Synaptic, transcriptional and chromatin genes disrupted in autism (original) (raw)

Accession codes

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 (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000298.v1.p1).

Change history

• 12 November 2014

A minor change was made to the author affiliations.

References

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Acknowledgements

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

Author notes

1. Department of Biostatistics, Columbia University, New York, New York 10032, USA.
2. Lists of participants appear in the Supplementary Information.

Authors and Affiliations

1. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, 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, 15213, Pennsylvania, USA
   Xin He, A. Ercument Cicek & Kathryn Roeder
4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA
   Arthur P. Goldberg, Menachem Fromer, Pamela Sklar & Joseph D. Buxbaum
5. Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
   Kaitlin Samocha, Menachem Fromer, Jack Kosmicki & Aarno Palotie
6. Department of Statistics, Carnegie Mellon University, Pittsburgh, 15213, Pennsylvania, 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, 15213, Pennsylvania, 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. Center for Mental Disorders, 79106 Freiburg, Germany.,
    Monica Biscaldi
13. 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
14. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Nicholas G. Campbell, Emily L. Crawford & James S. Sutcliffe
15. Department of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA
    Nicholas G. Campbell, Emily L. Crawford & James S. Sutcliffe
16. Genomic Medicine Group, CIBERER, University of Santiago de Compostela and Galician Foundation of Genomic Medicine (SERGAS), 15706 Santiago de Compostela, Spain.,
    Angel Carracedo
17. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.,
    Angel Carracedo
18. Harvard Medical School, Boston, 02115, Massachusetts, USA
    Maria H. Chahrour, R. Sean Hill, Timothy W. Yu, Christopher A. Walsh & Mark J. Daly
19. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, 02115, Massachusetts, USA
    Maria H. Chahrour, R. Sean Hill, Timothy W. Yu & Christopher A. Walsh
20. 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
21. Department of Internal Medicine, University of Utah, Salt Lake City, 84132, Utah, USA
    Hilary Coon
22. Department of Psychiatry, University of Utah, Salt Lake City, 84108, Utah, USA
    Hilary Coon
23. Duke Institute for Brain Sciences, Duke University, Durham, 27708, North Carolina, USA
    Geraldine Dawson
24. Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s, Newfoundland A1B 3V6, Canada.,
    Bridget A. Fernandez
25. Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.,
    Louise Gallagher & Michael Gill
26. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, Pennsylvania, USA
    Evan Geller, Chiao-Feng Lin, Otto Valladares, Li-San Wang & Gerard D. Schellenberg
27. Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, 60608, Illinois, USA
    Stephen J. Guter & Edwin H. Cook
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, 10029, New York, 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, 10029, New York, USA
    Avi Ma’ayan
35. Department of Psychiatry Kaiser Permanente, San Francisco, 94118, California, USA
    Alison L. McInnes
36. The Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, 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, 10029, New York, USA
    Abraham Reichenberg
42. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, Texas, USA
    Aniko Sabo
43. Department of Psychiatry, University of California at San Francisco, San Francisco, 94143–0984, California, 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, 20892-9663, Maryland, USA
    Thomas Lehner
50. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA
    Aarno Palotie
51. Institute for Molecular Medicine Finland, University of Helsinki, FI-00014 Helsinki, Finland.,
    Aarno Palotie
52. Department of Psychiatry, Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,
    Aarno Palotie
53. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, 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, 30322, Georgia, USA
    Michael E. Zwick & David J. Cutler
56. Department of Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
    Mark J. Daly
57. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA
    Joseph D. Buxbaum
58. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA
    Joseph D. Buxbaum

