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

Christopher G Bell; Fei Gao; Wei Yuan; Leonie Roos; Richard J Acton; Yudong Xia; Jordana Bell; Kirsten Ward; Massimo Mangino; Pirro G Hysi; Jun Wang; Timothy D Spector

doi:10.1038/s41467-017-01586-1

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

Christopher G Bell^*, Fei Gao, Wei Yuan, Leonie Roos, Richard J Acton, Yudong Xia, Jordana Bell, Kirsten Ward, Massimo Mangino, Pirro G Hysi, Jun Wang, Timothy D Spector

^*Corresponding author for this work

King's College London

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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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-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.

Original language	English
Article number	8
Journal	Nature Communications
Volume	9
Early online date	2 Jan 2018
DOIs	https://doi.org/10.1038/s41467-017-01586-1
Publication status	Published - 1 Dec 2018

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title = "Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci",

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-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.",

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T1 - Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci

AU - Bell, Christopher G

AU - Gao, Fei

AU - Yuan, Wei

AU - Roos, Leonie

AU - Acton, Richard J

AU - Xia, Yudong

AU - Bell, Jordana

AU - Ward, Kirsten

AU - Mangino, Massimo

AU - Hysi, Pirro G

AU - Wang, Jun

AU - Spector, Timothy D

PY - 2018/12/1

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N2 - 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-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.

AB - 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-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.

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DO - 10.1038/s41467-017-01586-1

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

M1 - 8

ER -

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

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