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Nat Commun. 2014 Dec 12;5:5719. doi: 10.1038/ncomms6719.

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

Author information

1
Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
2
BGI-Shenzhen, Shenzhen 518083, China.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
4
Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA.
5
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK [2] Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK.
6
Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals, Barcelona 08908, Spain.
7
1] Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals, Barcelona 08908, Spain [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia 08907, Spain [3] Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia 08010, Spain.
8
Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.
9
1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK [2] King Abdulaziz University, Jeddah 22254, Saudi Arabia.
10
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, oxford OX3 7LE, UK [3] Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK.
11
1] BGI-Shenzhen, Shenzhen 518083, China [2] King Abdulaziz University, Jeddah 22254, Saudi Arabia [3] Department of Biology, University of Copenhagen, Copenhagen DK-2200, Denmark [4] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark.

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.

PMID:
25502755
PMCID:
PMC4284644
DOI:
10.1038/ncomms6719
[Indexed for MEDLINE]
Free PMC Article

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