An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

Abstract

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.Funding support for this project was obtained from the European Research Council (project number 250157) and BGI. The study was also supported by TwinsUK, which is funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013); and also receives support from the National Institute for Health Research (NIHR) BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas' NHS Foundation Trust and King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. M.M. is the holder of Wellcome Trust Senior Investigator Award (Wellcome 098381). T.D.S. is the holder of an ERC Advanced Principal Investigator award (ERC 250157). A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Skeletal muscle 450k methylation project is supported by European Community's Seventh Framework Programme (FP7/2007-2013) under DEXLIFE project (grant agreement no. HEALTH-F2-2011-279228)