Novel DNA methylation sites of glucose and insulin homeostasis: an integrative cross-omics analysis
Authors: Liu Jun , Carnero-Montoro Elena , van Dongen Jenny , Lent Samantha , Nedeljkovic Ivana , Ligthart Symen , Tsai Pei-Chien , Martin Tiphaine C. , Mandaviya Pooja R. , Jansen Rick , Peters Marjolein J. , Duijts Liesbeth , Jaddoe Vincent W.V. , Tiemeier Henning , Felix Janine F. , Chu Audrey Y. , Levy Daniel , Hwang Shih-Jen , Bressler Jan , Gondalia Rahul , Salfati Elias L. , Herder Christian , Hidalgo Bertha A. , Tanaka Toshiko , Moore Ann Zenobia , Lemaitre Rozenn N. , Jhun Min A. , Smith Jennifer A. , Sotoodehnia Nona , Bandinelli Stefania , Ferrucci Luigi , Arnett Donna K. , Grallert Harald , Assimes Themistocles L. , Hou Lifang , Baccarelli Andrea , Whitsel Eric A. , van Dijk Ko Willems , Amin Najaf , Uitterlinden André G. , Sijbrands Eric J.G. , Franco Oscar H. , Dehghan Abbas , Spector Tim D. , Dupuis Josée , Hivert Marie-France , Rotter Jerome I. , Meigs James B. , Pankow James S. , van Meurs Joyce B.J. , Isaacs Aaron , Boomsma Dorret I. , Bell Jordana T. , Demirkan Ayşe , van Duijn Cornelia M. 
Published: October 2018

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.