title: 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.
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Idil
authors.initials: I
authors.lastname: Yet
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ferreira
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Kirsten J
authors.initials: KJ
authors.lastname: Ward
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA.
authors.forename: A Katrina
authors.initials: AK
authors.lastname: Loomis
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hyde
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Honglong
authors.initials: H
authors.lastname: Wu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Lu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Viñuela
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Hospital Duran i Reynals, Barcelona 08908, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Berdasco
authors.affiliation: 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.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.affiliation: 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.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: 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.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.
authors.forename: Sally L
authors.initials: SL
authors.lastname: John
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Twin Research &Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D020169:Caspases / Q000097:blood / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics; D011401:Promoter Regions, Genetic; D064546:Protein Kinase C beta / Q000097:blood / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000097:blood / Q000235:genetics; D013656:Taurocholic Acid / Q000097:blood; D014430:Twins, Monozygotic
chemical_list: D015415:Biomarkers; C441470:GPR61 protein, human; D007328:Insulin; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D013656:Taurocholic Acid; C579054:PRKCB protein, human; D064546:Protein Kinase C beta; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein