Abstract
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 × 10-3) and candidate genes from knockout mice (P = 5.2 × 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.
| Original language | English |
|---|---|
| Pages (from-to) | 71-76 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 570 |
| Issue number | 7759 |
| Early online date | 22 May 2019 |
| DOIs | |
| Publication status | Published - Jun 2019 |
ASJC Scopus subject areas
- General
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In: Nature, Vol. 570, No. 7759, 06.2019, p. 71-76.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
AU - Flannick, Jason
AU - Mercader, Josep M.
AU - Fuchsberger, Christian
AU - Udler, Miriam S.
AU - Mahajan, Anubha
AU - Wessel, Jennifer
AU - Teslovich, Tanya M.
AU - Caulkins, Lizz
AU - Koesterer, Ryan
AU - Barajas-Olmos, Francisco
AU - Blackwell, Thomas W.
AU - Boerwinkle, Eric
AU - Brody, Jennifer A.
AU - Centeno-Cruz, Federico
AU - Chen, Ling
AU - Chen, Siying
AU - Contreras-Cubas, Cecilia
AU - Córdova, Emilio
AU - Correa, Adolfo
AU - Cortes, Maria
AU - DeFronzo, Ralph A.
AU - Dolan, Lawrence
AU - Drews, Kimberly L.
AU - Elliott, Amanda
AU - Floyd, James S.
AU - Gabriel, Stacey
AU - Garay-Sevilla, Maria Eugenia
AU - García-Ortiz, Humberto
AU - Gross, Myron
AU - Han, Sohee
AU - Heard-Costa, Nancy L.
AU - Jackson, Anne U.
AU - Jørgensen, Marit E.
AU - Kang, Hyun Min
AU - Kelsey, Megan
AU - Kim, Bong-Jo
AU - Koistinen, Heikki A.
AU - Kuusisto, Johanna
AU - Leader, Joseph B.
AU - Linneberg, Allan
AU - Liu, Ching-Ti
AU - Liu, Jianjun
AU - Lyssenko, Valeriya
AU - Manning, Alisa K.
AU - Marcketta, Anthony
AU - Malacara-Hernandez, Juan Manuel
AU - Morris, Andrew D.
AU - Palmer, Colin N. A.
AU - Scott, Laura J.
AU - Morris, Andrew P.
N1 - Sequencing for T2D-GENES cohorts was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U01DK085526 (Multiethnic Study of Type Diabetes Genes) and National Human Genome Research Institute (NHGRI) grant U54HG003067 (Large Scale Sequencing and Analysis of Genomes). Sequencing for GoT2D cohorts was funded by National Institutes of Health (NIH) 1RC2DK088389 (Low-Pass Sequencing and High Density SNP Genotyping in Type 2 Diabetes). Sequencing for ProDiGY cohorts was funded by NIDDK U01DK085526. Sequencing for SIGMA cohorts was funded by the Carlos Slim Foundation (Slim Initiative in Genomic Medicine for the Americas (SIGMA)). Analysis was supported by NIDDK grant U01DK105554 (AMP T2D-GENES Data Coordination Center and Web Portal). The Mount Sinai IPM Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. The Wake Forest study was supported by NIH R01 DK066358. Oxford cohorts and analysis is funded by The European Commission (ENGAGE: HEALTH-F4-2007-201413); MRC (G0601261, G0900747-91070); NIH (RC2-DK088389, DK085545, R01-DK098032 and U01DK105535); Wellcome Trust (064890, 083948, 085475, 086596, 090367, 090532, 092447, 095101, 095552, 098017, 098381, 100956, 101630 and 203141). The FUSION study is supported by NIH grants DK062370 and DK072193. The research from the Korean cohort was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, South Korea (grant numbers HI14C0060, HI15C1595). The Malmö Preventive Project and the Scania Diabetes Registry were supported by a Swedish Research Council grant (Linné) to the Lund University Diabetes Centre. The Botnia and The PPP-Botnia studies (L.G. and T.T.) have been financially supported by grants from Folkhälsan Research Foundation, the Sigrid Juselius Foundation, The Academy of Finland (grants 263401, 267882 and 312063 to L.G. and 312072 to T.T.), Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS, 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, Perklén Foundation, Närpes Health Care Foundation and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland, Municipal Heath Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, Närpes and Korsholm. The assistance of the Botnia Study Group is acknowledged. This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083 and N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences. The Diabetic Cohort (DC) and Multi-Ethnic Cohort (MEC) were supported by individual research grants and clinician scientist award schemes from the National Medical Research Council (NMRC) and the Biomedical Research Council (BMRC) of Singapore. The DC, MEC, Singapore Indian Eye Study (SINDI) and Singapore Prospective Study Program (SP2) were supported