Article | Published:

Synaptic, transcriptional and chromatin genes disrupted in autism

Nature volume 515, pages 209215 (13 November 2014) | Download Citation

This article has been updated


The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability–transcription coupling, as well as histone-modifying enzymes and chromatin remodellers—most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

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Change history

  • 12 November 2014

    A minor change was made to the author affiliations.


Data deposits

New data included in this manuscript have been deposited at dbGAP merged with our published data under accession number phs000298.v1.p1 and is available for download at (


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This work was supported by National Institutes of Health (NIH) grants U01MH100233, U01MH100209, U01MH100229 and U01MH100239 to the Autism Sequencing Consortium. Sequencing at Broad Institute was supported by NIH grants R01MH089208 (M.J.D.) and new sequencing by U54 HG003067 (S. Gabriel, E. Lander). Other funding includes NIH R01 MH089482, R37 MH057881 (B.D. and K.R.), R01 MH061009 (J.S.S.), UL1TR000445 (NCAT to VUMC); P50 HD055751 (E.H.C.); MH089482 (J.S.S.), NIH RO1 MH083565 and RC2MH089952 (C.A.W.), NIMH MH095034 (P.S), MH077139 (P.F. Sullivan); 5UL1 RR024975 and P30 HD15052. The DDD Study is funded by HICF-1009-003 and WT098051. UK10K is funded by WT091310. We also acknowledge The National Children’s Research Foundation, Our Lady’s Children’s Hospital, Crumlin; The Meath Foundation; AMNCH, Tallaght; The Health Research Board, Ireland and Autism Speaks, U.S.A. C.A.W. is an Investigator of the Howard Hughes Medical Institute. S.D.R., A.P.G., C.S.P., Y.K. and S.-C.F. are Seaver fellows, supported by the Seaver foundation. A.P.G. is also supported by the Charles and Ann Schlaifer Memorial Fund. P.F.B. is supported by a UK National Institute for Health Research (NIHR) Senior Investigator award and the NIHR Biomedical Research Centre in Mental Health at the South London & Maudsley Hospital. A.C. is supported by María José Jove Foundation and the grant FIS PI13/01136 of the Strategic Action from Health Carlos III Institute (FEDER). This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We acknowledge the assistance of D. Hall and his team at National Database for Autism Research. We thank Jian Feng for providing a list of targets of both RBFOX1 and H3K4me3. We thank M. Potter for data coordination; K. Moore and J. Reichert for technical assistance; and, S. Lindsay for helping with molecular validation. We acknowledge the clinicians and organizations that contributed to samples used in this study. Finally, we are grateful to the many families whose participation made this study possible.

Author information


  1. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Silvia De Rubeis
    • , Arthur P. Goldberg
    • , Christopher S. Poultney
    • , Yan Kou
    • , Shih-Chen Fu
    • , Jessica M. Brownfeld
    • , Jinlu Cai
    • , Alexander Kolevzon
    • , Abraham Reichenberg
    •  & Joseph D. Buxbaum
  2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York 10029, New York, USA.

    • Silvia De Rubeis
    • , Arthur P. Goldberg
    • , Christopher S. Poultney
    • , Yan Kou
    • , Menachem Fromer
    • , Shih-Chen Fu
    • , Jessica M. Brownfeld
    • , Jinlu Cai
    • , Alexander Kolevzon
    • , Shaun Purcell
    • , Abraham Reichenberg
    • , Pamela Sklar
    •  & Joseph D. Buxbaum
  3. Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.

    • Xin He
    • , A. Ercument Cicek
    •  & Kathryn Roeder
  4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Arthur P. Goldberg
    • , Menachem Fromer
    • , Pamela Sklar
    •  & Joseph D. Buxbaum
  5. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Kaitlin Samocha
    • , Menachem Fromer
    • , Jack Kosmicki
    •  & Aarno Palotie
  6. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.

    • Li Liu
    • , Jing Lei
    • , Chad Schafer
    •  & Kathryn Roeder
  7. Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.

    • Susan Walker
    • , Christian R. Marshall
    • , Deepthi Rajagopalan
    • , Kristiina Tammimies
    • , Ryan K. C. Yuen
    •  & Stephen W. Scherer
  8. The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.

    • Tarjinder Singh
    • , Lucy Crooks
    • , Karola Rehnström
    •  & Jeffrey C. Barrett
  9. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

    • Lambertus Klei
    •  & Bernie Devlin
  10. Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.

    • Branko Aleksic
    •  & Norio Ozaki
  11. Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Medical Center Freiburg; Center for Mental Disorders, 79106 Freiburg, Germany.

    • Monica Biscaldi
  12. Department of Child Psychiatry & SGDP Centre, King’s College London Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.

