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Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Nature Neuroscience volume 20, pages 602611 (2017) | Download Citation

Abstract

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10−4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

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Acknowledgements

We thank the families for their participation in the study, The Centre for Applied Genomics and Google for their analytical and technical support, and staff at Autism Speaks for organizational and fundraising support. This work was funded by Autism Speaks, Autism Speaks Canada, the Canadian Institute for Advanced Research, the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics Institute, the Government of Ontario, the Canadian Institutes of Health Research (CIHR), NeuroDevNet, Ontario Brain Institute, the Catherine and Maxwell Meighen Foundation and The Hospital for Sick Children Foundation. Special thanks to B. and (the late) S. Wright for their vision in helping to conceptualize and develop this project and to foundational philanthropic supporters C. Dolan, G. Gund, B. Marcus, V. and J. Morgan and S. Wise. R.K.C.Y. is funded by the CIHR Postdoctoral Fellowship, NARSAD Young Investigator award and Thrasher Early Career Award. R.W. is funded by the Ontario Brain Institute and NeuroDevNet. M.U. is funded by the Banting Postdoctoral Fellowship. M.W. is funded by a CIHR (Institute of Genetics) Clinical Investigatorship Award. L.Z. is funded by the Stollery Children's Hospital Foundation Chair in Autism Research. P.S. is funded by the Patsy and Jamie Anderson Chair in Child and Youth Mental Health. B.M.K. is funded by the Canada Research Chair in Law and Medicine. S.W.S. is funded by the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children.

Author information

Affiliations

  1. The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

    • Ryan K C Yuen
    • , Daniele Merico
    • , Jennifer L Howe
    • , Bhooma Thiruvahindrapuram
    • , Rohan V Patel
    • , Joe Whitney
    • , Zhuozhi Wang
    • , Giovanna Pellecchia
    • , Janet A Buchanan
    • , Susan Walker
    • , Christian R Marshall
    • , Mohammed Uddin
    • , Mehdi Zarrei
    • , Eric Deneault
    • , Lia D'Abate
    • , Ada J S Chan
    • , Stephanie Koyanagi
    • , Tara Paton
    • , Sergio L Pereira
    • , Ny Hoang
    • , Worrawat Engchuan
    • , Edward J Higginbotham
    • , Karen Ho
    • , Sylvia Lamoureux
    • , Weili Li
    • , Jeffrey R MacDonald
    • , Thomas Nalpathamkalam
    • , Wilson W L Sung
    • , Fiona J Tsoi
    • , John Wei
    • , Lizhen Xu
    • , Irene Drmic
    • , Sanne Jilderda
    • , Bonnie MacKinnon Modi
    • , Barbara Kellam
    • , Michael Szego
    • , Marc Woodbury-Smith
    • , Lisa J Strug
    •  & Stephen W Scherer
  2. Deep Genomics Inc., Toronto, Canada.

    • Daniele Merico
    •  & Brendan J Frey
  3. Google, Mountain View, California, USA.

    • Matt Bookman
    • , Nicole Deflaux
    • , Jonathan Bingham
    •  & David Glazer
  4. Verily Life Sciences, South San Francisco, California, USA.

    • Matt Bookman
    • , Nicole Deflaux
    • , Jonathan Bingham
    •  & David Glazer
  5. Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.

    • Christian R Marshall
  6. Department of Molecular Genetics, University of Toronto, Toronto, Canada.

    • Lia D'Abate
    • , Ada J S Chan
    • , Cheryl Cytrynbaum
    • , Rosanna Weksberg
    •  & Stephen W Scherer
  7. Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.

    • Ny Hoang
    • , Wendy Roberts
    • , Irene Drmic
    • , Sanne Jilderda
    •  & Bonnie MacKinnon Modi
  8. Public Population Project in Genomics and Society, McGill University, Montreal, Canada.

    • Anne-Marie Tasse
    •  & Emily Kirby
  9. BioTeam Inc., Middleton, Massachusetts, USA.

    • William Van Etten
    •  & Simon Twigger
  10. Dalla Lana School of Public Health and the Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Michael Szego
    •  & Cheryl Cytrynbaum
  11. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

    • Cheryl Cytrynbaum
    •  & Rosanna Weksberg
  12. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.

    • Cheryl Cytrynbaum
    • , Rosanna Weksberg
    •  & Melissa T Carter
  13. Department of Pediatrics, University of Alberta, Edmonton, Canada.

    • Lonnie Zwaigenbaum
  14. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada.

    • Marc Woodbury-Smith
    • , Ann Thompson
    •  & Christina Chrysler
  15. Bloorview Research Institute, University of Toronto, Toronto, Canada. .

