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

Research output: Contribution to journalArticleAcademicpeer-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 languageEnglish
Article number2581
Pages (from-to)2581
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this