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; Tim D Spector

doi:10.1038/ncomms6719

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 McCarthySally L John, Jordana T Bell, Jun Wang, Tim D Spector

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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.

Original language	English
Article number	5719
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6719
Publication status	Published - 12 Dec 2014

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Yuan, W., Xia, Y., Bell, C. G., Yet, I., Ferreira, T., Ward, K. J., Gao, F., Loomis, A. K., Hyde, C. L., Wu, H., Lu, H., Liu, Y., Small, K. S., Viñuela, A., Morris, A. P., Berdasco, M., Esteller, M., Brosnan, M. J., Deloukas, P., ... Spector, T. D. (2014). An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins. Nature Communications, 5, Article 5719. https://doi.org/10.1038/ncomms6719

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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.",

author = "Wei Yuan and Yudong Xia and Bell, {Christopher G} and Idil Yet and Teresa Ferreira and Ward, {Kirsten J} and Fei Gao and Loomis, {A Katrina} and Hyde, {Craig L} and Honglong Wu and Hanlin Lu and Yuan Liu and Small, {Kerrin S} and Ana Vi{\~n}uela and Morris, {Andrew P} and Mar{\'i}a Berdasco and Manel Esteller and Brosnan, {M Julia} and Panos Deloukas and McCarthy, {Mark I} and John, {Sally L} and Bell, {Jordana T} and Jun Wang and Spector, {Tim D}",

year = "2014",

month = dec,

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Yuan, W, Xia, Y, Bell, CG , Yet, I, Ferreira, T, Ward, KJ, Gao, F, Loomis, AK, Hyde, CL, Wu, H, Lu, H, Liu, Y, Small, KS, Viñuela, A, Morris, AP, Berdasco, M, Esteller, M, Brosnan, MJ, Deloukas, P, McCarthy, MI, John, SL, Bell, JT, Wang, J & Spector, TD 2014, 'An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins', Nature Communications, vol. 5, 5719. https://doi.org/10.1038/ncomms6719

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T1 - An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

AU - Yuan, Wei

AU - Xia, Yudong

AU - Bell, Christopher G

AU - Yet, Idil

AU - Ferreira, Teresa

AU - Ward, Kirsten J

AU - Gao, Fei

AU - Loomis, A Katrina

AU - Hyde, Craig L

AU - Wu, Honglong

AU - Lu, Hanlin

AU - Liu, Yuan

AU - Small, Kerrin S

AU - Viñuela, Ana

AU - Morris, Andrew P

AU - Berdasco, María

AU - Esteller, Manel

AU - Brosnan, M Julia

AU - Deloukas, Panos

AU - McCarthy, Mark I

AU - John, Sally L

AU - Bell, Jordana T

AU - Wang, Jun

AU - Spector, Tim D

PY - 2014/12/12

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N2 - 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.

AB - 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.

U2 - 10.1038/ncomms6719

DO - 10.1038/ncomms6719

M3 - Article

C2 - 25502755

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5719

ER -

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

Abstract

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