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

Nature Geneticsvolume 50, pages727–736 (2018)Cite this article

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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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Fig. 1: Burden analyses for gene-defined annotation categories.
Fig. 2: Defining annotation categories.
Fig. 3: Category-wide association study.
Fig. 4: Structural variation in 519 ASD families.
Fig. 5: Effective number of tests in CWAS and power calculation.

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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.

Authors and 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

Authors
  1. Donna M. Werling

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  2. Harrison Brand

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  3. Joon-Yong An

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  4. Matthew R. Stone

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  5. Lingxue Zhu

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  6. Joseph T. Glessner

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  7. Ryan L. Collins

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  8. Shan Dong

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  9. Ryan M. Layer

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  10. Eirene Markenscoff-Papadimitriou

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  11. Andrew Farrell

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  12. Grace B. Schwartz

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  13. Harold Z. Wang

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  14. Benjamin B. Currall

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  15. Xuefang Zhao

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  16. Jeanselle Dea

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  17. Clif Duhn

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  18. Carolyn A. Erdman

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  19. Michael C. Gilson

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  20. Rachita Yadav

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  21. Robert E. Handsaker

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  22. Seva Kashin

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  23. Lambertus Klei

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  24. Jeffrey D. Mandell

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  25. Tomasz J. Nowakowski

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  26. Yuwen Liu

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  27. Sirisha Pochareddy

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  28. Louw Smith

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  29. Michael F. Walker

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  30. Matthew J. Waterman

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  31. Xin He

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  32. Arnold R. Kriegstein

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  33. John L. Rubenstein

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  34. Nenad Sestan

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  35. Steven A. McCarroll

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  36. Benjamin M. Neale

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  37. Hilary Coon

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  38. A. Jeremy Willsey

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  39. Joseph D. Buxbaum

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  40. Mark J. Daly

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  41. Matthew W. State

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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 ofP-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.

Corresponding authors

Correspondence toBernie Devlin,Michael E. Talkowski orStephan J. Sanders.

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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.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15 and Supplementary Note

Supplementary Tables

Supplementary Tables 1–13

Supplementary Data

Visualization plots of de novo structural variants

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Werling, D.M., Brand, H., An, JY.et al. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.Nat Genet50, 727–736 (2018). https://doi.org/10.1038/s41588-018-0107-y

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