The mystery of missing heritability: Genetic interactions create phantom heritability
Open accessAbstract
Human genetics has been haunted by the mystery of “missing heritability” of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of ( i ) the heritability due to these variants (numerator), estimated directly from their observed effects, to ( ii ) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator—that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating “phantom heritability.” Specifically, ( i ) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; ( ii ) this assumption is not justified, because models with interactions are also consistent with observable data; and ( iii ) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.
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- Authors
- Zuk, O., Hechter, E., Sunyaev, S. R., & Lander, E. S.
- Affiliations
- Broad Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-01-05
- Volume
- 109
- Issue
- 4
- Pages
- 1193-1198
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3268279
- OpenAlex
- W2110808585
- Cited by
- 1,542
- References
- 56
- Citations by year
- 2026: 31 · 2025: 44 · 2024: 78 · 2023: 59 · 2022: 76 · 2021: 76 · 2020: 100 · 2019: 100 · 2018: 109 · 2017: 126 · 2016: 123 · 2015: 146 · 2014: 156 · 2013: 184 · 2012: 129
- FWCI
- 118.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Human Genome Research Institute (U54HG003067, HG003067)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- missing heritability, genetic interactions, epistasis, heritability estimation, Crohn's disease, isolated populations, polygenic traits
- MeSH terms
- Genetics, Population, Humans, Models, Genetic, Genetic Variation, Genetic Predisposition to Disease, Multifactorial Inheritance, Genetic Diseases, Inborn
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