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

Author

Listed:
  • 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
    University of Liverpool)

  • María Berdasco

    (Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals)

  • Manel Esteller

    (Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals
    School of Medicine, University of Barcelona
    Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona)

  • 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
    King Abdulaziz University)

  • Mark I. McCarthy

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford
    Oxford NIHR Biomedical Research Centre, Churchill Hospital)

  • Sally L. John

    (Pfizer Worldwide Research and Development)

  • Jordana T. Bell

    (King's College London)

  • Jun Wang

    (BGI-Shenzhen
    King Abdulaziz University
    University of Copenhagen
    The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen)

  • Tim D. Spector

    (King's College London)

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.

Suggested Citation

  • 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 Vi, 2014. "An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins," Nature Communications, Nature, vol. 5(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6719
    DOI: 10.1038/ncomms6719
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    Cited by:

    1. Joshua A. Lees & João M. Dias & Francis Rajamohan & Jean-Philippe Fortin & Rebecca O’Connor & Jimmy X. Kong & Emily A. G. Hughes & Ethan L. Fisher & Jamison B. Tuttle & Gabrielle Lovett & Bethany L. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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