    • Patrick F. Bolton
    •  & Sarah R. Curran
  13. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Nicholas G. Campbell
    • , Emily L. Crawford
    •  & James S. Sutcliffe
  14. Department of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

    • Nicholas G. Campbell
    • , Emily L. Crawford
    •  & James S. Sutcliffe
  15. Genomic Medicine Group, CIBERER, University of Santiago de Compostela and Galician Foundation of Genomic Medicine (SERGAS), 15706 Santiago de Compostela, Spain.

    • Angel Carracedo
  16. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.

    • Angel Carracedo
  17. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Maria H. Chahrour
    • , R. Sean Hill
    • , Timothy W. Yu
    • , Christopher A. Walsh
    •  & Mark J. Daly
  18. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Maria H. Chahrour
    • , R. Sean Hill
    • , Timothy W. Yu
    •  & Christopher A. Walsh
  19. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.

    • Andreas G. Chiocchetti
    • , Eftichia Duketis
    • , Michael Sachse
    •  & Christine M. Freitag
  20. Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132, USA.

    • Hilary Coon
  21. Department of Psychiatry, University of Utah, Salt Lake City, Utah 84108, USA.

    • Hilary Coon
  22. Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27708, USA.

    • Geraldine Dawson
  23. Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s, Newfoundland A1B 3V6, Canada.

    • Bridget A. Fernandez
  24. Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.

    • Louise Gallagher
    •  & Michael Gill
  25. University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Evan Geller
    • , Chiao-Feng Lin
    • , Otto Valladares
    • , Li-San Wang
    •  & Gerard D. Schellenberg
  26. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60608, USA.

    • Stephen J. Guter
    •  & Edwin H. Cook
  27. Department of Biostatistics, Columbia University, New York, New York 10032, USA.

  28. Hospital Nacional de Niños Dr Saenz Herrera, CCSS, Child Developmental and Behavioral Unit, San José, Costa Rica.

    • Patricia Jimenez Gonzalez
  29. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

    • Helena Kilpinen
  30. Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

    • Sabine M. Klauck
  31. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Alexander Kolevzon
  32. Institute of Child Health, University College London, London, WC1N 1EH, UK.

    • Irene Lee
    •  & David Skuse
  33. Department of Clinical Chemistry, Fimlab Laboratories, SF-33100 Tampere, Finland.

    • Terho Lehtimäki
  34. Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Avi Ma’ayan
  35. Department of Psychiatry Kaiser Permanente, San Francisco, California 94118, USA.

    • Alison L. McInnes
  36. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Benjamin Neale
    • , Christine Stevens
    •  & Mark J. Daly
  37. MRC Centre for Neuropsychiatric Genetics and Genomics, and the Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, CF24 4HQ, UK.

    • Michael J. Owen
  38. Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Universidad Complutense, 28040 Madrid, Spain.

    • Mara Parellada
  39. Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

    • Jeremy R. Parr
  40. Department of Child Psychiatry, University of Tampere and Tampere University Hospital, 33521 Tampere, Finland SF-33101.

    • Kaija Puura
  41. Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Abraham Reichenberg
  42. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

    • Aniko Sabo
  43. Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143–0984, USA.

    • Stephan J. Sanders
    • , Lauren A. Weiss
    • , A. Jeremy Willsey
    •  & Matthew W. State
  44. Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Translational Brain Medicine in Psychiatry and Neurology, University Hospital RWTH Aachen / JARA Brain Translational Medicine, 52056 Aachen, Germany.

    • Martin Schulte-Rüther
  45. Department of Child and Adolescent Mental Health, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, WC1N 3JH, UK.

    • David Skuse
  46. Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario L8S 4K1, Canada.

    • Peter Szatmari
  47. Department of Child and Adolescent Psychiatry, Saarland University Hospital, D-66424 Homburg, Germany.

    • Annette Voran
  48. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

    • Christina M. Hultman
  49. National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-9663, USA.

    • Thomas Lehner
  50. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Aarno Palotie
  51. Institute for Molecular Medicine Finland, University of Helsinki, FI-00014 Helsinki, Finland.

    • Aarno Palotie
  52. Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Aarno Palotie
  53. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Pamela Sklar
    •  & Joseph D. Buxbaum
  54. McLaughlin Centre, University of Toronto, Toronto, Ontario M5S 1A1, Canada.

    • Stephen W. Scherer
  55. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Michael E. Zwick
    •  & David J. Cutler
  56. Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Mark J. Daly
  57. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Joseph D. Buxbaum
  58. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Joseph D. Buxbaum
  59. Lists of participants appear in the Supplementary Information.


  1. The DDD Study

  2. Homozygosity Mapping Collaborative for Autism

  3. UK10K Consortium

  4. The Autism Sequencing Consortium


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Lists of participants appear in the Supplementary Information.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Extended data

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