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Nat Commun. 2019 Jun 13;10(1):2581. doi: 10.1038/s41467-019-10487-4.

An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.

Author information

1
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands. jun.liu@ndph.ox.ac.uk.
2
Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7FL, UK. jun.liu@ndph.ox.ac.uk.
3
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
4
Center for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/Andalusian Government, PTS, Granada, 18007, Spain.
5
Department of Twin Research and Genetic Epidemiology, King's College London, London, WC2R 2LS, UK.
6
Department of Biological Psychology, Amsterdam Public Health (APH) research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081BT, The Netherlands.
7
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
8
Department of Biomedical Sciences, Chang Gung University, Taoyuan, 333, Taiwan.
9
Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, 333, Taiwan.
10
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
11
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12
Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
13
Department of Psychiatry and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081BT, The Netherlands.
14
Division of Neonatology, Department of Pediatrics, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
15
Division of Respiratory Medicine, Department of Pediatrics, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
16
Department of Pediatrics, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
17
Generation R Study Group, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
18
Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
19
Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA.
20
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
21
The Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, MA, 01702, USA.
22
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
23
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
24
Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
25
German Center for Diabetes Research (DZD), München-Neuherberg, 85764, Germany.
26
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, 40225, Germany.
27
Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, 40225, Germany.
28
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
29
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, 21224, USA.
30
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
31
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
32
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, 50137, Italy.
33
School of Public Health, University of Kentucky, Lexington, KY, 40536, USA.
34
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, Neuherberg, 85764, Germany.
35
Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, 60611, USA.
36
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
37
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
38
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, NC, 27516, USA.
39
Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
40
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
41
Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, 3012, Switzerland.
42
Department of Epidemiology and Biostatistics, Imperial College London, London, SW7 2AZ, UK.
43
Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1K0A5, Canada.
44
Diabetes Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
45
Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, 02215, USA.
46
The Institute for Translational Genomics and Population Sciences and Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
47
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
48
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
49
Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
50
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55455, USA.
51
CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), and Departments of Biochemistry and Physiology, Maastricht University, Maastricht, 6211LK, The Netherlands.
52
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands. a.demirkan@surrey.ac.uk.
53
Department of Genetics, University Medical Center Groningen, Groningen, 9713GZ, The Netherlands. a.demirkan@surrey.ac.uk.
54
Section of Statistical Multi-Omics, Department of Experimental and Clinical Research, School of Bioscience and Medicine, Univeristy of Surrey, Guildford, GU2 7XH, UK. a.demirkan@surrey.ac.uk.
55
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands. cornelia.vanduijn@ndph.ox.ac.uk.
56
Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7FL, UK. cornelia.vanduijn@ndph.ox.ac.uk.
57
Leiden Academic Center for Drug Research, Leiden University, Leiden, 2311EZ, The Netherlands. cornelia.vanduijn@ndph.ox.ac.uk.

Abstract

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.

PMID:
31197173
PMCID:
PMC6565679
DOI:
10.1038/s41467-019-10487-4
[Indexed for MEDLINE]
Free PMC Article

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