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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References

  1. 1.

    et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

  2. 2.

    et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

  3. 3.

    et al. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans. PLoS Genet. 9, e1003355 (2013).

  4. 4.

    , , & Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).

  5. 5.

    et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

  6. 6.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

  7. 7.

    et al. Parent-of-origin–specific allelic associations among 106 genomic loci for age at menarche. Nature 514, 92–97 (2014).

  8. 8.

    et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

  9. 9.

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  10. 10.

    1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  11. 11.

    , , & GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

  12. 12.

    et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).

  13. 13.

    UK10K Consortium. The UK10K project: rare variants in health and disease. Nature (in the press).

  14. 14.

    et al. Estimation of SNP heritability from dense genotype data. Am. J. Hum. Genet. 93, 1151–1155 (2013).

  15. 15.

    et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014).

  16. 16.

    , , & Improved heritability estimation from genome-wide SNPs. Am. J. Hum. Genet. 91, 1011–1021 (2012).

  17. 17.

    et al. Quantifying missing heritability at known GWAS loci. PLoS Genet. 9, e1003993 (2013).

  18. 18.

    , , & Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. Mol. Psychiatry 17, 474–485 (2012).

  19. 19.

    Evolution in health and medicine Sackler colloquium: genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc. Natl. Acad. Sci. USA 107, 1752–1756 (2010).

  20. 20.

    , , & The deleterious mutation load is insensitive to recent population history. Nat. Genet. 46, 220–224 (2014).

  21. 21.

    , & Selection and explosive growth may hamper the performance of rare variant association tests. bioRxiv doi: (2015).

  22. 22.

    et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  23. 23.

    , , , & Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism–derived genomic relationships and restricted maximum likelihood. Bioinformatics 28, 2540–2542 (2012).

  24. 24.

    et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247–250 (2012).

  25. 25.

    & Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat. Rev. Genet. 13, 36–46 (2012).

  26. 26.

    , , , & Sequencing depth and coverage: key considerations in genomic analyses. Nat. Rev. Genet. 15, 121–132 (2014).

  27. 27.

    & Genetics and Analysis of Quantitative Traits (Sinauer Associates, 1998).

  28. 28.

    , & From Galton to GWAS: quantitative genetics of human height. Genet. Res. (Camb.) 92, 371–379 (2010).

  29. 29.

    et al. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLoS Genet. 9, e1003520 (2013).

  30. 30.

    et al. Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs. Am. J. Hum. Genet. 93, 865–875 (2013).

  31. 31.

    et al. Leveraging population admixture to characterize the heritability of complex traits. Nat. Genet. 46, 1356–1362 (2014).

  32. 32.

    et al. Whole-genome sequence–based analysis of high-density lipoprotein cholesterol. Nat. Genet. 45, 899–901 (2013).

  33. 33.

    et al. Genotype-imputation accuracy across worldwide human populations. Am. J. Hum. Genet. 84, 235–250 (2009).

  34. 34.

    , , , & Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

  35. 35.

    et al. Extremely low-coverage sequencing and imputation increases power for genome-wide association studies. Nat. Genet. 44, 631–635 (2012).

  36. 36.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  37. 37.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  38. 38.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  39. 39.

    & Recovery of inter-block information when block sizes are unequal. Biometrika 58, 545–554 (1971).

Download references

Acknowledgements

This research was supported by the Australian National Health and Medical Research Council (grants 1052684, 1078037 and 1050218), the Australian Research Council (grant 130102666), the US National Institutes of Health (R01MH100141), the Sylvia and Charles Viertel Charitable Foundation and the University of Queensland Foundation. This study makes use of data from the database of Genotypes and Phenotypes (dbGaP) available under accessions phs000090, phs000091 and phs000428 and the EGCUT, LifeLines, TwinGene and UK10K studies (see the Supplementary Note for the full set of acknowledgments for these data).

Author information

Author notes

    • Jian Yang
    •  & Peter M Visscher

    These authors jointly supervised this work.

Affiliations

  1. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.

    • Jian Yang
    • , Andrew Bakshi
    • , Zhihong Zhu
    • , Gibran Hemani
    • , Anna A E Vinkhuyzen
    • , Sang Hong Lee
    • , Matthew R Robinson
    • , Naomi R Wray
    •  & Peter M Visscher
  2. University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia.

    • Jian Yang
    •  & Peter M Visscher
  3. Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, Bristol, UK.

    • Gibran Hemani
  4. School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.

    • Sang Hong Lee
  5. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.

    • John R B Perry
  6. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Ilja M Nolte
    • , Jana V van Vliet-Ostaptchouk
    •  & Harold Snieder
  7. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Jana V van Vliet-Ostaptchouk
  8. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tonu Esko
    • , Lili Milani
    • , Reedik Mägi
    •  & Andres Metspalu
  9. Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.

    • Tonu Esko
  10. Program in Medical and Populational Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Tonu Esko
  11. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Tonu Esko
  12. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Andres Metspalu
  13. Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Anders Hamsten
  14. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Patrik K E Magnusson
    •  & Nancy L Pedersen
  15. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
  16. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Erik Ingelsson
  17. Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.

    • Nicole Soranzo
  18. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Nicole Soranzo
  19. Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.

    • Matthew C Keller
  20. Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.

    • Matthew C Keller
  21. Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia.

    • Michael E Goddard
  22. Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia.

    • Michael E Goddard

Consortia

  1. The LifeLines Cohort Study

    A full list of members and affiliations appears in the Supplementary Note.

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  4. Search for Gibran Hemani in:

  5. Search for Anna A E Vinkhuyzen in:

  6. Search for Sang Hong Lee in:

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  10. Search for Jana V van Vliet-Ostaptchouk in:

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  18. Search for Nancy L Pedersen in:

  19. Search for Erik Ingelsson in:

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Contributions

J.Y. and P.M.V. conceived and designed the study. J.Y. performed statistical analyses and simulations. M.E.G., J.Y. and P.M.V. derived the theory. A.B., Z.Z. and G.H. performed the imputation analysis. S.H.L., M.R.R., M.C.K. and N.R.W. provided statistical support. A.A.E.V., J.R.B.P., I.M.N., J.V.v.V.-O., H.S., the LifeLines Cohort Study, T.E., L.M., R.M., A.M., A.H., P.K.E.M., N.L.P., E.I. and N.S. contributed to data collection. J.Y. wrote the manuscript with the participation of all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jian Yang.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–19, Supplementary Tables 1–4 and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.3390

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