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

Wei Yuan, Yudong Xia, Christopher G. Bell, Idil Yet, Teresa Ferreira, Kirsten J. Ward, Fei Gao, A. Katrina Loomis, Craig L. Hyde, Honglong Wu, Hanlin Lu, Yuan Liu, Kerrin S. Small, Ana Viñuela, Andrew P. Morris, María Berdasco, Manel Esteller, M. Julia Brosnan, Panos Deloukas, Mark I. McCarthy, Sally L. John, Jordana T. Bell, Jun Wang () and Tim D. Spector ()
Additional contact information
Wei Yuan: King's College London
Yudong Xia: BGI-Shenzhen
Christopher G. Bell: King's College London
Idil Yet: King's College London
Teresa Ferreira: Wellcome Trust Centre for Human Genetics, University of Oxford
Kirsten J. Ward: King's College London
Fei Gao: BGI-Shenzhen
A. Katrina Loomis: Pfizer Worldwide Research and Development
Craig L. Hyde: Pfizer Worldwide Research and Development
Honglong Wu: BGI-Shenzhen
Hanlin Lu: BGI-Shenzhen
Yuan Liu: BGI-Shenzhen
Kerrin S. Small: King's College London
Ana Viñuela: King's College London
Andrew P. Morris: Wellcome Trust Centre for Human Genetics, University of Oxford
María Berdasco: Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals
Manel Esteller: Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals
M. Julia Brosnan: Pfizer Worldwide Research and Development
Panos Deloukas: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Mark I. McCarthy: Wellcome Trust Centre for Human Genetics, University of Oxford
Sally L. John: Pfizer Worldwide Research and Development
Jordana T. Bell: King's College London
Jun Wang: BGI-Shenzhen
Tim D. Spector: King's College London

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6719

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