Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

Details

Title
Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
Author
Xue, Angli 1   VIAFID ORCID Logo  ; Wu, Yang 1   VIAFID ORCID Logo  ; Zhu, Zhihong 1 ; Zhang, Futao 1 ; Kemper, Kathryn E 1 ; Zheng, Zhili 2 ; Yengo, Loic 1 ; Lloyd-Jones, Luke R 1 ; Sidorenko, Julia 3 ; Wu, Yeda 1 ; Agbessi, Mawussé 4 ; Ahsan, Habibul 5 ; Alves, Isabel 4 ; Andiappan, Anand 6 ; Awadalla, Philip 4 ; Battle, Alexis 7 ; Beutner, Frank 8 ; Bonder, Marc Jan 9 ; Boomsma, Dorret 10 ; Christiansen, Mark 11 ; Claringbould, Annique 9 ; Deelen, Patrick 9 ; Tõnu Esko 12 ; Marie-Julie Favé 4 ; Franke, Lude 9 ; Frayling, Timothy 13 ; Gharib, Sina 14 ; Gibson, Gregory 15 ; Gibran Hemani 16 ; Jansen, Rick 10 ; Kähönen, Mika 17 ; Kalnapenkis, Anette 12 ; Silva Kasela 12 ; Kettunen, Johannes 18 ; Kim, Yungil 7 ; Kirsten, Holger 19 ; Kovacs, Peter 20 ; Krohn, Knut 21 ; Kronberg-Guzman, Jaanika 12 ; Kukushkina, Viktorija 12 ; Kutalik, Zoltan 22 ; Lee, Bernett 6 ; Lehtimäki, Terho 23 ; Loeffler, Markus 19 ; Marigorta, Urko M 15 ; Metspalu, Andres 12 ; Milani, Lili 12 ; Müller-Nurasyid, Martina 24 ; Nauck, Matthias 25 ; Nivard, Michel 10 ; Penninx, Brenda 10 ; Perola, Markus 18 ; Pervjakova, Natalia 12 ; Pierce, Brandon 5 ; Powell, Joseph 1 ; Prokisch, Holger 26 ; Psaty, Bruce 27 ; Raitakari, Olli 28 ; Ring, Susan 29 ; Ripatti, Samuli 18 ; Rotzschke, Olaf 6 ; Ruëger, Sina 22 ; Saha, Ashis 7 ; Scholz, Markus 19 ; Schramm, Katharina 24 ; Seppälä, Ilkka 23 ; Stumvoll, Michael 20 ; Sullivan, Patrick 30 ; Teumer, Alexander 31 ; Thiery, Joachim 32 ; Lin, Tong 5 ; Tönjes, Anke 33 ; Jenny van Dongen 10 ; Joyce van Meurs 34 ; Verlouw, Joost 34 ; Völker, Uwe 35 ; Võsa, Urmo 9 ; Yaghootkar, Hanieh 13 ; Zeng, Biao 15 ; McRae, Allan F 36 ; Visscher, Peter M 36   VIAFID ORCID Logo  ; Zeng, Jian 1 ; Yang, Jian 37   VIAFID ORCID Logo 

1  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia 
2  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China 
3  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia 
4  Computational Biology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada 
5  Department of Public Health Sciences, University of Chicago, Chicago, IL, USA 
6  Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore 
7  Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA 
8  Heart Center Leipzig, Universität Leipzig, Leipzig, Germany 
9  Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands 
10  Faculty of Genes, Behavior and Health, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands 
11  Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States of America 
12  Estonian Genome Center, University of Tartu, Tartu, Estonia 
13  Exeter Medical School, University of Exeter, Exeter, UK 
14  Department of Medicine, University of Washington, Seattle, WA, USA 
15  School of Biological Sciences, Georgia Tech, Atlanta, GA, USA 
16  MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK 
17  Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland 
18  National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland 
19  Institut für Medizinische InformatiK, Statistik und Epidemiologie, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany 
20  IFB Adiposity Diseases, Department of Medicine, Universität Leipzig, Leipzig, Germany 
21  Interdisciplinary Center for Clinical Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany 
22  Lausanne University Hospital, Lausanne, Switzerland 
23  Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland 
24  Institute of Genetic Epidemiology, Helmholtz Zentrum München, München, Germany 
25  Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany 
26  Institute of Human Genetics, Helmholtz Zentrum München, München, Germany 
27  Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA 
28  Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; University of Turku, Turku, Finland 
29  School of Social and Community Medicine, University of Bristol, Bristol, UK 
30  Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden 
31  Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany 
32  Institute for Laboratory Medicine, LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany 
33  Division of Endocrinology and Nephrology, Department of Medicine, Universität Leipzig, Leipzig, Germany 
34  Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands 
35  Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany 
36  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia 
37  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia 
Pages
1-14
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04951-w
ProQuest document ID
2077456796
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.