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Dominance Genetic Variation Contributes Little to the Missing Heritability for Human Complex Traits
Open accessAbstract
For human complex traits, non-additive genetic variation has been invoked to explain "missing heritability," but its discovery is often neglected in genome-wide association studies. Here we propose a method of using SNP data to partition and estimate the proportion of phenotypic variance attributed to additive and dominance genetic variation at all SNPs (hSNP(2) and δSNP(2)) in unrelated individuals based on an orthogonal model where the estimate of hSNP(2) is independent of that of δSNP(2). With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of δSNP(2) averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average hSNP(2) = 0.15). There were a few traits that showed substantial estimates of δSNP(2), none of which were replicated in a larger sample of 11,965 individuals. We further performed genome-wide association analyses of the 79 quantitative traits and detected SNPs with genome-wide significant dominance effects only at the ABO locus for factor VIII and von Willebrand factor. All these results suggest that dominance variation at common SNPs explains only a small fraction of phenotypic variation for human complex traits and contributes little to the missing narrow-sense heritability problem.
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“While non-linear genetic factors explain little variation in complex traits beyond a purely additive model51,”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [51]
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Metadata
- Authors
- Zhu, Z., Bakshi, A., Vinkhuyzen, A. A. E., Hemani, G., Lee, S. H., Nolte, I. M., van Vliet-Ostaptchouk, J. V., Snieder, H., Esko, T., Milani, L., Mägi, R., Metspalu, A., Hill, W. G., Weir, B. S., Goddard, M. E., Visscher, P. M., & Yang, J.
- Affiliations
- The University of Queensland (AU)
- University Medical Center Groningen (NL)
- University of Tartu (EE)
- University of Edinburgh (GB)
- University of Washington (US)
- The University of Melbourne (AU)
- Corresponding author
- Yang, Jian
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 96
- Issue
- 3
- Pages
- 377-385
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4375616
- OpenAlex
- W2022100988
- Cited by
- 224
- References
- 41
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 18 · 2023: 23 · 2022: 22 · 2021: 22 · 2020: 25 · 2019: 21 · 2018: 24 · 2017: 17 · 2016: 23 · 2015: 9
- FWCI
- 16.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- EPubDev Repository (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- RUNE (Research UNE) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute of Mental Health (MH100141, R01MH100141)
- National Institute of General Medical Sciences (GM 099568, P01GM099568, GM-057091, R01GM075091)
- 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, non-additive genetic effects, additive genetic variance, narrow-sense heritability, quantitative traits, single nucleotide polymorphisms, orthogonal models, ABO blood group system, factor VIII, von Willebrand factor, European Americans
- MeSH terms
- Evaluation Studies as Topic, Female, Humans, Male, Models, Genetic, Phenotype, Cohort Studies, Linear Models, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study
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