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Allele-specific methylation in the human genome: Implications for genetic studies of complex disease
Open accessAbstract
Across the genome, outside of a small number of known imprinted genes and regions subject to X-inactivation in females, DNA methylation at CpG dinucleotides is often assumed to be complementary across both alleles in a diploid cell. However, recent findings suggest the reality is more complex, with the discovery that allele-specific methylation (ASM) is a common feature across the genome. A key observation is that the majority of ASM is associated with genetic variation in cis, although a noticeable proportion is also non-cis in nature and mediated, for example, by parental origin. ASM appears to be both quantitative, characterized by subtle skewing of DNA methylation between alleles, and heterogeneous, varying across tissues and between individuals. These findings have important implications for complex disease genetics; whilst cis-mediated ASM provides a functional consequence for non-coding genetic variation, heterogeneous and quantitative ASM complicates the identification of disease-associated loci. We propose that non-cis ASM could contribute toward the 'missing heritability' of complex diseases, rendering certain loci hemizygous and masking the direct association between genotype and phenotype. We suggest that the interpretation of results from genomewide association studies can be improved by the incorporation of epi-allelic information, and that in order to fully understand the extent and consequence of ASM in the human genome, a comprehensive sequencing-based analysis of allelic methylation patterns across tissues and individuals is required.
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“DNA methylation has been shown to frequently occur in an allele-specific manner (He et al., 2015;Meaburn, Schalkwyk, & Mill, 2010;Shoemaker, Deng, Wang, & Zhang, 2010).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Meaburn, Schalkwyk, & Mill, 2010
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Metadata
- Authors
- Meaburn, E. L., Schalkwyk, L. C., & Mill, J.
- Affiliations
- King's College London (GB)
- Corresponding author
- Mill, Jonathan
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2010-10
- Volume
- 5
- Issue
- 7
- Pages
- 578-582
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC3052843
- OpenAlex
- W2008091117
- Cited by
- 132
- References
- 32
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 9 · 2019: 9 · 2018: 6 · 2017: 14 · 2016: 8 · 2015: 12 · 2014: 9 · 2013: 11 · 2012: 14
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Epigenetics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- BIROn (Birkbeck, University of London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- allele-specific methylation, DNA methylation, CpG, parental origin, missing heritability, complex disease genetics, genome-wide association study, epigenetic inheritance, tissue heterogeneity
- MeSH terms
- Alleles, Disease, Environment, Female, Genetic Complementation Test, Genotype, Humans, Models, Biological, Genetic Variation, Genome, Human, DNA Methylation, Genetic Predisposition to Disease, X Chromosome Inactivation, Genome-Wide Association Study
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