH from NHLBI [R01-HL-087700, R01-HL-088215]
- NIH from NIDDK [R01-DK-8925601, R01-DK-075681]
- Medical Research Council [MC_U106179471, G0700931]
- Wellcome Trust [098051, WT098051, WT091310, 084723/Z/08/Z]
- National Heart, Lung and Blood Institute Division of Intramural Research
- National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, R01DK079888, P30DK063491]
- NIDDK [K24 DK080140]
- American Diabetes Association Mentor-Based Postdoctoral Fellowship [7-09-MN-32]
- Canadian Diabetes Association Research Fellowship Award
- University of Verona, Italy
- NIDDK Research Career Award [K23 DK65978]
- Massachusetts General Hospital Physician Scientist Development Award
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- Swedish Heart-Lung Foundation
- Umea Medical Research Foundation
- Vasterbotten County Council
- NIH grants through the National Heart, Lung, and Blood Institute [HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, HL112064, HL087698]
- National Institute of Nursing Research [NR0224103]
- U.S. Federal Government from the National Heart, Lung, and Blood Institute [HHSN268201100037C]
- Novo Nordisk
- Swedish Research Council
- Pahlssons Foundation
- Heart Foundation of Northern Sweden
- Swedish Heart Lung Foundation
- Skane Regional Health Authority
- Swedish Diabetes Association
- Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]
- Scottish Funding Council
- Faculty of Biology and Medicine of Lausanne
- Intramural Research Program of the NIH, National Institute on Aging [Z01 AG000949-02, Z01 AG007390-07]
- Timber Merchant Vilhelm Bang's Foundation
- Danish Heart Foundation [07-10-R61-A1754-B838-22392F]
- Health Insurance Foundation (Helsefonden) [2012B233]
- EU FP7 [257082, HEALTH-F5-2011-282510]
- Danish Research Council
- Danish Centre for Health Technology Assessment
- Novo Nordisk Inc.
- Research Foundation of Copenhagen County
- Ministry of Internal Affairs and Health
- Danish Heart Foundation
- Danish Pharmaceutical Association
- Augustinus Foundation
- Ib Henriksen Foundation
- Becket Foundation
- Danish Diabetes Association
- Lundbeck Foundation
- Novo Nordisk Foundation
- EU FP6 programme [LSHM_CT_2006_037197]
- Andrea and Charles Bronfman Philanthropies
- Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai
- National Institute of Diabetes and Digestive and Kidney Diseases [HL060944, HL061019, HL060919, HL047887, HL047889, HL047890, HL47902]
- National Heart, Lung and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]
- National Institute on Minority Health and Health Disparities
- NHLBI of the National Institutes of Health [R01HL107816]
- National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust
- British Heart Foundation [SP/04/002]
- National Institute for Health Research [RP-PG-0407-10371]
- United States Environmental Protection Agency (EPA) [RD83169701]
- National Center for Advancing Translational Sciences [UL1-TR000124]
- Cedars-Sinai Winnick Clinical Scholars Award
- Academy of Finland [77299, 124243]
- NIH [DK062370, DK093757, DK072193]
- Diabetes UK
- Magnus Bergvall Foundation
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- Tore Nilsson foundation
- Fredrik and Ingrid Thuring foundation
- Ake-wiberg Foundation
- Karolinska Institutet Foundation
- Swedish e-science Research Center (SeRC)
- EU [QLG1-CT-2001-01252]
- AstraZeneca (Sweden)
- European Union grant [QLG1-CT-2001-01252]
- AstraZeneca
- Boehringer-Ingelheim
- LillyCo
- Research Institute for Diseases in the Elderly [014-93-015
- RIDE2]
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810]
- CHANCES [242244]
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- NWO grant veni (veni) [916.12.154]
- EUR Fellowship
- Foundation for Strategic Research
- Swedish Research Council [8691, 12660, 20653]
- European Commission [LSHM-CT-2007-037273]
