Abstract

Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.

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Acknowledgements

We thank R. Walters for discussions. A.G. is supported by the Knut and Alice Wallenberg Foundation (2015.0327) and the Swedish Research Council (2016-00250). M.G.N. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635) to Dorret I. Boomsma. V.S. was supported by the Finnish Foundation for Cardiovascular Research. This study was supported by grants from the National Human Genome Research Institute (U54 HG003067 and R01 HG006855); the National Institute of Mental Health (1U01MH105666-01 and 1R01MH101244-02); the National Institute of Diabetes and Digestive and Kidney Disease (1U54DK105566-02); the Stanley Center for Psychiatric Research; the Alexander and Margaret Stewart Trust; the National Institutes of Mental Health (R01 MH077139 and RC2 MH089905); the Sylvan C. Herman Foundation; EU H2020 grants 692145, 676550 and 654248; Estonian Research Council Grant IUT20-60, NIASC, EIT–Health; NIH-BMI Grant No. 2R01DK075787-06A1; and by the EU through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 GENTRANSMED).

Author information

Author notes

    • Andrea Ganna
    •  & Giulio Genovese

    These authors contributed equally to this work.

Affiliations

  1. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Andrea Ganna
    • , Daniel P Howrigan
    • , Andrea Byrnes
    • , Mitja I Kurki
    • , Alex Bloemendal
    • , Jonathan M Bloom
    • , Jacqueline I Goldstein
    • , Timothy Poterba
    • , Cotton Seed
    • , Elise B Robinson
    • , Mark J Daly
    • , Aarno Palotie
    •  & Benjamin M Neale
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Andrea Ganna
    • , Giulio Genovese
    • , Daniel P Howrigan
    • , Andrea Byrnes
    • , Mitja I Kurki
    • , Seyedeh M Zekavat
    • , Christopher W Whelan
    • , Alex Bloemendal
    • , Jonathan M Bloom
    • , Jacqueline I Goldstein
    • , Timothy Poterba
    • , Cotton Seed
    • , Robert E Handsaker
    • , Pradeep Natarajan
    • , Elise B Robinson
    • , Sekar Kathiresan
    • , Mark J Daly
    • , Steven A McCarroll
    • , Tõnu Esko
    •  & Benjamin M Neale
  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Andrea Ganna
    • , Giulio Genovese
    • , Daniel P Howrigan
    • , Andrea Byrnes
    • , Mitja I Kurki
    • , Christopher W Whelan
    • , Alex Bloemendal
    • , Jonathan M Bloom
    • , Jacqueline I Goldstein
    • , Timothy Poterba
    • , Cotton Seed
    • , Robert E Handsaker
    • , Diane Gage
    • , Elise B Robinson
    • , Mark J Daly
    • , Steven A McCarroll
    • , Aarno Palotie
    •  & Benjamin M Neale
  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Andrea Ganna
    • , Patrick F Sullivan
    •  & Christina M Hultman
  5. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Giulio Genovese
    • , Christopher W Whelan
    • , Robert E Handsaker
    •  & Steven A McCarroll
  6. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.

    • Mitja I Kurki
    •  & Aarno Palotie
  7. Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Seyedeh M Zekavat
    • , Pradeep Natarajan
    •  & Sekar Kathiresan
  8. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Mart Kals
    • , Reedik Mägi
    • , Andres Metspalu
    •  & Tõnu Esko
  9. Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia.

    • Mart Kals
  10. Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.

    • Michel G Nivard
  11. Department of Health, THL-National Institute for Health and Welfare, Helsinki, Finland.

    • Veikko Salomaa
    •  & Jaana Suvisaari
  12. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Shaun M Purcell
    •  & Pamela Sklar
  13. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Shaun M Purcell
    •  & Pamela Sklar
  14. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Patrick F Sullivan

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Contributions

A.G. and G.G. designed the study, performed the analysis and wrote the manuscript. B.M.N. supervised the project. D.H., A. Byrnes, M.I.K., S.M.Z., C.W.W., M.K., M.G.N., P.N. and R.M. performed the analyses. A. Bloemendal, J.M.B., J.I.G., T.P., C.S. and R.E.H. developed and provided computational tools. D.G. provide data management support. E.B.R., A.M., V.S., J.S., S.M.P., P.S., S.K., M.J.D., S.A.M., P.F.S., A.P., T.E. and C.M.H. collected and provided the data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andrea Ganna.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Educational attainment coding for each study

  2. 2.

    Supplementary Table 2

    Distribution of YOE by study, year of birth and sex

  3. 3.

    Supplementary Table 3

    Number and distribution of URVs by study

  4. 4.

    Supplementary Table 4

    Large pathogenic CNVs included in the study and number of carriers

About this article

Publication history

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DOI

https://doi.org/10.1038/nn.4404

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