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Epigenetic Inheritance and the Missing Heritability Problem
Open accessAbstract
Epigenetic phenomena, and in particular heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. This article presents a model of transgenerational epigenetic inheritance and explores the effect of epigenetic inheritance on the risk and recurrence risk of a complex disease. The model assumes that epigenetic modifications of the genome are gained and lost at specified rates and that each modification contributes multiplicatively to disease risk. The potentially high rate of loss of epigenetic modifications causes the probability of identity in state in close relatives to be smaller than is implied by their relatedness. As a consequence, the recurrence risk to close relatives is reduced. Although epigenetic modifications may contribute substantially to average risk, they will not contribute much to recurrence risk and heritability unless they persist on average for many generations. If they do persist for long times, they are equivalent to mutations and hence are likely to be in linkage disequilibrium with SNPs surveyed in genomewide association studies. Thus epigenetic modifications are a potential solution to the problem of missing causality of complex diseases but not to the problem of missing heritability. The model highlights the need for empirical estimates of the persistence times of heritable epialleles.
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“Genome-wide association studies (GWAS) are not generally powered to detect epistasis or G×E121, and they are not designed to detect epigenetic influences122”
From Rare and common variants: twenty arguments (2012) · cites this paper as [122]
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Common SNPs explain a large proportion of the heritability for human height
Yang, J., Benyamin, B., McEvoy, B. P., Gordon, S., Henders, A. K., Nyholt, D. R., Madden, P. A., Heath, A. C., Martin, N. G., Montgomery, G. W., et al. (2010) · Nature Genetics · doi:10.1038/ng.608 · Cited by 4,446
“Epigenetic mutations may cause resemblance between relatives and contribute to heritability if stably inherited, but in that case they would be equivalent to DNA sequence variants, would show LD with the assayed SNPs and would not contribute to missing heritabilit”
BackgroundThe mystery of missing heritability: Genetic interactions create phantom heritability
Zuk, O., Hechter, E., Sunyaev, S. R., & Lander, E. S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119675109 · Cited by 1,542
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Metadata
- Authors
- Slatkin, M.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Slatkin, Montgomery
- ORCID
- Slatkin, Montgomery
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-07-01
- Volume
- 182
- Issue
- 3
- Pages
- 845-850
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC2710163
- OpenAlex
- W2150732692
- Cited by
- 337
- References
- 21
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 7 · 2021: 12 · 2020: 20 · 2019: 11 · 2018: 14 · 2017: 21 · 2016: 19 · 2015: 40 · 2014: 34 · 2013: 26 · 2012: 40
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM040282, R01‑GM40282)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- epigenetic inheritance, transgenerational epigenetic inheritance, missing heritability, complex diseases, recurrence risk, epialleles, identity by state, linkage disequilibrium, genome-wide association study, disease risk
- MeSH terms
- Algorithms, Animals, Humans, Models, Genetic, Mutation, Time Factors, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Genome-Wide Association Study
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