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

Epidemiology & Community Health

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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 (US)
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

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Publisher Copyright:
© 2019, Crown.

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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

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

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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.}",

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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.

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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.

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

Abstract

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