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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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“Computer Simulation The Inheritance Model of DNA Methylation Both theoretical and empirical studies showed that DNA methylation could be inherited in a way similar to genetic mutation (Richards 2008; Jablonka and Raz 2009; Slatkin 2009; Becker et al. 2011; Schmitz et al. 2011; Cortijo et al. 2014).”
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“ecause only epigenetic states can, potentially, be reset in grandchildren, therefore epigenetic effects would be expected to diminish more in grandparental analyses than expected based on relatedness [147]. Similarly, whole-genome- and exome-sequencing studies of families, which allow for counting new mutations by com…”
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“But, is it more than that? Could epigenetic inheritance be in some cases so stable that it creates essentially permanent changes in a species? Epigenetic inheritance is compatible with Darwinian evolution if epigenetic states that specify traits can remain stable in the germline through generations; in other words epi…”
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“The possibility that epigenetic modifications are responsible for missing heritability was discussed by Slatkin (2009) [134].”
BackgroundVariability among individuals is generated at the gene expression level
Peck, L. S., Thorne, M. A. S., Hoffman, J. I., Morley, S. A., & Clark, M. S. (2015) · Ecology · doi:10.1890/14-0726.1 · Cited by 16
Molecular Approaches for Dissecting and Improving Drought and Heat Tolerance in Rice
Shanmugavadivel, P. S., Prakash, C., & Mithra, S. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-814332-2.00042-3 · Cited by 19
Kim, B.-H., Initiative, A. D. N., Choi, Y.-H., Yang, J., Kim, S., Nho, K. T., & Lee, J. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191175 · Cited by 15
Towards understanding and acting on risk factors for developmental psychopathology
Moreno, C. (2018) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-018-1117-0 · Cited by 15
“Evidence supports the role of both genetic and epigenetic alterations as mediators of the intergenerational transmission of mental disorders [11].”
BackgroundHelanterä, H., & Uller, T. (2020) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2019.0366 · Cited by 14
“This approach is based on the idea that genetic and epigenetic factors contribute in different ways to similarity of relatives [44].”
BackgroundOn Optimal Gene‐Based Analysis of Genome Scans
Bacanu, S. (2012) · Genetic Epidemiology · doi:10.1002/gepi.21625 · Cited by 14
“However, a considerable portion of the predicted genetic contribution to many traits of interest remains unknown [Manolio et al., 2009; Slatkin, 2009].”
BackgroundTransgenerational epigenetic variance for body weight in meat quails
de Paiva, J. T., de Resende, M. D. V., Resende, R. T., de Oliveira, H. R., Silva, H. T., Caetano, G. C., Lopes, P. S., & Silva, F. F. E. (2018) · Journal of Animal Breeding and Genetics · doi:10.1111/jbg.12329 · Cited by 17
BÖRSCH-HAUBOLD, A. G., Montero, I., Konrad, K., & Haubold, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097568 · Cited by 16
“Epigenetic variation underlies part of phenotypic variation [60] and is an important substrate for natural selection in the wild, especially if epigenetic settings respond to environmental change [33–35,37].”
BackgroundLópez-Lambraño, Á. A., Martínez-Acosta, L., Gámez-Balmaceda, E., Medrano-Barboza, J. P., López, J. F. R., & López-Ramos, A. A. (2020) · Agriculture · doi:10.3390/agriculture10080333 · Cited by 14
Gene-culture co-evolution: teaching, learning, and correlations between relatives
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“…of genetic transmission, they can have a variety of effects on familial correlations among quantitative phenotypes and on the likelihood of a discretely defined disease, such as rheumatoid arthritis (Slatkin 2009; Tal et al. 2009; Feinberg & Irizarry 2010; Furrow et al. 2011; Liu et al. 2013).”