by individual research grants and clinician scientist award schemes from the NMRC and the BMRC of Singapore. The Longevity study at Albert Einstein College of Medicine, USA was funded by The American Federation for Aging Research, the Einstein Glenn Center and the NIA (PO1AG027734, R01AG046949, 1R01AG042188 and P30AG038072). The TwinsUK study was funded by the Wellcome Trust and European Community’s Seventh Framework Programme (FP7/2007-2013) and received support from the 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 in partnership with King’s College London. Framingham Heart Study is supported by NIH contract NHLBI N01-HC-25195 and HHSN268201500001I. This research was also supported by NIA AG08122 and AG033193, NIDDK U01DK085526, U01DK078616 and K24 DK080140, NHLBI R01 HL105756, and grant supplement R01 HL092577-06S1 for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. The Mexico City Diabetes Study has been supported by the following grants: RO1HL 24799 from the NHLBI; Consejo Nacional de Ciencia y Tecnología 2092, M9303, F677-M9407, 251M, 2005-C01-14502 and SALUD 2010-2151165; and Consejo Nacional de Ciencia y Tecnología (CONACyT) (Fondo de Cooperación Internacional en Ciencia y Tecnología (FONCICYT) C0012-2014-01-247974). The KARE cohort was supported by grants from Korea Centers for Disease Control and Prevention (4845–301, 4851–302, 4851–307) and an intramural grant from the Korea National Institute of Health (2016-NI73001-00). The Diabetes in Mexico Study was supported by Consejo Nacional de Ciencia y Tecnología grant number S008-2014-1-233970 and by Instituto Carlos Slim de la Salud, AC. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the NHLBI, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). We thank the staff and participants of the ARIC study for their important contributions. Funding support for ‘Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium’ was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHARGE sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273 and R01HL086694). Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO) and exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). The infrastructure for the Analysis Commons is supported by R01HL105756 (NHLBI, to B.M.P.), U01HL130114 (NHLBI, to B.M.P.) and 5RC2HL102419 (NHLBI, to E. Boerwinkle). The LuCAMP project was funded by the Lundbeck Foundation and produced by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (http://www.lucamp.org/). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (https://cbmr.ku.dk/). Further funding came from the Danish Council for Independent Research Medical Sciences. The Inter99 was initiated by T. Jørgensen (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T. F. Thomsen. The steering committee comprises the former two and C. Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, the Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation and the Danish Diabetes Association. D.R.W. is supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The NHLBI Exome Sequencing Project (ESP) was supported through the NHLBI Grand Opportunity (GO) program and funded by grants RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO) and RC2 HL102924 (WHISP) for providing data and DNA samples for analysis. The exome sequencing for the NHLBI ESP was supported by NHLBI grants RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). This research was supported by the Multi-Ethnic Study of Atherosclerosis (MESA) contracts 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 and UL1-TR-001420. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, TSCI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research (DRC) grant DK063491. The San Antonio Mexican American Family Studies (SAMAFS) are supported by the following grants/institutes. The San Antonio Family Heart Study (SAFHS) and San Antonio Family Diabetes/Gallbladder Study (SAFDGS) were supported by U01DK085524, R01 HL0113323, P01 HL045222, R01 DK047482 and R01 DK053889. The Veterans Administration Genetic Epidemiology Study (VAGES) study was supported by a Veterans Administration Epidemiologic grant. The Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) study was supported by NIH grant U01DK57295. The SAMAFS research team acknowledges the contributions of H. E. Abboud to the research activities of the SAMAFS. Sample collection, research and analysis from the