RT Journal Article
SR Electronic
T1 Novel DNA methylation sites of glucose and insulin homeostasis: an integrative cross-omics analysis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 432070
DO 10.1101/432070
A1 Jun Liu
A1 Elena Carnero-Montoro
A1 Jenny van Dongen
A1 Samantha Lent
A1 Ivana Nedeljkovic
A1 Symen Ligthart
A1 Pei-Chien Tsai
A1 Tiphaine C. Martin
A1 Pooja R. Mandaviya
A1 Rick Jansen
A1 Marjolein J. Peters
A1 Liesbeth Duijts
A1 Vincent W.V. Jaddoe
A1 Henning Tiemeier
A1 Janine F. Felix
A1 Audrey Y Chu
A1 Daniel Levy
A1 Shih-Jen Hwang
A1 Jan Bressler
A1 Rahul Gondalia
A1 Elias L. Salfati
A1 Christian Herder
A1 Bertha A. Hidalgo
A1 Toshiko Tanaka
A1 Ann Zenobia Moore
A1 Rozenn N. Lemaitre
A1 Min A. Jhun
A1 Jennifer A. Smith
A1 Nona Sotoodehnia
A1 Stefania Bandinelli
A1 Luigi Ferrucci
A1 Donna K. Arnett
A1 Harald Grallert
A1 Themistocles L. Assimes
A1 Lifang Hou
A1 Andrea Baccarelli
A1 Eric A Whitsel
A1 Ko Willems van Dijk
A1 Najaf Amin
A1 André G. Uitterlinden
A1 Eric J.G. Sijbrands
A1 Oscar H. Franco
A1 Abbas Dehghan
A1 Tim D. Spector
A1 Josée Dupuis
A1 Marie-France Hivert
A1 Jerome I. Rotter
A1 James B. Meigs
A1 James S. Pankow
A1 Joyce B.J. van Meurs
A1 Aaron Isaacs
A1 Dorret I. Boomsma
A1 Jordana T. Bell
A1 Ayşe Demirkan
A1 Cornelia M. van Duijn
YR 2018
UL http://biorxiv.org/content/early/2018/10/18/432070.abstract
AB Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of the functional relevance of the phenomenon remains limited. Because obesity is the main risk factor for T2D and a driver of methylation from previous study, we aimed to explore the effect of DNA methylation in the early phases of T2D pathology while accounting for body mass index (BMI). We performed a blood-based epigenome-wide association study (EWAS) of fasting glucose and insulin among 4,808 non-diabetic European individuals and replicated the findings in an independent sample consisting of 11,750 non-diabetic subjects. We integrated blood-based in silico cross-omics databases comprising genomics, epigenomics and transcriptomics collected by BIOS project of the Biobanking and BioMolecular resources Research Infrastructure of the Netherlands (BBMRI-NL), the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and the tissue-specific Genotype-Tissue Expression (GTEx) project. We identified and replicated nine novel differentially methylated sites in whole blood (P-value < 1.27 × 10−7): sites in LETM1, RBM20, IRS2, MAN2A2 genes and 1q25.3 region were associated with fasting insulin; sites in FCRL6, SLAMF1, APOBEC3H genes and 15q26.1 region were associated with fasting glucose. The association between SLAMF1, APOBEC3H and 15q26.1 methylation sites and glucose emerged only when accounted for BMI. Follow-up in silico cross-omics analyses indicate that the cis-acting meQTLs near SLAMF1 and SLAMF1 expression are involved in glucose level regulation. Moreover, our data suggest that differential methylation in FCRL6 may affect glucose level and the risk of T2D by regulating FCLR6 expression in the liver. In conclusion, the present study provided nine new DNA methylation sites associated with glycemia homeostasis and also provided new insights of glycemia related loci into the genetics, epigenetics and transcriptomics pathways based on the integration of cross-omics data in silico.