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

Jun Liu; Elena Carnero-Montoro; Jenny van Dongen; Samantha Lent; Ivana Nedeljkovic; Symen Ligthart; Pei Chien Tsai; Tiphaine C. Martin; Pooja R. Mandaviya; Rick Jansen; Marjolein J. Peters; Liesbeth Duijts; Vincent W.V. Jaddoe; Henning Tiemeier; Janine F. Felix; Gonneke Willemsen; Eco J.C. de Geus; Audrey Y. Chu; Daniel Levy; Shih Jen Hwang; Jan Bressler; Rahul Gondalia; Elias L. Salfati; Christian Herder; Bertha A. Hidalgo; Toshiko Tanaka; Ann Zenobia Moore; Rozenn N. Lemaitre; Min A. Jhun; Jennifer A. Smith; Nona Sotoodehnia; Stefania Bandinelli; Luigi Ferrucci; Donna K. Arnett; Harald Grallert; Themistocles L. Assimes; Lifang Hou; Andrea Baccarelli; Eric A. Whitsel; Ko Willems van Dijk; Najaf Amin; André G. Uitterlinden; Eric J.G. Sijbrands; Oscar H. Franco; Abbas Dehghan; Tim D. Spector; Josée Dupuis; Marie France Hivert; Jerome I. Rotter; James B. Meigs; James S. Pankow; Joyce B.J. van Meurs; Aaron Isaacs; Dorret I. Boomsma; Jordana T. Bell; Ayşe Demirkan; Cornelia M. van Duijn

doi:10.1038/s41467-019-10487-4

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

Jun Liu, Elena Carnero-Montoro, Jenny van Dongen, Samantha Lent, Ivana Nedeljkovic, Symen Ligthart, Pei Chien Tsai, Tiphaine C. Martin, Pooja R. Mandaviya, Rick Jansen, Marjolein J. Peters, Liesbeth Duijts, Vincent W.V. Jaddoe, Henning Tiemeier, Janine F. Felix, Gonneke Willemsen, Eco J.C. de Geus, Audrey Y. Chu, Daniel Levy, Shih Jen HwangJan Bressler, Rahul Gondalia, Elias L. Salfati, Christian Herder, Bertha A. Hidalgo, Toshiko Tanaka, Ann Zenobia Moore, Rozenn N. Lemaitre, Min A. Jhun, Jennifer A. Smith, Nona Sotoodehnia, Stefania Bandinelli, Luigi Ferrucci, Donna K. Arnett, Harald Grallert, Themistocles L. Assimes, Lifang Hou, Andrea Baccarelli, Eric A. Whitsel, Ko Willems van Dijk, Najaf Amin, André G. Uitterlinden, Eric J.G. Sijbrands, Oscar H. Franco, Abbas Dehghan, Tim D. Spector, Josée Dupuis, Marie France Hivert, Jerome I. Rotter, James B. Meigs, James S. Pankow, Joyce B.J. van Meurs, Aaron Isaacs, Dorret I. Boomsma, Jordana T. Bell, Ayşe Demirkan, Cornelia M. van Duijn

College of Public Health

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

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.

Original language	English
Article number	2581
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10487-4
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, Crown.

