Dominance Genetic Variation Contributes Little to the Missing Heritability for Human Complex Traits
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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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Non-linear genetic factors explain little variation in complex traits beyond a purely additive model.
“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]
The Discussion (page not supplied) reports that dominance variance averaged about one-fifth of additive variance across 79 quantitative traits. That supports the claim for dominance, but the study did not estimate all non-linear genetic factors, including epistasis, so the broader wording goes beyond its findings. (LLM, conf=0.84)
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Heritability and genetic variance of dementia with Lewy bodies
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On Negative Heritability and Negative Estimates of Heritability
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Canalization and Robustness in Human Genetics and Disease
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Genome-wide scan for commons SNPs affecting bovine leukemia virus infection level in dairy cattle
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rTASSEL: An R interface to TASSEL for analyzing genomic diversity
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Maternal-by-environment but not genotype-by-environment interactions in a fish without parental care
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Human genetic analyses of organelles highlight the nucleus in age-related trait heritability
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Social Science Genetics and FertilityPreprint
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Non-additive QTL mapping of lactation traits in 124,000 cattle reveals novel recessive loci
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Self-citationGene action, genetic variation, and GWAS: A user-friendly web tool
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Capturing additional genetic risk from family history for improved polygenic risk prediction
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A polygenic score method boosted by non-additive models
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Genome-wide estimates of heritability and genetic correlations in essential tremor
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- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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