- Knut and Alice Wallenberg Foundation
- Torsten and Ragnar Soderberg Foundation
- Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet
- Stockholm County Council [560183]
- National Medical Research Council (NMRC), Singapore [0796/2003, IRG07nov013, IRG09nov014, NMRC 1176/2008, STaR/0003/2008, CG/SERI/2010]
- Biomedical Research Council (BMRC), Singapore [08/1/35/19/550, 09/1/35/19/616]
- European Union (European Social Fund-ESF)
- National Strategic Reference Framework (NSRF)
- Uppsala University
- Knut och Alice Wallenberg Foundation
- European Research Council
- Swedish Diabetes Foundation [2013-024]
- Swedish Heart-Lung Foundation [20120197]
- Wellcome Trust Research Career Development Fellowship [086596/Z/08/Z]
- Fondazione Compagnia di San Paolo-Torino
- Fondazione Cariplo-Milano
- Italian Ministry of Health Progetto Finalizzato
- Italian Ministry of Health Progetto [CCM 2010, PRIN 2009]
- National Heart, Lung, and Blood Institute [HL043851, HL080467]
- National Cancer Institute [CA047988]
- Donald W. Reynolds Foundation
- Fondation Leducq
- [HL120393]
- [UL1RR025005]
- [M01-RR000052]
- [DK081350]
- [HG007112]
- [R01HL071051]
- [R01HL071205]
- [R01HL071250]
- [R01HL071251]
- [R01HL071252]
- [R01HL071258]
- [R01HL071259]
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC085080, N01HC095163, N01HC055222, N01HC095166, N01HC095169, N01HC085086, N01HC095167, N01HC095159, N01HC095161, N01HC085082, N01HC095168, N01HC085083, N01HC085081, N01HC085079, N01HC095165, N01HC095164, N01HC095160, N01HC095162] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA047988, UM1CA182913] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000124, UL1TR000150, UL1TR001079, UL1TR001422] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024156, UL1RR025005, M01RR000052] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [U10EY017337, R01EY014684] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R43HL095160, R01HL087641, R01HL088215, R01HL087652, T32HL007208, R01HL071025, R01HL112064, R01HL060944, R01HL059367, R44HL095169, R01HL105756, R01HL093029, RC2HL102419, R01HL071259, R13HL095166, R01HL120393, R01HL043851, R01HL095163, U01HL120393, R21HL095165, R01HL068986, R01HL080467, ZIAHL006175, R01HL080295, U01HL047902, R01HL071051, R01HL084099, R01HL085083, R01HL087700, U01HL047890, R01HL103612, T32HL072757, R01HL071205, U01HL047892, ZIAHL006173, U01HL047889, R43HL095161, R01HL071252, R43HL095169, R01HL060919, R01HL064278, U01HL047887, R01HL058625, U01HL072518, R01HL071258, R01HL117078, R01HL107816, ZIAHL006002, R01HL087698, R01HL059684, R01HL061019, R01HL071251, R01HL071250, U01HL080295, R18HL058625, R01HL086694] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG004402, R00HG006698, U01HG004729, U54HG003273, R01HG007112] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R56DK062370, K99DK081350, P30DK063491, R01DK093757, P60DK020541, U01DK062370, P30DK020572, R01DK079888, R01DK062370, R01DK089256, R01DK075681, R01DK072193, P30DK079626, K24DK080140, P30DK020541, K23DK065978, R01DK078616, R00DK081350, U01DK078616] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG032098, ZIAAG007390, N01AG062106, R01AG023629, N01AG062103, ZIAAG000949, Z01AG000949, N01AG062101, N01AG012100, Z01AG007390, R56AG023629] Funding Source: NIH RePORTER
- MRC [G0700931, MC_UU_12015/1, MC_UU_12015/5, MC_UP_A100_1003, G0600717, MC_PC_U127561128] Funding Source: UKRI
- Medical Research Council [G0600717B, MC_PC_U127561128, MC_UP_A100_1003, G0600717, MC_PC_13048, MC_UU_12015/1, MC_UU_12015/5] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10109, NF-SI-0512-10135, NF-SI-0611-10219, NF-SI-0507-10380] Funding Source: researchfish
- Chief Scientist Office [CZD/16/6/4] Funding Source: researchfish
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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