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Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus
Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus
Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10(-4), permutation p?=?1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.
1932-6203
e14040
Bell, Christopher G.
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Finer, Sarah
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Lindgren, Cecilia M.
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Wilson, Gareth A.
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Rakyan, Vardhman K.
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Teschendorff, Andrew E.
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Akan, Pelin
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Stupka, Elia
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Down, Thomas A.
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Prokopenko, Inga
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Morison, Ian M.
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Mill, Jonathan
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Pidsley, Ruth
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Deloukas, Panos
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Frayling, Timothy M.
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McCarthy, Mark I.
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Hattersley, Andrew T.
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Beck, Stephan
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Hitman, Graham A.
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Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Finer, Sarah
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Lindgren, Cecilia M.
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Wilson, Gareth A.
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Rakyan, Vardhman K.
39c272f9-6ec7-4ac4-8c15-c80c8d936438
Teschendorff, Andrew E.
b1d5937a-e56f-4fbf-8f38-70e756e2cdda
Akan, Pelin
15a47b81-d3c3-405e-a454-bd5c941ba4b8
Stupka, Elia
03fd8179-6b7b-4602-8556-976169046d2f
Down, Thomas A.
a98a5916-dcf8-471a-b230-84baa460c09c
Prokopenko, Inga
e56ceffd-52b1-4503-ac82-adc537595e6e
Morison, Ian M.
465fdbe4-3f60-4217-836f-478dcdd81fe1
Mill, Jonathan
167ecfa8-a1f5-462a-a599-529cb124206a
Pidsley, Ruth
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Deloukas, Panos
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Frayling, Timothy M.
ddaaa2c7-b281-4c60-a8d8-8f4657d46974
McCarthy, Mark I.
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Hattersley, Andrew T.
429254b8-e75b-46bd-a6f6-274130336b0d
Beck, Stephan
50f0c07a-19a8-4bca-adbc-af41a3800412
Hitman, Graham A.
22873747-ee78-4d93-9022-154098151c2f

Bell, Christopher G., Finer, Sarah, Lindgren, Cecilia M., Wilson, Gareth A., Rakyan, Vardhman K., Teschendorff, Andrew E., Akan, Pelin, Stupka, Elia, Down, Thomas A., Prokopenko, Inga, Morison, Ian M., Mill, Jonathan, Pidsley, Ruth, Deloukas, Panos, Frayling, Timothy M., McCarthy, Mark I., Hattersley, Andrew T., Beck, Stephan and Hitman, Graham A. (2010) Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE, 5 (11), e14040. (doi:10.1371/journal.pone.0014040). (PMID:19718037)

Record type: Article

Abstract

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10(-4), permutation p?=?1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.

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Published date: 18 November 2010
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400989
URI: http://eprints.soton.ac.uk/id/eprint/400989
ISSN: 1932-6203
PURE UUID: e1c7a774-d15a-4142-90b1-1d1a49f3ecb5
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 08:56
Last modified: 17 Dec 2019 01:33

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Contributors

Author: Christopher G. Bell ORCID iD
Author: Sarah Finer
Author: Cecilia M. Lindgren
Author: Gareth A. Wilson
Author: Vardhman K. Rakyan
Author: Andrew E. Teschendorff
Author: Pelin Akan
Author: Elia Stupka
Author: Thomas A. Down
Author: Inga Prokopenko
Author: Ian M. Morison
Author: Jonathan Mill
Author: Ruth Pidsley
Author: Panos Deloukas
Author: Timothy M. Frayling
Author: Mark I. McCarthy
Author: Andrew T. Hattersley
Author: Stephan Beck
Author: Graham A. Hitman

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