Funding

We gratefully acknowledge the BIOS consortium (https://www.bbmri.nl/?p=259) of Biobanking and BioMolecular resources Research Infrastructure of the Netherlands (BBMRI-NL) and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. This work is part of the CardioVasculair Onderzoek Nederland (CVON 2012-03), the Common mechanisms and pathways in Stroke and Alzheimer's disease (CoSTREAM) project (https://www.costream.eu, grant agreement No 667375), Memorabel program (project number 733050814), Netherlands X-omics Research Infrastructure and U01-AG061359 NIA. The full list of funding information of each cohort is found in Supplementary Note 2. J.L., C.M.v.D. and A.Demirkan have used exchange grants from the Personalized pREvention of Chronic DIseases consortium (PRECeDI) (H2020-MSCA-RISE-2014). A.Demirkan is supported by a Veni grant (2015) from ZonMw (VENI 91616165). C.M.v.D. received funding of CardioVasculair Onderzoek Nederland (CVON2012-03) of the Netherlands Heart Foundation. B.A.H. was supported by NHLBI K01 award (K01 HL130609-02). V.W.V.J. received a grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). J.F.F. has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595 (Dyna-HEALTH). J.B.M. is supported by K24 DK080140. J.T.B. received funding support from the JPI ERA-HDHL DIMENSION project (BBSRC BB/S020845/1) and from the ESRC (ES/N000404/1). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Funders	Funder number
CardioVasculair Onderzoek Nederland	733050814, U01-AG061359
National Institute on Aging
National Heart, Lung, and Blood Institute (NHLBI)	K01 HL130609-02, ZIAHL006001
National Heart, Lung, and Blood Institute (NHLBI)
Horizon 2020 Framework Programme	667375, 633595, K24 DK080140
Horizon 2020 Framework Programme
Biotechnology and Biological Sciences Research Council	BB/S020845/1
Biotechnology and Biological Sciences Research Council
Economic and Social Research Council	ES/N000404/1
Economic and Social Research Council
H2020 European Research Council	ERC-2014-CoG-648916
H2020 European Research Council
ZonMw Memorabel	CVON2012-03, VENI 91616165
ZonMw Memorabel
Hartstichting
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VIDI 016.136.361
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-10487-4

Cite this

Liu, J., Carnero-Montoro, E., van Dongen, J., Lent, S., Nedeljkovic, I., Ligthart, S., Tsai, P. C., Martin, T. C., Mandaviya, P. R., Jansen, R., Peters, M. J., Duijts, L., Jaddoe, V. W. V., Tiemeier, H., Felix, J. F., Willemsen, G., de Geus, E. J. C., Chu, A. Y., Levy, D., ... van Duijn, C. M. (2019). An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis. Nature Communications, 10(1), Article 2581. https://doi.org/10.1038/s41467-019-10487-4

@article{a5081ac1d4b347deb824a6362780c410,

title = "An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis",

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.",

author = "Jun Liu and Elena Carnero-Montoro and \{van Dongen\}, Jenny and Samantha Lent and Ivana Nedeljkovic and Symen Ligthart and Tsai, \{Pei Chien\} and Martin, \{Tiphaine C.\} and Mandaviya, \{Pooja R.\} and Rick Jansen and Peters, \{Marjolein J.\} and Liesbeth Duijts and Jaddoe, \{Vincent W.V.\} and Henning Tiemeier and Felix, \{Janine F.\} and Gonneke Willemsen and \{de Geus\}, \{Eco J.C.\} and Chu, \{Audrey Y.\} and Daniel Levy and Hwang, \{Shih Jen\} and Jan Bressler and Rahul Gondalia and Salfati, \{Elias L.\} and Christian Herder and Hidalgo, \{Bertha A.\} and Toshiko Tanaka and Moore, \{Ann Zenobia\} and Lemaitre, \{Rozenn N.\} and Jhun, \{Min A.\} and Smith, \{Jennifer A.\} and Nona Sotoodehnia and Stefania Bandinelli and Luigi Ferrucci and Arnett, \{Donna K.\} and Harald Grallert and Assimes, \{Themistocles L.\} and Lifang Hou and Andrea Baccarelli and Whitsel, \{Eric A.\} and \{van Dijk\}, \{Ko Willems\} and Najaf Amin and Uitterlinden, \{Andr{\'e} G.\} and Sijbrands, \{Eric J.G.\} and Franco, \{Oscar H.\} and Abbas Dehghan and Spector, \{Tim D.\} and Jos{\'e}e Dupuis and Hivert, \{Marie France\} and Rotter, \{Jerome I.\} and Meigs, \{James B.\} and Pankow, \{James S.\} and \{van Meurs\}, \{Joyce B.J.\} and Aaron Isaacs and Boomsma, \{Dorret I.\} and Bell, \{Jordana T.\} and Ay{\c s}e Demirkan and \{van Duijn\}, \{Cornelia M.\}",

