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; Andre G. Uitterlinden; Eric J. G. Sijbrands; Oscar H. Franco; Abbas Dehghan; Tim D. Spector; Josee Dupuis; Marie-France Hivert; Jerome Rotter; James B. Meigs; James S. Pankow; Joyce B. J. van Meurs; Aaron Isaacs; Dorret Boomsma; Jordana T. Bell; Ayse 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, Andre G. Uitterlinden, Eric J. G. Sijbrands, Oscar H. Franco, Abbas Dehghan, Tim D. Spector, Josee Dupuis, Marie-France Hivert, Jerome Rotter, James B. Meigs, James S. Pankow, Joyce B. J. van Meurs, Aaron Isaacs, Dorret Boomsma, Jordana T. Bell, Ayse Demirkan^*, Cornelia M. van Duijn^*

^*Corresponding author for this work

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

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
Number of pages	11
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-10487-4
Publication status	Published - 13 Jun 2019

Keywords

EPIGENOME-WIDE ASSOCIATION
BODY-MASS INDEX
WAIST CIRCUMFERENCE
DIABETES-MELLITUS
FASTING GLUCOSE
GLYCEMIC TRAITS
UP-REGULATION
TYPE-2
GENE
EXPRESSION

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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, Article 2581. https://doi.org/10.1038/s41467-019-10487-4

@article{c6091d7607944e9988e2dcbd8fa16999,

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.",

keywords = "EPIGENOME-WIDE ASSOCIATION, BODY-MASS INDEX, WAIST CIRCUMFERENCE, DIABETES-MELLITUS, FASTING GLUCOSE, GLYCEMIC TRAITS, UP-REGULATION, TYPE-2, GENE, EXPRESSION",

author = "Jun Liu and Elena Carnero-Montoro and {van Dongen}, Jenny and Samantha Lent and Ivana Nedeljkovic and Symen Ligthart and Pei-Chien Tsai 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 Shih-Jen Hwang 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, {Andre G.} and Sijbrands, {Eric J. G.} and Franco, {Oscar H.} and Abbas Dehghan and Spector, {Tim D.} and Josee Dupuis and Marie-France Hivert and Jerome Rotter and Meigs, {James B.} and Pankow, {James S.} and {van Meurs}, {Joyce B. J.} and Aaron Isaacs and Dorret Boomsma and Bell, {Jordana T.} and Ayse Demirkan and {van Duijn}, {Cornelia M.}",

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

year = "2019",

month = jun,

day = "13",

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

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Liu, J, Carnero-Montoro, E, van Dongen, J, Lent, S, Nedeljkovic, I, Ligthart, S, Tsai, P-C, 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, S-J, 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, M-F, Rotter, J, Meigs, JB, Pankow, JS, van Meurs, JBJ, Isaacs, A, Boomsma, D, 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, 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, Andre G.

AU - Sijbrands, Eric J. G.

AU - Franco, Oscar H.

AU - Dehghan, Abbas

AU - Spector, Tim D.

AU - Dupuis, Josee

AU - Hivert, Marie-France

AU - Rotter, Jerome

AU - Meigs, James B.

AU - Pankow, James S.

AU - van Meurs, Joyce B. J.

AU - Isaacs, Aaron

AU - Boomsma, Dorret

AU - Bell, Jordana T.

AU - Demirkan, Ayse

AU - van Duijn, Cornelia M.

N1 - Funding Information: 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. Publisher Copyright: © 2019, Crown.

PY - 2019/6/13

Y1 - 2019/6/13

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.

KW - EPIGENOME-WIDE ASSOCIATION

KW - BODY-MASS INDEX

KW - WAIST CIRCUMFERENCE

KW - DIABETES-MELLITUS

KW - FASTING GLUCOSE

KW - GLYCEMIC TRAITS

KW - UP-REGULATION

KW - TYPE-2

KW - GENE

KW - EXPRESSION

U2 - 10.1038/s41467-019-10487-4

DO - 10.1038/s41467-019-10487-4

M3 - Article

C2 - 31197173

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 2581

ER -