    • Jessica Brian
    • , Lili Senman
    • , Alana Iaboni
    • , Krissy Doyle-Thomas
    • , Jonathan Leef
    •  & Evdokia Anagnostou
  16. Department of Psychiatry, McGill University, Montreal, Canada.

    • Tal Savion-Lemieux
    •  & Mayada Elsabbagh
  17. Departments of Pediatrics and of Psychology & Neuroscience, Dalhousie University and Autism Research Centre, IWK Health Centre, Halifax, Canada.

    • Isabel M Smith
  18. Department of Psychiatry, Queen's University, Kinston, Canada.

    • Xudong Liu
  19. Children's Health Research Institute, London, Ontario, Canada.

    • Rob Nicolson
  20. Western University, London, Ontario, Canada.

    • Rob Nicolson
  21. Autism Speaks, New York, New York, USA.

    • Vicki Seifer
    • , Angie Fedele
    •  & Mathew T Pletcher
  22. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.

    • Edwin H Cook
  23. Department of Radiology, University of Washington, Seattle, Washington, USA.

    • Stephen Dager
  24. Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington, USA.

    • Annette Estes
  25. Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.

    • Louise Gallagher
  26. Sleep Disorders Division, Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Beth A Malow
  27. Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK.

    • Jeremy R Parr
  28. Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Sarah J Spence
  29. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Jacob Vorstman
  30. Department of Electrical and Computer Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada.

    • Brendan J Frey
  31. Department of Medicine, University of California San Diego, La Jolla, California, USA.

    • James T Robinson
  32. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Canada.

    • Lisa J Strug
  33. Disciplines of Genetics and Medicine, Memorial University of Newfoundland and Provincial Medical Genetic Program, Eastern Health, St. John's, Canada.

    • Bridget A Fernandez
  34. Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Canada.

    • Melissa T Carter
  35. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.

    • Joachim Hallmayer
  36. Centre of Genomics and Policy, McGill University, Montreal, Canada.

    • Bartha M Knoppers
  37. Child Youth and Family Services, Centre for Addiction and Mental Health, Toronto, Canada.

    • Peter Szatmari
  38. Department of Psychiatry, University of Toronto, Toronto, Canada.

    • Peter Szatmari
  39. Department of Psychiatry, The Hospital for Sick Children, Toronto, Canada.

    • Peter Szatmari
  40. Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.

    • Robert H Ring
  41. McLaughlin Centre, University of Toronto, Toronto, Canada.

    • Stephen W Scherer

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Contributions

R.K.C.Y. and S.W.S. conceived and designed the experiments. R.K.C.Y., D.M., M.B., B.T., R.V.P., J. Whitney, N.D., J. Bingham, Z.W., S.W. and G.P. processed and analyzed the whole genome sequencing data. S.W., L.D., A.J.S.C., S.K., T.P., E.J.H. and S.L. designed and performed experiments for variant characterization and validation. J.A.B., C.R.M., M.U., M.Z., E.D., S.L.P., W.E., K.H., W.L., J.R.M., T.N., W.W.L.S., F.J.T., J. Wei, L.X., W.V.E., S.T., B.J.F., J.T.R. and L.J.S. helped perform different components of analysis and validation experiments. R.K.C.Y., M.B., J.L.H., R.H.R., D.G., M.T.P. and S.W.S. coordinated the whole genome sequencing experiments. R.K.C.Y., R.H.R., D.G., M.T.P. and S.W.S. conceived and coordinated the project. N.H., A.-M.T., E.K., W.R., I.D., S.J., B.M.M., B.K., M.S., C. Cytrynbaum, R.W., L.Z., M.W.-S., J. Brian, L.S., A.I., K.D.-T., A.T., C. Chrysler, J.L., T.S.-L., I.M.S., X.L., R.N., V.S., A.F., E.H.C., S.D., A.E., L.G., B.A.M., J.R.P., S.J.S., J.V., B.A.F., M.E., M.T.C., J.H., B.M.K., E.A. and P.S. managed, recruited, diagnosed and examined the recruited participants. R.K.C.Y. and S.W.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephen W Scherer.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary note

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Quality of WGS.

  2. 2.

    Supplementary Table 2

    Number of de novo SNVs and indels.

  3. 3.

    Supplementary Table 3

    All de novo variants detected.

  4. 4.

    Supplementary Table 4

    All de novo LOF variants detected.

  5. 5.

    Supplementary Table 5

    All damaging variants in ASD-risk genes.

  6. 6.

    Supplementary Table 6

    Genes associated with syndromic or related disorders and their potential drug targets

  7. 7.

    Supplementary Table 7

    Summary of all samples included in MSSNG DB4.

  8. 8.

    Supplementary Table 8

    Pathogenic CNVs detected.

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DOI

https://doi.org/10.1038/nn.4524

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