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Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci

Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci
Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci
Integrating epigenetic data with genome-wide association study (GWAS) results can reveal disease mechanisms. The genome sequence itself also shapes the epigenome, with CpG density and transcription factor binding sites (TFBSs) strongly encoding the DNA methylome.Therefore, genetic polymorphism impacts on the observed epigenome. Furthermore, large genetic variants alter epigenetic signal dosage. Here, we identify DNA methylation variability between GWAS-SNP risk and non-risk haplotypes. In three subsets comprising 3128 MeDIP-seq peripheral-blood DNA methylomes, we find 7173 consistent and functionally enriched Differentially Methylated Regions. 36.8% can be attributed to common non-SNP genetic variants. CpG-SNPs, as well as facilitative TFBS-motifs, are also enriched. Highlighting their functional potential, CpG-SNPs strongly associate with allele-specific DNase-I hypersensitivity sites. Our results demonstrate strong DNA methylation allelic differences driven by obligatory or facilitative genetic effects, with potential direct or regional disease related repercussions. These allelic variations require disentangling from pure tissue-specificmodifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.
Bell, Christopher G.
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Gao, Fei
fa3e4707-8319-49fa-897b-b27f7a534508
Yuan, Wei
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Roos, Leonie
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Acton, Richard J.
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Xia, Yudong
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Bell, Jordana
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Ward, Kirsten
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Mangino, Massimo
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Hysi, Pirro G.
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Wang, Jun
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Spector, Tim D.
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Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Gao, Fei
fa3e4707-8319-49fa-897b-b27f7a534508
Yuan, Wei
934197a6-0708-4967-ab09-032f8327e4e5
Roos, Leonie
70d8ead4-e032-4422-bb5a-c36f31d471a2
Acton, Richard J.
252d4402-7cd9-4016-a428-4ef3de5fafe2
Xia, Yudong
1a3cbe01-cb90-4144-939f-ab2c72779f12
Bell, Jordana
48ac3b6f-cc9f-4311-b683-c8fa862c03c1
Ward, Kirsten
0d581684-6bdd-40a6-9cad-ec46bf82ed47
Mangino, Massimo
19ad1660-3639-45a8-93d6-e6a9b5c1c64b
Hysi, Pirro G.
72cc4ed2-a5f5-467c-b623-1175747b944f
Wang, Jun
dac45864-634f-41ec-ba2a-1e59ad23ae97
Spector, Tim D.
1e47066c-6620-4f86-af6f-89d9e130ffc2

Bell, Christopher G., Gao, Fei, Yuan, Wei, Roos, Leonie, Acton, Richard J., Xia, Yudong, Bell, Jordana, Ward, Kirsten, Mangino, Massimo, Hysi, Pirro G., Wang, Jun and Spector, Tim D. (2018) Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci. Nature Communications, 9 (1). (doi:10.1038/s41467-017-01586-1).

Record type: Article

Abstract

Integrating epigenetic data with genome-wide association study (GWAS) results can reveal disease mechanisms. The genome sequence itself also shapes the epigenome, with CpG density and transcription factor binding sites (TFBSs) strongly encoding the DNA methylome.Therefore, genetic polymorphism impacts on the observed epigenome. Furthermore, large genetic variants alter epigenetic signal dosage. Here, we identify DNA methylation variability between GWAS-SNP risk and non-risk haplotypes. In three subsets comprising 3128 MeDIP-seq peripheral-blood DNA methylomes, we find 7173 consistent and functionally enriched Differentially Methylated Regions. 36.8% can be attributed to common non-SNP genetic variants. CpG-SNPs, as well as facilitative TFBS-motifs, are also enriched. Highlighting their functional potential, CpG-SNPs strongly associate with allele-specific DNase-I hypersensitivity sites. Our results demonstrate strong DNA methylation allelic differences driven by obligatory or facilitative genetic effects, with potential direct or regional disease related repercussions. These allelic variations require disentangling from pure tissue-specificmodifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.

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Accepted/In Press date: 29 September 2017
e-pub ahead of print date: 2 January 2018
Published date: 1 December 2018

Identifiers

Local EPrints ID: 416684
URI: https://eprints.soton.ac.uk/id/eprint/416684
PURE UUID: de6976eb-840c-4367-9615-5ef16eb53040
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242
ORCID for Richard J. Acton: ORCID iD orcid.org/0000-0002-2574-9611

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Date deposited: 04 Jan 2018 17:30
Last modified: 08 Aug 2018 00:28

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Contributors

Author: Fei Gao
Author: Wei Yuan
Author: Leonie Roos
Author: Richard J. Acton ORCID iD
Author: Yudong Xia
Author: Jordana Bell
Author: Kirsten Ward
Author: Massimo Mangino
Author: Pirro G. Hysi
Author: Jun Wang
Author: Tim D. Spector

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