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Am J Hum Genet. 2014 May 1;94(5):677-94. doi: 10.1016/j.ajhg.2014.03.018. Epub 2014 Apr 24.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Author information

1
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Institut National de la Santé et de la Recherche Médicale U1130, 75005 Paris, France; Centre National de la Recherche Scientifique UMR 8246, 75005 Paris, France; Neuroscience Paris Seine, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, 75005 Paris, France.
3
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
4
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.
6
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
7
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands.
9
Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, ON L8S 4K1, Canada.
10
National Children's Research Centre, Our Lady's Children's Hospital, Dublin 12, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
11
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
12
Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal; Center for Biodiversity, Functional, & Integrative Genomics, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal.
13
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada.
14
Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
15
John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
16
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Goethe University, 60528 Frankfurt am Main, Germany.
17
Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
18
Vanderbilt Brain Institute, Center for Human Genetics Research, and Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
19
Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; Children's University Hospital Temple Street, Dublin 1, Ireland.
20
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
21
Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
22
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
23
Cancer Care Ontario, Toronto, ON M5G 2L7, Canada.
24
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
25
Department of Pediatrics, University of Alberta, Edmonton, AB T6B 2H3, Canada.
26
School of Education, University of Birmingham, Birmingham B15 2TT, UK.
27
Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford OX3 7JX, UK.
28
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
29
Unité de Recherche Interdisciplinaire Octogone, Centre d'Etudes et de Recherches en Psychopathologie, Toulouse 2 University, 31058 Toulouse, France.
30
Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
31
Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
32
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
33
NewYork-Presbyterian/Weill Cornell Medical Center, New York, NY 10065, USA.
34
FondaMental Foundation, 94010 Créteil, France; Institut National de la Santé et de la Recherche U955, Psychiatrie Génétique, 94010 Créteil, France; Faculté de Médecine, Université Paris Est, 94010 Créteil, France; Department of Psychiatry, Henri Mondor-Albert Chenevier Hospital, Assistance Publique - Hôpitaux de Paris, 94010 Créteil, France.
35
Institute of Health and Society, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
36
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
37
Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr. Sáenz Herrera, Caja Costarricense de Seguro Social, San José, Costa Rica.
38
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA; Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA.
39
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA.
40
Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester M13 9PL, UK; Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.
41
Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland.
42
Gillberg Neuropsychiatry Centre, University of Gothenburg, 41119 Gothenburg, Sweden.
43
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada.
44
FondaMental Foundation, 94010 Créteil, France; Human Genetics and Cognitive Functions Unit, Institut Pasteur, 75015 Paris, France; Centre National de la Recherche Scientifique URA 2182 (Genes, Synapses, and Cognition), Institut Pasteur, 75015 Paris, France; Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France.
45
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
46
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; FondaMental Foundation, 94010 Créteil, France.
47
Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal.
48
FondaMental Foundation, 94010 Créteil, France; Human Genetics and Cognitive Functions Unit, Institut Pasteur, 75015 Paris, France; Centre National de la Recherche Scientifique URA 2182 (Genes, Synapses, and Cognition), Institut Pasteur, 75015 Paris, France; University Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France.
49
Institute of Psychiatry, King's College London, London SE5 8AF, UK; South London & Maudsley Biomedical Research Centre for Mental Health, London SE5 8AF, UK.
50
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University of Frankfurt, 60528 Frankfurt, Germany.
51
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
52
Paediatric Neurodisability, King's Health Partners, King's College London, London WC2R 2LS, UK.
53
Bloorview Research Institute, University of Toronto, Toronto, ON M4G 1R8, Canada.
54
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
55
Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
56
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Dalla Lana School of Public Health, Toronto, ON M5T 3M7, Canada.
57
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
58
Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics and Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
59
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Office of the President, Tufts University, Medford, MA 02155, USA.
60
Division of Molecular Genome Analysis, German Cancer Research Center (Deutsches Krebsforschungszentrum), 69120 Heidelberg, Germany.
61
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
62
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
63
Utah Autism Research Program, Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
64
Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone, Pisa, Italy.
65
Department of Psychiatry, Stanford University Medical School, Stanford, CA 94305, USA.
66
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
67
Institut National de la Santé et de la Recherche Médicale U1130, 75005 Paris, France; Centre National de la Recherche Scientifique UMR 8246, 75005 Paris, France; Neuroscience Paris Seine, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, 75005 Paris, France. Electronic address: catalina.betancur@inserm.fr.
68
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada. Electronic address: stephen.scherer@sickkids.ca.

Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

PMID:
24768552
PMCID:
PMC4067558
DOI:
10.1016/j.ajhg.2014.03.018
[Indexed for MEDLINE]
Free PMC Article

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