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An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Nature Geneticsvolume 50pages727736 (2018) | Download Citation

Abstract

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

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Acknowledgements

We are grateful to the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by grants from the Simons Foundation for Autism Research Initiative (SFARI 385110 to N.S., A.J.W., M.W.S., S.J.S.; 385027 to M.E.T., J.D.B., B.D., M.J.D., X.H., K.R.; 388196 to G.M., H.C., A.R.Q.; and 346042 to M.E.T.), the US National Institutes of Health (R37MH057881 and U01MH111658 to B.D. and K.R.; HD081256 and GM061354 to M.E.T.; U01MH105575 to M.W.S.; U01MH111662 to M.W.S. and S.J.S.; R01MH110928 and U01MH100239-03S1 to M.W.S., S.J.S., A.J.W.; U01MH111661 to J.D.B.; K99DE026824 to H.B.; U01MH100229 to M.J.D.), the Autism Science Foundation to D.M.W., and the March of Dimes to M.E.T. M.E.T. was also supported by the Desmond and Ann Heathwood MGH Research Scholars award. We thank the SSC principal investigators (A. L. Beaudet, R. Bernier, J. Constantino, E. H. Cook Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D. H. Ledbetter, C. Lord, C. L. Martin, D. M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. W. State, W. Stone, J. S. Sutcliffe, C. A. Walsh, and E. Wijsman) and the coordinators and staff at the SSC clinical sites; the SFARI staff, in particular N. Volfovsky; D. B. Goldstein for contributing to the experimental design; the Rutgers University Cell and DNA repository for accessing biomaterials; and the New York Genome Center for generating the WGS data.

Author information

Author notes

  1. These authors contributed equally: Donna M. Werling, Harrison Brand, Joon-Yong An, Matthew R. Stone, Lingxue Zhu.

Affiliations

  1. Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    • Donna M. Werling
    • , Joon-Yong An
    • , Shan Dong
    • , Eirene Markenscoff-Papadimitriou
    • , Grace B. Schwartz
    • , Jeanselle Dea
    • , Clif Duhn
    • , Carolyn A. Erdman
    • , Michael C. Gilson
    • , Jeffrey D. Mandell
    • , Tomasz J. Nowakowski
    • , Louw Smith
    • , Michael F. Walker
    • , John L. Rubenstein
    • , A. Jeremy Willsey
    • , Matthew W. State
    •  & Stephan J. Sanders
  2. Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    • Harrison Brand
    • , Matthew R. Stone
    • , Joseph T. Glessner
    • , Ryan L. Collins
    • , Harold Z. Wang
    • , Benjamin B. Currall
    • , Xuefang Zhao
    • , Rachita Yadav
    •  & Michael E. Talkowski
  3. Department of Neurology, Harvard Medical School, Boston, MA, USA

    • Harrison Brand
    • , Joseph T. Glessner
    • , Ryan L. Collins
    • , Benjamin B. Currall
    • , Xuefang Zhao
    • , Rachita Yadav
    •  & Michael E. Talkowski
  4. Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA

    • Harrison Brand
    • , Joseph T. Glessner
    • , Benjamin B. Currall
    • , Xuefang Zhao
    • , Rachita Yadav
    • , Robert E. Handsaker
    • , Seva Kashin
    • , Steven A. McCarroll
    • , Benjamin M. Neale
    • , Mark J. Daly
    •  & Michael E. Talkowski
  5. Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA

    • Lingxue Zhu
    •  & Kathryn Roeder
  6. Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA

    • Ryan L. Collins
  7. Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Ryan M. Layer
    • , Andrew Farrell
    • , Aaron R. Quinlan
    •  & Gabor T. Marth
  8. USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Ryan M. Layer
    • , Andrew Farrell
    • , Aaron R. Quinlan
    •  & Gabor T. Marth
  9. Department of Genetics, Harvard Medical School, Boston, MA, USA

    • Robert E. Handsaker
    • , Seva Kashin
    •  & Steven A. McCarroll
  10. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    • Lambertus Klei
    •  & Bernie Devlin
  11. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA

    • Tomasz J. Nowakowski
  12. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA

    • Tomasz J. Nowakowski
  13. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    • Yuwen Liu
    •  & Xin He
  14. Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA

    • Sirisha Pochareddy
    •  & Nenad Sestan
  15. Department of Biology, Eastern Nazarene College, Quincy, MA, USA

    • Matthew J. Waterman
  16. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    • Arnold R. Kriegstein
  17. Analytical and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Benjamin M. Neale
    •  & Mark J. Daly
  18. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Benjamin M. Neale
    •  & Mark J. Daly
  19. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Hilary Coon
  20. Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Hilary Coon
    •  & Aaron R. Quinlan
  21. Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    • A. Jeremy Willsey
  22. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
  23. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
  24. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
  25. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
  26. Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA

    • Kathryn Roeder
  27. Departments of Pathology and Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Michael E. Talkowski

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Contributions

Experimental design: D.M.W., H.B., J.-Y.A., M.R.S., J.T.G., M.J.W., X.H., N.S., B.M.N., H.C., A.J.W., J.D.B., M.J.D., M.W.S., A.R.Q., G.T.M., K.R., B.D., M.E.T., and S.J.S. Identification of de novo SNVs and indels: D.M.W., J.-Y.A., S.D., M.C.G., J.D.M., L.S., A.J.W., and S.J.S. Identification of structural variants: H.B., J.-Y.A., M.R.S., J.T.G., R.L.C., R.M.L., A.F., H.Z.W., X.Z., M.C.G., R.E.H., S.K., L.S., S.A.M., A.R.Q., G.T.M., and M.E.T. Confirmation of de novo variants: D.M.W., H.B., S.D., G.B.S., H.Z.W., B.B.C., J.D., C.D., C.A.E., R.Y., M.F.W., and M.J.W. Annotation of functional regions: D.M.W., J.-Y.A., S.D., E.M.-P., J.D.M., Y.L., S.P., J.L.R., N.S., M.E.T., and S.J.S. Generation of midfetal H3K27ac and ATAC–seq data: E.M.-P., T.J.N., A.R.K., and J.L.R. Development of genomic prediction score and de novo score: L.Z., L.K., K.R., and B.D. Analysis of SNVs and indels (Figs. 1–3): D.M.W., J.-Y.A., and S.J.S. Analysis of structural variants (Fig. 4): H.B., M.R.S., J.T.G., X.Z., and M.E.T. Assessment of P-value correlations, effective number of tests, and power analysis (Figs. 3 and 5): D.M.W., J.-Y.A., L.Z., G.B.S., K.R., B.D., and S.J.S. Manuscript preparation: D.M.W., H.B., J.-Y.A., M.R.S., L.Z., J.T.G., R.L.C., S.D., B.M.N., H.C., J.D.B., M.J.D., M.W.S., A.R.Q., G.T.M., K.R., B.D., M.E.T., and S.J.S.

Competing interests

J.L.R. is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation. B.M.N. is an SAB member of Deep Genomics and serves as a consultant for Avanir Therapeutics. All other authors declare no competing interests.

Corresponding authors

Correspondence to Bernie Devlin or Michael E. Talkowski or Stephan J. Sanders.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–13

  4. Supplementary Data

    Visualization plots of de novo structural variants

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DOI

https://doi.org/10.1038/s41588-018-0107-y

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