Hong Kong Diabetes Register (HKDR) at the Chinese University of Hong Kong (CUHK) were supported by the Hong Kong Foundation for Research and Development in Diabetes established under the auspices of the Chinese University of Hong Kong, the Hong Kong Government Research Grants Committee Central Allocation Scheme (CUHK 1/04C), a Research Grants Council Earmarked Research Grant (CUHK4724/07M), the Innovation and Technology Fund (ITS/088/08 and ITS/487/09FP) and the Research Grants Committee Theme-based Research Scheme (T12-402/13N). The TODAY contribution to this study was completed with funding from NIDDK and the NIH Office of the Director (OD) through grants U01DK61212, U01DK61230, U01DK61239, U01DK61242 and U01DK61254; from the National Center for Research Resources General Clinical Research Centers Program grants M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children’s Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children’s Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University) and M01-RR14467 (University of Oklahoma Health Sciences Center); and from the NCRR Clinical and Translational Science Awards grants UL1-RR024134 (Children’s Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children’s Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St Louis), UL1-RR025758 (Massachusetts General Hospital) and UL1-RR025780 (University of Colorado Denver). The Pakistan Genetic Resource (PGR) is funded through endowments awarded to CNCD, Pakistan. J.F. is supported by BADERC DK057521. R.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855 and R01DK107786). A.P.M. is supported by the NIH-NIDDK (U01DK105535); and a Wellcome Trust Senior Fellow in Basic Biomedical Science (award WT098017). J.C.F. is supported by NIDDK K24 DK110550 and P30 DK057521. G.I.B. is supported by P30 DK020595. Y.S.C. acknowledges support from the National Research Foundation of Korea (NRF) grant (NRF-2017R1A2B4006508). C.-Y.C. is supported by Clinician Scientist Award (NMRC/CSA-SI/0012/2017) of the Singapore Ministry of Health’s National Medical Research Council. R.C.W.M. and J.C. acknowledges support from the Hong Kong Research Grants Council Theme-based Research Scheme (T12-402/13N), Research Grants Council General Research Fund (14110415), the Focused Innovation Scheme, the Vice-Chancellor One-off Discretionary Fund, the Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong, as well as the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Collaboration Fund. We thank all medical and nursing staff of the Prince of Wales Hospital Diabetes Mellitus Education Centre, Hong Kong. LuCAMP thanks A. Forman, T. H. Lorentzen and G. J. Klavsen for laboratory assistance, P. Sandbeck for data management, G. Lademann for secretarial support and T. F. Toldsted for grant management. We thank study participants of the DC, MEC, SINDI and SP2 for their contributions and the National University Hospital Tissue Repository (NUHTR). We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. This study was provided with biospecimens and data from the Korean Genome Analysis Project (4845-301), the Korean Genome and Epidemiology Study (4851-302) and the Korea Biobank Project (4851-307, KBP-2013-11 and KBP-2014-68) that were supported by the Korea Centers for Disease Control and Prevention, South Korea. The Pakistan Genomic Resource (PGR) thank all the study participants for their participation. For this publication, biosamples from the KORA Biobank as part of the Joint Biobank Munich (JBM) have been used. M.I.M. is a Wellcome Trust Senior Investigator (WT098381) and a National Institute of Health Research (NIHR) Senior Investigator; the views expressed in this article are his views and not necessarily those of the NHS, the NIHR, or the Department of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2019/6
Y1 - 2019/6
N2 - 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 × 10-3) and candidate genes from knockout mice (P = 5.2 × 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.
AB - 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 × 10-3) and candidate genes from knockout mice (P = 5.2 × 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.
UR - https://www.scopus.com/pages/publications/85066251977
U2 - 10.1038/s41586-019-1231-2
DO - 10.1038/s41586-019-1231-2
M3 - Article
C2 - 31118516
SN - 0028-0836
VL - 570
SP - 71
EP - 76
JO - Nature
JF - Nature
IS - 7759
ER -