Abstract

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

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Acknowledgements

We thank S. Hyman, T. Lehner and N. Kanwisher for comments on the manuscript. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council, the Wellcome Trust (grant 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Autism Speaks (7132) provided support for the analysis of autistic trait–related data in ALSPAC (to B.S.P.). This work was also supported by the Medical Research Council Integrative Epidemiology Unit (MC_UU_12013/1-9). This publication is the work of the authors, and E.B.R. and M.J.D. will serve as guarantors for the contents of this paper. The ALSPAC GWAS data were generated by the Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. E.B.R. was funded by National Institute of Mental Health grant 1K01MH099286-01A1 and Brain Behavior Research Foundation (NARSAD) Young Investigator grant 22379. We thank the families who took part in the Simons Simplex Collection study and the clinicians who collected data at each of the study sites. The iPSYCH project is funded by the Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.) and the National Institute of Mental Health (5U01MH094432-02 to M.J.D.). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found on the ExAC website (see URLs). This work was also supported by a grant from the Simons Foundation (SFARI 307705; to S.J.S.).

Author information

Author notes

    • Elise B Robinson
    •  & Beate St Pourcain

    These authors contributed equally to this work.

Affiliations

  1. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Elise B Robinson
    • , Verneri Anttila
    • , Jack A Kosmicki
    • , Brendan Bulik-Sullivan
    • , Julian Maller
    • , Kaitlin E Samocha
    • , Stephan Ripke
    • , Joanna Martin
    • , Jacqueline Goldstein
    • , Daniel Howrigan
    • , Timothy Poterba
    • , Raymond Walters
    • , Benjamin M Neale
    •  & Mark J Daly
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Elise B Robinson
    • , Verneri Anttila
    • , Jack A Kosmicki
    • , Brendan Bulik-Sullivan
    • , Julian Maller
    • , Kaitlin E Samocha
    • , Stephan Ripke
    • , Joanna Martin
    • , Richard Belliveau
    • , Ashley Dumont
    • , Jacqueline Goldstein
    • , Daniel Howrigan
    • , Jennifer Moran
    • , Timothy Poterba
    • , Christine Stevens
    • , Raymond Walters
    • , Benjamin M Neale
    •  & Mark J Daly
  3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Elise B Robinson
    • , Verneri Anttila
    • , Jack A Kosmicki
    • , Brendan Bulik-Sullivan
    • , Julian Maller
    • , Kaitlin E Samocha
    • , Stephan Ripke
    • , Joanna Martin
    • , Jacqueline Goldstein
    • , Daniel Howrigan
    • , Timothy Poterba
    • , Raymond Walters
    • , Benjamin M Neale
    •  & Mark J Daly
  4. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • Beate St Pourcain
    • , David M Evans
    •  & George Davey Smith
  5. Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.

    • Beate St Pourcain
  6. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

    • Jack A Kosmicki
  7. Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Denmark.

    • Jakob Grove
    • , Thomas D Als
    • , Ditte Demontis
    • , Francesco Lescai
    • , Manuel Mattheisen
    • , Preben Bo Mortensen
    •  & Anders D Børglum
  8. Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark.

    • Jakob Grove
    • , Thomas Werge
    • , Thomas D Als
    • , Ditte Demontis
    • , Thomas F Hansen
    • , Francesco Lescai
    • , Manuel Mattheisen
    • , Ole Mors
    • , Merete Nordentoft
    • , Preben Bo Mortensen
    •  & Anders D Børglum
  9. Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.

    • Jakob Grove
    • , Thomas D Als
    • , Ditte Demontis
    • , Francesco Lescai
    • , Manuel Mattheisen
    •  & Anders D Børglum
  10. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.

    • Jakob Grove
  11. Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Kaitlin E Samocha
  12. Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.

    • Stephan J Sanders
  13. Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.

    • Stephan Ripke
  14. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.

    • Mads V Hollegaard
    • , David M Hougaard
    • , Marie Baekvad-Hansen
    • , Jonas Grauholm
    • , Christine S Hansen
    • , Bent Norgaard-Pedersen
    •  & Jesper Poulsen
  15. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.

    • Thomas Werge
    •  & Thomas F Hansen
  16. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

    • Thomas Werge
  17. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

    • Benjamin M Neale
  18. Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.

    • David M Evans
  19. Behavioural Sciences Unit, Institute of Child Health, University College London, London, UK.

    • David Skuse
  20. National Centre for Register-based Research, University of Aarhus, Aarhus, Denmark.

    • Preben Bo Mortensen
  21. Department of Psychological Sciences, Centre for Brain and Cognitive Development, Birkbeck University of London, London, UK.

    • Angelica Ronald
  22. Research Department P, Aarhus University Hospital, Risskov, Denmark.

    • Ole Mors
  23. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.

    • Merete Nordentoft

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  1. iPSYCH-SSI-Broad Autism Group

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Contributions

E.B.R., B.S.P., V.A., J.A.K., B.B.-S., J.G., J. Maller, K.E.S., S.J.S., D.M.E., S.R., J. Martin, M.V.H., T.W., D.M.H., P.B.M. and A.D.B. generated data and/or conducted analyses. E.B.R., B.S.P., B.B.-S., B.M.N., J. Martin, D.S. and M.J.D. designed the experiment and tools. P.B.M., A.D.B., A.R., G.D.S. and M.J.D. supervised the research. E.B.R., B.S.P. and M.J.D. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Elise B Robinson or Mark J Daly.

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DOI

https://doi.org/10.1038/ng.3529

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