Abstract

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

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Data deposits

Data included in this manuscript have been deposited at dbGaP under accession number phs000298.v1.p1 and is available for download at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id5phs000298.v1.p1.

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Acknowledgements

This work was directly supported by NIH grants R01MH089208 (M.J.D.), R01 MH089025 (J.D.B.), R01 MH089004 (G.D.S.), R01MH089175 (R.A.G.) and R01 MH089482 (J.S.S.), and supported in part by NIH grants P50 HD055751 (E.H.C.), RO1 MH057881 (B.D.) and R01 MH061009 (J.S.S.). Y.K., G.C. and S.Y. are Seaver Fellows, supported by the Seaver Foundation. We thank T. Lehner, A. Felsenfeld and P. Bender for their support and contribution to the project. We thank S. Sanders and M. State for discussions on the interpretation of de novo events. We thank D. Reich for comments on the abstract and message of the manuscript. We thank E. Lander and D. Altshuler for comments on the manuscript. We acknowledge the assistance of M. Potter, A. McGrew and G. Crockett without whom these studies would not be possible, and Center for Human Genetics Research resources: Computational Genomics Core, Genetic Studies Ascertainment Core and DNA Resources core, supported in part by NIH NCRR grant UL1 RR024975, and the Vanderbilt Kennedy Center for Research on Human Development (P30 HD015052). This work was supported in part by R01MH084676 (S.S.). We acknowledge the clinicians and organizations that contributed to samples used in this study and the particular support of the Mount Sinai School of Medicine, University of Illinois-Chicago, Vanderbilt University, the Autism Genetics Resource Exchange and the institutions of the Boston Autism Consortium. We acknowledge A. Estes and G. Dawson for patient collection/characterization. We acknowledge partial support from U54 HG003273 (R.A.G.) and U54 HG003067 (E. Lander). J.D.B., B.D., M.J.D., R.A.G., A.S., G.D.S. and J.S.S. are lead investigators in the Autism Sequencing Consortium (ASC). The ASC is comprised of groups sharing massively parallel sequencing data in autism. Finally, we are grateful to the many families, without whose participation this project would not have been possible.

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Affiliations

  1. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA

    • Benjamin M. Neale
    • , Kaitlin E. Samocha
    • , Elaine Lim
    • , Elizabeth Rossin
    • , Andrew Kirby
    • , Menachem Fromer
    •  & Mark J. Daly
  2. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Benjamin M. Neale
    • , Kaitlin E. Samocha
    • , Christine Stevens
    • , Paz Polak
    • , Jared Maguire
    • , Benjamin F. Voight
    • , Elaine Lim
    • , Elizabeth Rossin
    • , Andrew Kirby
    • , Jason Flannick
    • , Menachem Fromer
    • , Khalid Shakir
    • , Tim Fennell
    • , Kiran Garimella
    • , Eric Banks
    • , Ryan Poplin
    • , Stacey Gabriel
    • , Mark DePristo
    • , Shamil Sunyaev
    •  & Mark J. Daly
  3. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Yan Kou
    • , Avi Ma’ayan
    •  & Ruth Dannenfelser
  4. Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Yan Kou
    • , Vladimir Makarov
    • , Seungtai Yoon
    • , Guiqing Cai
    • , Jayon Lihm
    •  & Joseph D. Buxbaum
  5. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15232, USA

    • Li Liu
    • , Chad Schafer
    •  & Kathryn Roeder
  6. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA

    • Aniko Sabo
    • , Uma Nagaswamy
    • , Donna Muzny
    • , Jeffrey G. Reid
    • , Irene Newsham
    • , Yuanqing Wu
    • , Lora Lewis
    • , Yi Han
    • , Eric Boerwinkle
    •  & Richard A. Gibbs
  7. Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Chiao-Feng Lin
    • , Li-San Wang
    • , Evan T. Geller
    • , Otto Valladares
    •  & Gerard D. Schellenberg
  8. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Vladimir Makarov
    • , Seungtai Yoon
    • , Guiqing Cai
    • , Jayon Lihm
    •  & Joseph D. Buxbaum
  9. Division of Genetics, Department of Medicine Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Paz Polak
    •  & Shamil Sunyaev
  10. Vanderbilt Brain Institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University, Nashville, Tennessee 37232, USA

    • Emily L. Crawford
    • , Nicholas G. Campbell
    •  & James S. Sutcliffe
  11. Biostatistics Department and Computer Science Department, Johns Hopkins University, Baltimore, Maryland 21205, USA

    • Han Liu
    •  & Tuo Zhao
  12. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Omar Jabado
    • , Zuleyma Peralta
    •  & Joseph D. Buxbaum
  13. Department of Pharmacology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA

    • Benjamin F. Voight
  14. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA

    • Jack R. Wimbish
    • , Braden E. Boone
    •  & Shawn E. Levy
  15. INSERM U952 and CNRS UMR 7224 and UPMC Univ Paris 06, 75005 Paris, France

    • Catalina Betancur
  16. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA

    • Eric Boerwinkle
  17. Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Joseph D. Buxbaum
  18. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60608, USA

    • Edwin H. Cook Jr
  19. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • Bernie Devlin

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Contributions

Laboratory work: A.S., C.St., G.C., O.J., Z.P., J.D.B., D.M., I.N., Y.W., L.L., Y.H., S.G., E.L.C., N.G.C. and E.T.G. Data processing: B.M.N., K.E.S., E.L., A.K., J.F., M.F., K.S., T.F., K.G., E.Ba., R.P., M.DeP., S.G., S.Y., V.M., J.L., J.D.B., A.S., C.St., U.N., J.G.R., J.R.W., B.E.B., S.E.L., C.F.L., L.S.W. and O.V. Statistical analysis: B.M.N., L.L., K.E.S., C.Sh., B.F.V., J.M., E.R., S.S., P.P., Y.K., A.M., R.D., C.-F.L., L.-S.W., H.L., T.Z., E.Bo., R.A.G., J.D.B., C.B., E.H.C., J.S.S., G.D.S., B.D., K.R. and M.J.D. Principal Investigators/study design: E.Bo., R.A.G., E.H.C., J.D.B., K.R., B.D., G.D.S., J.S.S. and M.J.D. Y.K., L.L., A.M., K.E.S., A.S. and C.-F.L. contributed equally to this work. E.Bo., J.D.B., E.H.C., B.D., R.A.G., K.R., G.D.S., J.S.S. and M.J.D. are lead investigators of the ARRA Autism Sequencing Collaboration.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joseph D. Buxbaum or Kathryn Roeder or Mark J. Daly.

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https://doi.org/10.1038/nature11011

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