note = "Publisher Copyright: {\textcopyright} 2019, Crown.",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10487-4",

language = "English",

volume = "10",

number = "1",

}

Liu, J, Carnero-Montoro, E, van Dongen, J, Lent, S, Nedeljkovic, I, Ligthart, S, Tsai, PC, Martin, TC, Mandaviya, PR, Jansen, R, Peters, MJ, Duijts, L, Jaddoe, VWV, Tiemeier, H, Felix, JF, Willemsen, G, de Geus, EJC, Chu, AY, Levy, D, Hwang, SJ, Bressler, J, Gondalia, R, Salfati, EL, Herder, C, Hidalgo, BA, Tanaka, T, Moore, AZ, Lemaitre, RN, Jhun, MA, Smith, JA, Sotoodehnia, N, Bandinelli, S, Ferrucci, L, Arnett, DK, Grallert, H, Assimes, TL, Hou, L, Baccarelli, A, Whitsel, EA, van Dijk, KW, Amin, N, Uitterlinden, AG, Sijbrands, EJG, Franco, OH, Dehghan, A, Spector, TD, Dupuis, J, Hivert, MF, Rotter, JI, Meigs, JB, Pankow, JS, van Meurs, JBJ, Isaacs, A, Boomsma, DI, Bell, JT, Demirkan, A & van Duijn, CM 2019, 'An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis', Nature Communications, vol. 10, no. 1, 2581. https://doi.org/10.1038/s41467-019-10487-4

TY - JOUR

T1 - An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis

AU - Liu, Jun

AU - Carnero-Montoro, Elena

AU - van Dongen, Jenny

AU - Lent, Samantha

AU - Nedeljkovic, Ivana

AU - Ligthart, Symen

AU - Tsai, Pei Chien

AU - Martin, Tiphaine C.

AU - Mandaviya, Pooja R.

AU - Jansen, Rick

AU - Peters, Marjolein J.

AU - Duijts, Liesbeth

AU - Jaddoe, Vincent W.V.

AU - Tiemeier, Henning

AU - Felix, Janine F.

AU - Willemsen, Gonneke

AU - de Geus, Eco J.C.

AU - Chu, Audrey Y.

AU - Levy, Daniel

AU - Hwang, Shih Jen

AU - Bressler, Jan

AU - Gondalia, Rahul

AU - Salfati, Elias L.

AU - Herder, Christian

AU - Hidalgo, Bertha A.

AU - Tanaka, Toshiko

AU - Moore, Ann Zenobia

AU - Lemaitre, Rozenn N.

AU - Jhun, Min A.

AU - Smith, Jennifer A.

AU - Sotoodehnia, Nona

AU - Bandinelli, Stefania

AU - Ferrucci, Luigi

AU - Arnett, Donna K.

AU - Grallert, Harald

AU - Assimes, Themistocles L.

AU - Hou, Lifang

AU - Baccarelli, Andrea

AU - Whitsel, Eric A.

AU - van Dijk, Ko Willems

AU - Amin, Najaf

AU - Uitterlinden, André G.

AU - Sijbrands, Eric J.G.

AU - Franco, Oscar H.

AU - Dehghan, Abbas

AU - Spector, Tim D.

AU - Dupuis, Josée

AU - Hivert, Marie France

AU - Rotter, Jerome I.

AU - Meigs, James B.

AU - Pankow, James S.

AU - van Meurs, Joyce B.J.

AU - Isaacs, Aaron

AU - Boomsma, Dorret I.

AU - Bell, Jordana T.

AU - Demirkan, Ayşe

AU - van Duijn, Cornelia M.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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UR - https://www.scopus.com/inward/citedby.url?scp=85067366036&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10487-4

DO - 10.1038/s41467-019-10487-4

M3 - Article

C2 - 31197173

AN - SCOPUS:85067366036

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2581

ER -

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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