BackgroundGenetics in child and adolescent psychiatry: methodological advances and conceptual issues
Hohmann, S., Adamo, N., Lahey, B. B., Faraone, S. V., & Banaschewski, T. (2015) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-015-0702-8 · Cited by 12
“Slatkin [135] proposed that epigenetic changes and mutations will contribute equally to average risk when found in the same population frequency, but the mutation will contribute more to recurrence risk, implying that inherited epigenetic”
BackgroundBacanu, S., Nelson, M. R., & Whittaker, J. C. (2011) · Genetic Epidemiology · doi:10.1002/gepi.20570 · Cited by 13
“However, a considerable portion of the predicted genetic contribution to many traits of interest remains unknown [Manolio et al., 2009; Slatkin, 2009].”
BackgroundIntroduction to the Special Section on Genomics
Grigorenko, E. L., & Dozier, M. (2013) · Child Development · doi:10.1111/cdev.12045 · Cited by 13
“However, as it stands now, initial analytical treatments and simulation studies suggest that epigenetic mechanisms can be considered as causal mechanisms for complex diseases, but not for the problem of missing heritability, unless the acquired epigenetic modifications have been persistent within families for many gen…”
Quick, “Imputation-free” meta-analysis with proxy-SNPs
Meesters, C., Leber, M., Herold, C., Angisch, M., Mattheisen, M., Drichel, D., Lacour, A., & Becker, T. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-231 · Cited by 12
“Bonn, Bonn, Germany Full list of author information is available at the end of the article variants with larger effects, common variants with even smaller effects than observed so far, incomplete coverage of current GWAS marker panels, but also epigenetic effects [5] or interactions between genetic variants [6].”
BackgroundAleyasin, S., Shirkavand, A., & Boroujeni, Z. (2018) · Indian Journal of Cancer · doi:10.4103/ijc.ijc_100_18 · Cited by 12
Nonsyndromic Orofacial Clefts in Chile: LINE-1 Methylation and MTHFR Variants
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Phenotypic, Genetic, and Epigenetic Variation among Diverse Sweet Cherry Gene Pools
Avramidou, E. V., Moysiadis, T., Ganopoulos, I. V., Michailidis, M., Kissoudis, C., Valasiadis, D., Kazantzis, K., Tsaroucha, E., Tsaftaris, A. S., Molassiotis, A. N., et al. (2021) · Agronomy · doi:10.3390/agronomy11040680 · Cited by 12
A Bayesian mixed modeling approach for estimating heritability
Nustad, H. E., Page, C. M., Reiner, A. H., Zucknick, M., & LeBlanc, M. (2018) · BMC Proceedings · doi:10.1186/s12919-018-0131-z · Cited by 12
“patterns are influenced by the environment, change over lifetime, and exhibit mitotic heritability [4].”
BackgroundEpigenetic inheritance mediates phenotypic diversity in natural populationsPreprint
Shahzad, Z., Moore, J. D., Choi, J., Cassin-Ross, G., Rouached, H., & Zilberman, D. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.15.435374 · Cited by 12
“However, these epialleles are either too unstable for the epigenetic states to influence a response to selection 8–10 (such as Cyc 13 , D1 14 and MANTLED 15 ), are confounded by trans genetic variation (such as PAI2 16 and IAA7 12 ), are artificially induced (such as FWA 17 and MANTLED 15 ), or…”
BackgroundEditorial: Advances in Genomics of Crossbred Farm Animals
Wu, X., & Zhao, S. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.709483 · Cited by 12
“Quantitative traits are determined by thousands of genes with small effects, which are often difficult to detect (Manolio et al., 2009; Slatkin, 2009).”
BackgroundYao, S., Guo, Y., Dong, S., Hao, R.-H., Chen, X., Chen, Y., Chen, J., Tian, Q., Deng, H., & Yang, T. (2017) · Human Genetics · doi:10.1007/s00439-017-1825-4 · Cited by 10
“In addition, epigenetic inheritance (Slatkin 2009) was not considered in GWASs, which is another possible cause of missing heritability.”
BackgroundFibrate Pharmacogenomics: Expanding Past the Genome
House, J. S., & Motsinger‐Reif, A. A. (2020) · Pharmacogenomics · doi:10.2217/pgs-2019-0140 · Cited by 12
“Epigenetic evidence of interindividual responses to fibrate For all complex traits, epigenetic programs may account for a significant fraction of ‘missing heritability’ [83].”
Background
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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