Journal
NATURE
Volume 570, Issue 7759, Pages 71-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-1231-2
Keywords
-
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK085526]
- National Human Genome Research Institute (NHGRI) [U54HG003067]
- National Institutes of Health (NIH) [1RC2DK088389]
- NIDDK [U01DK085526, U01DK105554, U01DK078616, K24 DK080140, K24 DK110550, P30 DK057521]
- Carlos Slim Foundation (Slim Initiative in Genomic Medicine for the Americas (SIGMA))
- Andrea and Charles Bronfman Philanthropies
- NIH [R01 DK066358, RC2-DK088389, DK085545, R01-DK098032, U01DK105535, DK062370, DK072193, NHLBI N01-HC-25195, HHSN268201500001I, U01DK57295, R01DK110113, U01HG007417, R01DK101855, R01DK107786]
- The European Commission [ENGAGE: HEALTH-F4-2007-201413]
- MRC [G0601261, G0900747-91070]
- Wellcome Trust [064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101, 095552, 098017, 098381, 100956, 101630, 203141]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, South Korea [HI14C0060, HI15C1595]
- Swedish Research Council
- Folkhalsan Research Foundation
- Sigrid Juselius Foundation
- Academy of Finland [263401, 267882, 312063, 312072]
- Nordic Center of Excellence in Disease Genetics, EU [EUFP7-MOSAIC FP7-600914]
- Ollqvist Foundation
- Swedish Cultural Foundation in Finland
- Finnish Diabetes Research Foundation
- Foundation for Life and Health in Finland
- Signe and Ane Gyllenberg Foundation
- Finnish Medical Society
- Paavo Nurmi Foundation
- Helsinki University Central Hospital Research Foundation
- Perklen Foundation
- Narpes Health Care Foundation
- Ahokas Foundation
- Ministry of Education in Finland
- Municipal Heath Care Center and Hospital in Jakobstad
- Health Care Center in Vasa
- Health Care Center in Narpes
- Health Care Center in Korsholm
- National Heart, Lung and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, U01HL130114]
- National Institute on Aging (NIA) [R01AG023629]
- NHLBI [U01HL130114, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, R01 HL105756, R01 HL092577-06S1, RO1HL 24799, RC2 HL-103010, RC2 HL-102925, RC2 HL-102926, R01HL105756, 5RC2HL102419, RC2 HL102925, RC2 HL102926]
- National Institute on Minority Health and Health Disparities
- National Institute of General Medical Sciences [U54GM115428]
- National Medical Research Council (NMRC)
- Biomedical Research Council (BMRC) of Singapore
- NMRC
- BMRC of Singapore
- American Federation for Aging Research
- Einstein Glenn Center
- NIA [PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, AG08122, AG033193]
- Wellcome Trust
- European Community's Seventh Framework Programme (FP7/2007-2013)
- National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- Consejo Nacional de Ciencia y Tecnologia [2092, M9303, F677-M9407, 251M, 2005-C01-14502, SALUD 2010-2151165]
- Consejo Nacional de Ciencia y Tecnologia (CONACyT) (Fondo de Cooperacion Internacional en Ciencia y Tecnologia (FONCICYT)) [C0012-2014-01-247974]
- Korea Centers for Disease Control and Prevention [4845-301, 4851-302, 4851-307]
- Korea National Institute of Health [2016-NI73001-00]
- Instituto Carlos Slim de la Salud, AC
- NHLBI, NIH, Department of Health and Human Services [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I]
- NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) [5RC2HL102419]
- Lundbeck Foundation
- Novo Nordisk Foundation
- Danish Council for Independent Research Medical Sciences
- Danish Research Council
- Danish Centre for Health Technology Assessment
- Novo Nordisk
- 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
- Danish Diabetes Academy - Novo Nordisk Foundation
- Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- NHLBI Grand Opportunity (GO) program
- Multi-Ethnic Study of Atherosclerosis (MESA) [HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420]
- National Center for Advancing Translational Sciences, TSCI grant [UL1TR001881]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research (DRC) grant [DK063491]
- Veterans Administration Epidemiologic grant
- Hong Kong Foundation for Research and Development in Diabetes
- Chinese University of Hong Kong
- Hong Kong Government Research Grants Committee Central Allocation Scheme [CUHK 1/04C]
- Research Grants Council Earmarked Research Grant [CUHK4724/07M]
- Innovation and Technology Fund [ITS/088/08, ITS/487/09FP]
- Research Grants Committee Theme-based Research Scheme [T12-402/13N]
- NIH Office of the Director (OD) [U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254]
- National Center for Research Resources General Clinical Research Centers Program [M01-RR00036, M01-RR00043-45, M01-RR00069, M01-RR00084, M01-RR01066, M01-RR00125, M01-RR14467]
- NCRR Clinical and Translational Science Awards [UL1-RR024134, UL1-RR024139, UL1-RR024153, UL1-RR024989, UL1-RR024992, UL1-RR025758, UL1-RR025780]
- BADERC [DK057521]
- NIH-NIDDK [U01DK105535]
- Wellcome Trust Senior Fellow in Basic Biomedical Science [WT098017]
- National Research Foundation of Korea (NRF) [NRF-2017R1A2B4006508]
- Clinician Scientist Award of the Singapore Ministry of Health's National Medical Research Council [NMRC/CSA-SI/0012/2017]
- Hong Kong Research Grants Council Theme-based Research Scheme [T12-402/13N]
- Research Grants Council General Research Fund [14110415]
- Focused Innovation Scheme
- Vice-Chancellor One-off Discretionary Fund
- Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong
- Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Collaboration Fund
- Korean Genome Analysis Project [4845-301]
- Korean Genome and Epidemiology Study [4851-302]
- Korea Biobank Project [4851-307, KBP-2013-11, KBP-2014-68]
- Korea Centers for Disease Control and Prevention, South Korea
- [RC2 HL103010]
- [RC2 HL102923]
- [RC2 HL102924]
- [U01DK085524]
- [R01 HL0113323]
- [P01 HL045222]
- [R01 DK047482]
- [R01 DK053889]
- [P30 DK020595]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG000024] Funding Source: NIH RePORTER
- Ministry of Health & Welfare (MHOW), Republic of Korea [2016-NI73001-00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- MRC [G0601261] Funding Source: UKRI
Ask authors/readers for more resources
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available