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Cited by 745Genetic Associations and EpidemiologyGenetic and phenotypic traits in livestockGenetics and Physical Performance

Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index

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The LifeLines Cohort Study, Yang, Jian, Bakshi, Andrew, Zhu, Zhihong, Hemani, Gibran, Vinkhuyzen, Anna A E, Lee, Sang Hong, Robinson, Matthew R +17 more·2015·Nature Genetics
DOI 10.1038/ng.3390PMC PMC4589513
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Abstract

We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

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  • The genetics of obesity are not sufficient to account for the variability of BMI.

    “However, the genetics of obesity are not sufficient to account for the variability of BMI [20,21].”

    From Advantages and Limitations of the Body Mass Index (BMI) to Assess Adult Obesity (2024) · cites this paper as [21]

  • The relationship between BMI and percent body fat is highly variable by race, ethnicity, sex, and age, and these factors may interact.

    “Apart from genetic factors, the relationship between BMI and percent body fat is highly variable by race, ethnicity, sex, and age (acknowledging that these simple constructs may mask more complex social elements), and these factors may interact [21].”

    From Advantages and Limitations of the Body Mass Index (BMI) to Assess Adult Obesity (2024) · cites this paper as [21]

    The Online Methods describe adjusting BMI for age and standardizing it within sex groups, but do not examine percent body fat. Searches for the BMI–percent-body-fat relationship and for variation by race, ethnicity, sex, age, or their interactions found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.75)

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Research works printed but not linked: 28

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Cited by

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Authors
Study, T. L. C., Yang, J., Bakshi, A., Zhu, Z., Hemani, G., Vinkhuyzen, A. A. E., Lee, S. H., Robinson, M. R., Perry, J. R. B., Nolte, I. M., van Vliet-Ostaptchouk, J. V., Snieder, H., Esko, T., Milani, L., Mägi, R., Metspalu, A., Hamsten, A., Magnusson, P. K. E., Pedersen, N. L., Ingelsson, E., Soranzo, N., Keller, M. C., Wray, N. R., Goddard, M. E., & Visscher, P. M.
Affiliations
  • The University of Queensland (AU)
  • University Medical Center Groningen (NL)
  • Broad Institute (US)
  • University of Tartu (EE)
  • Karolinska Institutet (SE)
  • Uppsala University (SE)
  • University of Colorado Boulder (US)
Corresponding author
Yang, Jian
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2015-08-31
Volume
47
Issue
10
Pages
1114-1120
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3390
PMC
PMC4589513
OpenAlex
W2188707104
Cited by
745
References
9
Citations by year
2026: 36 · 2025: 42 · 2024: 46 · 2023: 54 · 2022: 90 · 2021: 71 · 2020: 84 · 2019: 96 · 2018: 94 · 2017: 77 · 2016: 47 · 2015: 7
FWCI
46.53
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • EPubDev Repository (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • Wellcome Trust (102215)
  • Medical Research Council (MC_PC_15018, MC_UU_12015/2)
  • National Institute of Mental Health (R01MH100141)
  • National Institute of General Medical Sciences (P01GM099568)
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 › Genetics and Physical Performance
Keywords
missing heritability, heritability estimation, human height, body mass index, genetic variants, imputation, rare variants, natural selection, complex traits, whole genome sequencing, 1000 Genomes Project
MeSH terms
Body Height, Humans, Genetic Variation, Genome, Human, Body Mass Index

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