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

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
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
5719
Yuan, Wei
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Xia, Yudong
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Bell, Christopher G.
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Yet, Idil
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Ferreira, Teresa
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Ward, Kirsten J
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Gao, Fei
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Loomis, A Katrina
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Hyde, Craig L.
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Wu, Honglong
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Lu, Hanlin
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Liu, Yuan
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Small, Kerrin S.
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Viñuela, Ana
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Morris, Andrew P.
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Berdasco, María
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Esteller, Manel
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Brosnan, M Julia
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Deloukas, Panos
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McCarthy, Mark I.
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John, Sally L.
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Bell, Jordana T.
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Wang, Jun
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Spector, Tim D.
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Yuan, Wei
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Xia, Yudong
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Bell, Christopher G.
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Yet, Idil
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Ferreira, Teresa
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Ward, Kirsten J
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Gao, Fei
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Loomis, A Katrina
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Hyde, Craig L.
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Wu, Honglong
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Lu, Hanlin
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Liu, Yuan
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Small, Kerrin S.
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Viñuela, Ana
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Morris, Andrew P.
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Berdasco, María
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Esteller, Manel
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Brosnan, M Julia
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Deloukas, Panos
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McCarthy, Mark I.
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John, Sally L.
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Bell, Jordana T.
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Wang, Jun
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Spector, Tim D.
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Yuan, Wei, Xia, Yudong, Bell, Christopher G., Yet, Idil, Ferreira, Teresa, Ward, Kirsten J, Gao, Fei, Loomis, A Katrina, Hyde, Craig L., Wu, Honglong, Lu, Hanlin, Liu, Yuan, Small, Kerrin S., Viñuela, Ana, Morris, Andrew P., Berdasco, María, Esteller, Manel, Brosnan, M Julia, Deloukas, Panos, McCarthy, Mark I., John, Sally L., Bell, Jordana T., Wang, Jun and Spector, Tim D. (2014) An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins. Nature Communications, 5, 5719. (doi:10.1038/ncomms6719).

Record type: Article

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

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Accepted/In Press date: 31 October 2014
e-pub ahead of print date: 12 December 2014
Published date: 12 December 2014
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400981
URI: http://eprints.soton.ac.uk/id/eprint/400981
PURE UUID: 35857de4-2d21-4b01-8b05-acc6b6ee9a7f
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 07:46
Last modified: 26 Nov 2019 01:32

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