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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GWAS are generally not powered to detect epistasis or GxE and are not designed to detect epigenetic influences.
“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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“, 2001; Xiao and Boehnke, 2009) and missing heritability (Maher, 2008; McCarthy and Hirschhorn, 2008; Slatkin, 2009).”
BackgroundExperimental Evolution withCaenorhabditisNematodes
Teotónio, H., Estes, S., Phillips, P. C., & Baer, C. F. (2017) · Genetics · doi:10.1534/genetics.115.186288 · Cited by 93 · see citing works
“…be conducted in a rigorous population genetic framework, as there is already a set of theory that deals with the genetics and selection for intergenerational interactions ( e.g. , Lande and Price 1989; Lande and Kirkpatrick 1990; Slatkin 2009; Furrow and Feldman 2014; Proulx and Teotónio 2017).”
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“DNA sequence, (2) heritability and (3) plasticity and reversibility.”
BackgroundEpigenetics and phenotypic variability: some interesting insights from birds
Frésard, L., Morisson, M., Brun, J. M. J. M., Collin, A., Pain, B., Minvielle, F., & Frédérique Pitel, A. (2013) · Genetics Selection Evolution · doi:10.1186/1297-9686-45-16 · Cited by 91 · see citing works
“, their potentially transient nature) could constitute a challenge in the modeling of inheritance [158].”
BackgroundThe Human Microbiome and the Missing Heritability Problem
Sandoval‐Motta, S., Aldana, M., Martínez‐Romero, E., & Frank, A. (2017) · Frontiers in Genetics · doi:10.3389/fgene.2017.00080 · Cited by 89 · see citing works
“…to the fact that almost all epigenetic marks are removed in the embryo through reprogramming, the question of whether epigenetic marks can be transmitted across human generations Frontiers in Genetics | www.frontiersin.org 2 June 2017 | Volume 8 | Article 80 is still being debated (Slatkin, 2009).”
BackgroundThe Genetics of Pediatric Obesity
Chesi, A., & Grant, S. F. A. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.08.008 · Cited by 83 · see citing works
“Although the contribution of epigenetics to heritability is still subject to some debate [94], a recent study in Arabidopsis thaliana convincingly showed that, at least in plants, epigenetic changes are stable over several generations and contribute strongly to the heritability of complex traits [95].”
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Futuyma, D. J. (2015) · Interdisciplinary evolution research · doi:10.1007/978-3-319-15045-1_2 · Cited by 81 · see citing works
“Thus, the population dynamics of epigenetic mutations (“epimutations”) can be described in the same terms as sequence mutations (Haig 2007; Slatkin 2009).”
BackgroundJoint influence of small-effect genetic variants on human longevity
Yashin, A. I., Wu, D., Arbeev, K. G., & Ukraintseva, S. V. (2010) · Aging · doi:10.18632/aging.100191 · Cited by 81 · see citing works
“An important conclusion emerged from many such studies was that the complex traits are typically affected by a large number of common alleles, each of little predictive value, with small or statistically non-significant effect [1-5].”
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Zhang, G., & Nebert, D. W. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.036 · Cited by 78 · see citing works
“Moreover, an increasing number of studies have described epigenetic effects (Slatkin, 2009), parent-of-origin genetic contributions (Connolly & Heron, 2015), and inheritance of DNA-methylation patterns (Haque, Nilsson, Holder, & Skinner, 2016).”
BackgroundBonhomme, M., Fariello, M. I., Navier, H., Hajri, A., Badis, Y., Miteul, H., Samac, D. A., Dumas, B., Baranger, A., Jacquet, C., et al. (2019) · Heredity · doi:10.1038/s41437-019-0235-x · Cited by 76 · see citing works
New findings in the genetics of major psychoses
Nöthen, M. M., Nieratschker, V., Cichon, S., & Rietschel, M. (2010) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2010.12.1/mnoethen · Cited by 75 · see citing works
GENETIC VARIATION AND THE EVOLUTION OF EPIGENETIC REGULATION
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Molecular quantitative genetics
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“Of course, it will be some time before theoretical population and quantitative genetics will be able to get a handle on the cumulative and interactive effects of the non-standard systems of inheritance, although work in that direction has already started (Johannes et al. 2008; Slatkin 2009).”
BackgroundAncestral paternal genotype controls body weight and food intake for multiple generations
Yazbek, S. N., Spiezio, S. H., Nadeau, J. H., & Buchner, D. A. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq332 · Cited by 72 · see citing works
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“Notably though, theoretical modelling suggests that although epigenetic inheritance could explain missing causality of complex traits, it is specifically the metastability of epigenetic marks that will decrease their contribution to recurrence risk and hence the problem of missing heritability [108].”
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“In addition, the factors of primary interest in genetic counseling (ie, those that increase individual recurrence risk substantially) do not necessarily have much effect on average risk, the primary focus of most retrospective studies of schizophrenia, and vice versa.(230) Partial risk prediction as afforded by proven…”
BackgroundDNA methylation signatures in panic disorder
Iurato, S., Carrillo-Roa, T., Arloth, J., Czamara, D., Diener-Hölzl, L., Lange, J., Müller-Myhsok, B., Binder, E. B., & Erhardt, A. (2017) · Translational Psychiatry · doi:10.1038/s41398-017-0026-1 · Cited by 70 · see citing works
“Adverse life events have been shown to associate with speci fi c epigenetic modi fi cations, such as DNA methylation, which may mediate the lasting cellular consequences of these exposures in psychiatric disorders 14 , also in the context of gene – environment interactions 15 .”
BackgroundPast, present, and future of epigenetics applied to livestock breeding
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“Some authors have proposed models to estimate the amount of epigenetic variance that is inherited in populations (Slatkin, 2009; Varona et al., 2015).”
BackgroundMechanisms of Non-Genetic Inheritance and Psychiatric Disorders
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Uncovering the contribution of epigenetics to plant phenotypic variation in Mediterranean ecosystems
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Quantitative Epigenetics Through Epigenomic Perturbation of Isogenic Lines
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“In both cases, the cross was initiated from a wild-type (wt) plant and a plant carrying a single loss-of-function mutation in ddm1 ( Johannes et al. 2009) or met1 (Reinders et al. 2009), two genes involved in DNA methylation control.”
BackgroundInvasion genetics: Lessons from a ubiquitous bird, the house sparrow Passer domesticus
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“Epigenetically mediated phenotypes are both heritable (Slatkin, 2009) and influenced de novo by environments.”
BackgroundThe future of genomics for developmentalists
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Epigenetic Mechanisms and Microbiota as a Toolbox for Plant Phenotypic Adjustment to Environment
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Quantitative Epigenetics: A New Avenue for Crop Improvement
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“Epigenetic modifications could be one of the major causes of missing heritability [36].”
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Epigenetics: a new frontier in dentistry
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Adjusting to Global Change through Clonal Growth and Epigenetic Variation
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“Stochastic epimutations can be beneficial, or deleterious, and provided that they are stable across enough generations, can be acted upon in similar ways as genetic mutations (Slatkin, 2009).”
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Predicting chemical impacts on vertebrate endocrine systems
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Transgenerational Genetic Effects
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- 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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