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Nat Commun. 2018 Jan 2;9(1):8. doi: 10.1038/s41467-017-01586-1.

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

Author information

1
Department of Twin Research & Genetic Epidemiology, King's College London, London, SE1 7EH, UK. cgb@mrc.soton.ac.uk.
2
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK. cgb@mrc.soton.ac.uk.
3
Epigenomic Medicine, Biological Sciences, Faculty of Environmental and Natural Sciences, University of Southampton, Southampton, SO17 1BJ, UK. cgb@mrc.soton.ac.uk.
4
Human Development and Health Academic Unit, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK. cgb@mrc.soton.ac.uk.
5
BGI-Shenzhen, Shenzhen, 518083, China.
6
Department of Twin Research & Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
7
Institute of Cancer Research, Sutton, SM2 5NG, UK.
8
MRC London Institute of Medical Sciences, Imperial College London, Du Cane Road, London, W12 0NN, UK.
9
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, SO16 6YD, UK.
10
Epigenomic Medicine, Biological Sciences, Faculty of Environmental and Natural Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
11
Human Development and Health Academic Unit, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK.

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.

PMID:
29295990
PMCID:
PMC5750212
DOI:
10.1038/s41467-017-01586-1
[Indexed for MEDLINE]
Free PMC Article

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