Authors

1. Silvia De Rubeis
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2. Xin He
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3. Arthur P. Goldberg
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4. Christopher S. Poultney
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5. Kaitlin Samocha
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6. A. Ercument Cicek
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7. Yan Kou
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8. Li Liu
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9. Menachem Fromer
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10. Susan Walker
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11. Tarjinder Singh
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12. Lambertus Klei
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13. Jack Kosmicki
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14. Shih-Chen Fu
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15. Branko Aleksic
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16. Monica Biscaldi
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17. Patrick F. Bolton
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18. Jessica M. Brownfeld
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19. Jinlu Cai
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20. Nicholas G. Campbell
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21. Angel Carracedo
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22. Maria H. Chahrour
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23. Andreas G. Chiocchetti
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24. Hilary Coon
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25. Emily L. Crawford
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26. Lucy Crooks
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27. Sarah R. Curran
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28. Geraldine Dawson
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29. Eftichia Duketis
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30. Bridget A. Fernandez
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31. Louise Gallagher
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32. Evan Geller
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33. Stephen J. Guter
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34. R. Sean Hill
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35. Iuliana Ionita-Laza
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36. Patricia Jimenez Gonzalez
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37. Helena Kilpinen
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38. Sabine M. Klauck
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39. Alexander Kolevzon
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40. Irene Lee
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41. Jing Lei
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42. Terho Lehtimäki
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43. Chiao-Feng Lin
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44. Avi Ma’ayan
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45. Christian R. Marshall
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46. Alison L. McInnes
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47. Benjamin Neale
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48. Michael J. Owen
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49. Norio Ozaki
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50. Mara Parellada
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51. Jeremy R. Parr
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52. Shaun Purcell
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53. Kaija Puura
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54. Deepthi Rajagopalan
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55. Karola Rehnström
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56. Abraham Reichenberg
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57. Aniko Sabo
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58. Michael Sachse
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59. Stephan J. Sanders
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60. Chad Schafer
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61. Martin Schulte-Rüther
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62. David Skuse
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63. Christine Stevens
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64. Peter Szatmari
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65. Kristiina Tammimies
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66. Otto Valladares
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67. Annette Voran
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68. Li-San Wang
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69. Lauren A. Weiss
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70. A. Jeremy Willsey
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71. Timothy W. Yu
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72. Ryan K. C. Yuen
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73. Edwin H. Cook
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74. Christine M. Freitag
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75. Michael Gill
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76. Christina M. Hultman
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77. Thomas Lehner
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78. Aarno Palotie
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79. Gerard D. Schellenberg
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80. Pamela Sklar
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81. Matthew W. State
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82. James S. Sutcliffe
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83. Christopher A. Walsh
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84. Stephen W. Scherer
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86. Jeffrey C. Barrett
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87. David J. Cutler
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88. Kathryn Roeder
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89. Bernie Devlin
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90. Mark J. Daly
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91. Joseph D. Buxbaum
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Consortia

The DDD Study

Homozygosity Mapping Collaborative for Autism

UK10K Consortium

The Autism Sequencing Consortium

Contributions

Lists of participants appear in the Supplementary Information.

Study conception and design: J.D.B., D.J.C., M.J.D., S.D.R., B.D., M.F., A.P.G., X.H., T.L., C.S.P., K.Ro., M.W.S. and M.E.Z. Data analysis: J.C.B., P.F.B., J.D.B., J.C., A.E.C, D.J.C., M.J.D., S.D.R., B.D., M.F., S.-C.F., A.P.G., X.H., L.K., J.K., Y.K., L.L., A.M., C.S.P., S.P., K.Ro., K.S., C.S., T.S., C.St., S.W., L.W. and M.E.Z. Contribution of samples, WES data or analytical tools: B.A., J.C.B., M.B., P.F.B., J.D.B., J.C., N.G.C., A.C., M.H.C., A.G.C., A.E.C, H.C., E.L.C., L.C., S.R.C., D.J.C., M.J.D., G.D., S.D.R., B.D., E.D., B.A.F., C.M.F., M.F., L.G., E.G., M.G., A.P.G., S.J.G., X.H., R.H., C.M.H., I.I.-L., P.J.G., H.K., S.M.K., L.K., A.K., J.K., Y.K., I.L., J.L., T.Le., C.L., L.L., A.M., C.R.M., A.L.M., B.N., M.J.O., N.O., A.P., M.P., J.R.P., C.S.P., S.P., K.P., D.R., K.R., A.R., K.Ro., A.S., M.S., K.S., S.J.S., C.S., G.D.S., S.W.S., M.S.-R., T.S., P.S., D.S., M.W.S., C.St., J.S.S., P.Sz., K.T., O.V., A.V., S.W., C.A.W., L.W., L.A.W., J.A.W., T.W.Y., R.K.C.Y., M.E.Z. Writing of the paper: J.C.B., J.D.B., E.H.C., D.J.C., M.J.D., S.D.R., B.D., M.G., A.P.G., X.H., C.S.P., K.Ro., S.W.S., M.E.Z. Leads of ASC committees: J.D.B., E.H.C., M.J.D., B.D., M.G., K.Ro., M.W.S., J.S.S., M.E.Z. Administration of ASC: J.M.B.

