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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 languageEnglish (US)
Article number2581
JournalNature communications
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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