Corresponding authors

Correspondence toMark J. Daly or Joseph D. Buxbaum.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Workflow of the study.

The workflow began with 16 sample sets, as listed in Supplementary Table 1. DNA was obtained, and exomes were captured and sequenced. After variant calling, quality control was performed: duplicate subjects and incomplete families were removed and subjects with extreme genotyping, de novo, or variant rates were removed. Following cleaning, 3,871 subjects with ASD remained. Analysis proceeded separately for SNVs and indels, and CNVs. De novo and transmission/non-transmission variants were obtained for trio data (published de novo variants from 825 trios11,13,14,15 were incorporated). This led to the TADA analysis, which found 33 ASD risk genes with an FDR < 0.1; and 107 with an FDR < 0.3. CNVs were called in 2,305 ASD subjects. BAM, binary alignment/map; MAF, minor allele frequency.

Extended Data Figure 2 Expected number of ASD genes discovered as a function of sample size.

The multiple LoF test (red) is a restricted version of TADA that uses only the de novo LoF data. TADA (blue) models de novo LoF, de novo Mis3, LoF variants transmitted/not transmitted and LoF variants observed in case-control samples. The sample size (n) indicates either n trios for which we record de novo and transmitted variation (TADA), or n trios for which we record only de novo events (multiple LoF), plus n cases and n controls.

Extended Data Figure 3 Heat map of the numbers of variants used in TADA analysis from each data set in genes with an FDR < 0.3.

Left, variants in affected subjects; right, unaffected subjects. For the counts, we only included de novo LoF and Mis3 variants, transmitted/untransmitted and case-control LoF variants. These variant counts are normalized by the length of coding regions of each gene and sample size of each data set (|trio| + |case| for the left, |trio| + |control| for the right). Description of the samples can be found in Supplementary Table 1.

Extended Data Figure 4 Genome browser view of the CNV deletions identified in ASD-affected subjects.

The deletions are displayed in red if with unknown inheritance, in grey if inherited, and in black in unaffected subjects. Deletions in parents are not shown. For deletions within a single gene, all splicing isoforms are shown.

Extended Data Figure 5 Frequency of variants by gender.

Frequency of de novo (dn) and transmitted (Tr) variants per sample in males (black) and females (white) for genes with an FDR < 0.1 (top row), FDR < 0.3 (middle row), or all TADA genes (bottom row). The P values were determined by one-tailed permutation tests (*P < 0.05; **P < 0.01; ***P < 0.01).

Extended Data Figure 6 Enrichment terms for the four clusters identified by protein–protein interaction networks.

P values calculated using mouse-genome-informatics–mammalian-phenotype (MGI_Mammalian phenotype, blue), Kyoto encyclopaedia of genes and genomes (KEGG) pathways (red), and gene ontology biological processes (yellow) are indicated.

Extended Data Figure 7 De novo variants in SET lysine methyltransferases and jumonji lysine demethylases.

Mis3 variants are in black, LoF in red, and variants identified in other disorders in grey (Fig. 5). ARID, AT-rich interacting domain; AWS, associated with SET domain; BAH, bromo adjacent homology; bromo, bromodomain; FYR C, FY-rich C-terminal domain; FYR N, FY-rich N-terminal domain; HiMG, high mobility group box; JmjC, jumonji C domain; JmjN, jumonji N domain; PHD, plant homeodomain; PWWP, Pro-Trp-Trp-Pro domain; SET, Su(var)3-9, enhancer-of-zeste, trithorax domain.

Extended Data Figure 8 Transcription regulation network of TADA genes only.

Edges indicate transcription regulators (source nodes) and their gene targets (target nodes) based on the ChEA network.

Extended Data Table 1 CNVs hitting TADA genes

Full size table

Supplementary information

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De Rubeis, S., He, X., Goldberg, A. et al. Synaptic, transcriptional and chromatin genes disrupted in autism.Nature 515, 209–215 (2014). https://doi.org/10.1038/nature13772

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• Received: 18 May 2014
• Accepted: 18 August 2014
• Published: 29 October 2014
• Issue Date: 13 November 2014
• DOI: https://doi.org/10.1038/nature13772